Preparation method of thiamine nitrate crystal

Abstract

The invention discloses a preparation method of thiamine nitrate crystals. The invention belongs to the technical field of chemical engineering, and particularly discloses a thiamine nitrate crystal preparation method which comprises the following steps: step (1), performing wet grinding on turbid liquid containing thiamine nitrate particles at the temperature of 5-30 DEG C to obtain wet grinding liquid, and the particle size distribution of thiamine nitrate in the wet grinding liquid is as follows: D10: 10-100 microns, D50: 100-270 microns and D90: 350-720 microns; (2) heating to 35-50 DEG C, cooling to 20-40 DEG C, and carrying out heating and cooling circulation; and (3) cooling and crystallizing to obtain thiamine nitrate crystals. The thiamine nitrate prepared by the preparation method provided by the invention is large in particle, good in fluidity and good in application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical crystallization, and particularly relates to a method for preparing thiamine nitrate crystals. Background Art

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

[0003]

[0004] Thiamine nitrate is the nitrate of vitamin B1. Vitamin B1 is a compound formed by the combination of a pyrimidine ring and a thiazole ring. Because the molecule contains sulfur and amine, it is also called thiamine. Vitamin B1 naturally exists in foods such as rice bran, bran, lean meat, and peanuts. Pure products are usually prepared by chemical synthesis. It is a nutrient necessary for humans and animals. Lack of vitamin B1 can easily cause certain diseases. Commercially available vitamin B1 generally exists in two forms: its nitrate (thiamine nitrate) and hydrochloride (thiamine hydrochloride). Thiamine hydrochloride is often used as an injection due to its strong water solubility. It is generally a pharmaceutical grade product. Thiamine nitrate is often used as a nutritional supplement, food additive, feed additive, and multivitamin preparation.

[0005] At present, there are many domestic manufacturers producing thiamine nitrate, most of which adopt the method of dropwise neutralization in a reactor for crystallization. The particle size of the crystallized particles is generally small, with D90 of about 50 to 150 um, low bulk density (<0.6 g / ml), and the crystal morphology is long needle-shaped, resulting in poor product fluidity, which will seriously restrict the subsequent processing procedures of the product and affect the market competitiveness of the product.

[0006] Patent CN105384735A provides a method for improving the fluidity of thiamine nitrate, that is, adding some surfactants or additives into the crystal 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 crystals that are easy to flow. It is well known that adding other substances to drugs will have the risk of impurity residues. The production of drugs or foods itself has strict control over impurities. The efficiency of the crystal system to remove impurities or additives is affected by many factors such as process steps, operating conditions, etc. The addition of additives brings higher risks to the expansion of production and practical applications.

[0007] Patent CN107652281 A provides a method for improving the particle size and bulk density of thiamine nitrate crystals, that is, using a continuous neutralization method for reaction crystallization. It can effectively increase the average particle size of thiamine nitrate crystals from 10.84 (μm) to 20.59 um, and the natural bulk density from 0.35 g / ml to 0.61 g / ml. Although this method effectively improves the bulk density, the particle size is still small and the fluidity is poor.

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

[0009] The technical problem to be solved by the present invention is to overcome the defect that there are few existing methods for preparing large-particle thiamine nitrate crystals. To this end, the present application provides a method for preparing thiamine nitrate crystals. The preparation method provided by the present invention is easy to operate, and the obtained product has large particles, good fluidity, and good application prospects.

[0010] The present invention solves the above technical problems through the following solutions.

[0011] The present invention provides a method for preparing thiamine nitrate crystals, which comprises the following steps:

[0012] Step (1) wet-grinding a suspension containing thiamine nitrate particles at 5-30° C. to obtain a wet-grinding liquid, wherein the particle size distribution of thiamine nitrate in the wet-grinding liquid is: D10: 10-100 μm, D50: 100-270 μm, and D90: 350-720 μm;

[0013] Step (2) heating to 35-50°C, cooling to 20-40°C and performing a heating and cooling cycle;

[0014] Step (3) cooling and crystallizing to obtain thiamine nitrate crystals.

[0015] In the step (1), the suspension may be a suspension of thiamine nitrate particles and water, and the suspension may further optionally contain thiamine nitrate dissolved in water. The mass ratio of thiamine nitrate to water may be 1:(8-20), such as 1:14, 1.005:14, 1.025:10, 1:10 or 1.005:10, calculated on the basis of total thiamine nitrate. The total thiamine nitrate refers to the sum of thiamine nitrate particles and thiamine nitrate dissolved in water.

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

[0017] In the step (1), in the wet grinding liquid, the particle size distribution D10 of the thiamine nitrate may be 50-100 um, such as 61 um, 69 um, 67 um or 87 um.

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

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

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

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

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

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

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

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

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

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

[0028] In the step (1), the wet grinding can be carried out by using a machine that provides shear force, such as a wet grinder, an emulsifier or ultrasound, preferably a wet grinder.

[0029] In the step (1), when the wet grinding is performed using a wet grinder, the rotation speed of the wet grinder may be 1000-15000 rpm, preferably 1000-5000 rpm, such as 3000 rpm, 1000 rpm, 2000 rpm or 1500 rpm.

[0030] In the step (1), the wet grinding step can be monitored by detecting the particle size distribution, and the particle size distribution is satisfied. The wet grinding time can be 0.3-1.5 hours, such as 0.5h or 1h. Preferably, when a wet grinder is used at 1000-3000rpm, the wet grinding time can be 0.5-1h.

[0031] In the step (2), the temperature may be raised to 40-50°C, such as 40°C or 45°C.

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

[0033] In the step (2), the temperature difference between the heating and cooling (the temperature difference between the heating and cooling end points) may be 3-12°C, such as 5°C or 10°C.

[0034] In the step (2), the number of the heating and cooling cycles may be 1.

[0035] In the step (2), the heating rate is conventional in the art, such as 3 to 20° C. / h, such as 10° C. / h.

[0036] In the step (2), the cooling rate may be 5 to 15°C / h, for example, 10°C / h or 5°C / h.

[0037] In the step (2), after the heating is completed, the temperature can be maintained and then cooled, preferably maintained for 0.3-2 hours, such as 0.5 hours or 1 hour.

[0038] In the step (2), it is preferred to add an ammonium nitrate aqueous solution after cooling, for example, an ammonium nitrate aqueous solution with a mass content (mass of ammonium nitrate / total mass of solution) of 40% to 60%, preferably an ammonium nitrate aqueous solution with a mass content of 50% or 40%.

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

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

[0041] In the step (2), the aqueous ammonium nitrate solution may be added at the cooling end point temperature of the step (2) (e.g., 20-40° C.).

[0042] In the step (3), the cooling and crystallization may be performed by cooling to 0-10°C, for example, 5°C. More preferably, the cooling rate is 5-15°C / h (for example, 10°C / h or 5°C / h).

[0043] The step (3) may further comprise the following post-treatment steps: filtering, washing and drying to obtain the thiamine nitrate crystals. The washing may be performed by, for example, washing with an alcohol solvent, such as methanol and / or ethanol. The drying may be performed by, for example, vacuum drying, preferably at 40-70° C. (e.g., 40° C. or 50° C.).

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

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

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

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

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

[0049] In the preparation method, in step (3), the bulk density of the thiamine nitrate crystals may 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 step (3), the aspect ratio of the thiamine nitrate crystals may be 2:1-10:1, such as 5:1, 4:1, 6:1 or 8:1.

[0051] The preparation method may also include a method for preparing a thiamine nitrate granular suspension, which comprises the following steps:

[0052] At 40-60° C., a mixture A of thiamine nitrate and water is mixed with seed crystals and crystallized to obtain the suspension containing thiamine nitrate particles.

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

[0054] In the method for preparing the suspension containing thiamine nitrate particles, the mixing can be performed at 40-50°C, such as 45°C or 50°C.

[0055] In the method for preparing a suspension containing thiamine nitrate particles, the seed crystals are thiamine nitrate particles (eg, crystals) having a particle size distribution of D90: 400-600 um, D50: 150-250 um, and D10: 50-100 um.

[0056] In the method for preparing a suspension containing thiamine nitrate particles, the particle size distribution D10 of the seed crystals may be 80-100 um, for example 87 um.

[0057] In the method for preparing a suspension containing thiamine nitrate particles, the particle size distribution D50 of the seed crystals may be 200-220 um, for example 207 um.

[0058] In the method for preparing a suspension containing thiamine nitrate particles, the particle size distribution D90 of the seed crystals may be 480-50 um, for example 487 um.

[0059] In the method for preparing a suspension containing thiamine nitrate particles, the particle size distribution of the seed crystals may be: D10: 87 um, D50: 207 um, D90: 487 um.

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

[0061] In the method for preparing a suspension containing thiamine nitrate particles, the crystallization step may include two stages: the first stage: performing the crystallization at 40-50°C (e.g., 45°C, 50°C) (e.g., stirring), and the crystallization time of the first stage may be 1-2 hours; the second stage: cooling the crystallization. Preferably, the temperature is lowered to the temperature of the wet grinding, and the cooling rate is 3-15°C / h, such as 10°C / h or 5°C / h.

[0062] The preparation method may further include a preparation method of a mixture A of thiamine nitrate and water, which comprises the following steps: mixing and dissolving thiamine nitrate and water at 50-70° C. to obtain a mixture A of thiamine nitrate and water;

[0063] The amounts of thiamine nitrate and water used can be as described in any embodiment of the present invention.

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

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

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

[0067] Step (s2) mixing a mixture A of thiamine nitrate and water with seed crystals at 40-60° C., and crystallizing to obtain a mixture of thiamine nitrate particles and water;

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

[0069] Step (2) heating to 35-50°C, cooling to 20-40°C and performing a heating and cooling cycle;

[0070] Step (3) cooling and crystallizing to obtain thiamine nitrate crystals.

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

[0072] The aqueous suspension containing thiamine nitrate particles may be a suspension of thiamine nitrate crystals obtained by wet grinding.

[0073] In the aqueous suspension containing thiamine nitrate particles, the particle size distribution of the thiamine nitrate particles can be as described in any embodiment of the present invention.

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

[0075] The present invention provides the use of the aqueous suspension containing thiamine nitrate particles in preparing the thiamine nitrate crystals by cooling and crystallizing. Preferably, the thiamine nitrate crystals and the cooling and crystallizing are as described in any embodiment of the present invention.

[0076] The present invention provides a thiamine nitrate crystal, which is prepared by the above preparation method.

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

[0078] The particle size distribution D10 of the thiamine nitrate crystals may be 100-150 um, such as 128 um, 108 um or 112 um.

[0079] The D50 of the particle size distribution of the thiamine nitrate crystals may be 300-400 um, such as 313 um, 327 um or 371 um.

[0080] The D90 of the particle size distribution of the thiamine nitrate crystals may be 800-1100 um, such as 870 um, 893 um or 1010 um.

[0081] The repose angle of the thiamine nitrate crystals may be 30-35°, such as 30°, 33° or 35°.

[0082] The bulk density of the thiamine nitrate crystals may 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.

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

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

[0085] Terminology explanation:

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

[0087] In the present invention, D 50 It refers to the particle size value corresponding to when the cumulative distribution percentage from small to large reaches 50% in the particle size distribution.

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

[0089] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

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

[0091] The positive and progressive effects of the present invention are:

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

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

[0094] Figure 1 This is a polarizing microscope photograph of the short rod-shaped thiamine nitrate crystals obtained in Example 1.

[0095] Figure 2 This is a particle size distribution diagram of the short rod-shaped thiamine nitrate crystals obtained in Example 1.

[0096] Figure 3 This is a polarizing microscope photograph of the short rod-shaped thiamine nitrate crystals obtained in Example 2.

[0097] Figure 4 This is a polarizing microscope photograph of the long rod-shaped thiamine nitrate crystals obtained in Comparative Example 1.

[0098] Figure 5 This is a polarizing microscope photograph of the thiamine nitrate crystals obtained in Example 3.

[0099] Figure 6 This is a polarizing microscope photograph of the thiamine nitrate crystals obtained in Comparative Example 2.

[0100] Figure 7 This is a polarizing microscope photograph of the thiamine nitrate crystals obtained in Comparative Example 3.

[0101] Figure 8 This is a polarizing microscope photograph of the thiamine nitrate crystals obtained in Comparative Example 4.

[0102] Fig. 9 This is a polarizing microscope photograph of the thiamine nitrate crystals obtained in Example 4.

[0103] Fig.10 This is a polarizing microscope photograph of the thiamine nitrate crystals obtained in Comparative Example 5. DETAILED DESCRIPTION

[0104] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0105] The fluidity is reflected by the powder repose angle. According to the "Guidelines for Determination of Powder Fluidity", conventional detection methods in the field such as the fixed funnel method are used. The test method is to add an excess of the powder to be tested into a container with a fixed diameter bottom plate. When the powder flows out from the central hole at the bottom of the container, a sliding slope (vertical shear surface is a triangle) for powder outflow is formed at the orifice of the bottom plate inside the container. The angle formed by the sliding slope and the horizontal bottom is the repose angle.

[0106] Bulk density: According to the general rules of Part IV of the Pharmacopoeia, the bulk density of powders is determined by conventional detection methods in the field, such as the fixed mass method. The test method is to take about 100g of the powder sample to be tested (if necessary, it should be passed through a sieve with an aperture of 1.0mm to fully disperse the lumps formed during storage. The sieving operation should be gentle to avoid changing the properties of the powder), accurately weigh, slowly pour into a glass graduated cylinder, carefully scrape the top of the cup, and avoid compacting the powder. Record the apparent volume at the closest scale line and calculate the bulk density.

[0107] Example 1

[0108] (1) Add 100 g of thiamine nitrate (CAS: 532-43-4) powder and 1400 ml of water to a reaction kettle, heat to 55° C. to dissolve, then cool to 45° C., add 0.5 g of seed crystals (preparation method refers to Comparative Example 3, D10: 87 μm; D50: 207 μm; D90: 487 μm), and grow the crystals for 2 h;

[0109] (2) After cooling to 25°C at 10°C / h, the particle size distribution of the slurry was: D10: 95um, D50: 290um, D90: 750um, and wet grinding was performed at 25°C for 0.5h with wet grinding parameters of 2P4M and 1000rpm, and the particle size distribution of the slurry was: D10: 69um, D50: 202um, D90: 495um;

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

[0111] (4) Slowly add 100 ml of 50 wt% ammonium nitrate solution at 35° C. for 1 h;

[0112] (5) Continue cooling to 5°C at a rate of 10°C / h;

[0113] (6) Keep at 5°C for 1-2 h, filter, wash with methanol, and dry in vacuo at 40°C to obtain 93 g of thiamine nitrate solid.

[0114] The polarizing microscope photo of the obtained product is as follows Figure 1 ( Figures 1 to 10 The micrograph is at the same magnification (40X, 500 μm), and the particles are short rod-shaped. Figure 2 As shown. The sample particle size was tested using a Malvern particle size distribution tester, D10: 128um, D50: 371um, D90: 1010um. The angle of repose was 30 degrees, the bulk density was 0.83g / ml, the purity was 99.7%, and the aspect ratio was ~5:1.

[0115] Example 2

[0116] (1) Add 100 g of thiamine nitrate powder and 1000 ml of water to a reaction kettle, heat to 65° 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 grow the crystals for 1 hour;

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

[0118] (3) After wet grinding, the temperature was raised to 45°C at a rate of 10°C / h, maintained for 1 h, and then lowered to 35°C at a rate of 5°C / h;

[0119] (4) slowly adding 150 ml of 40 wt% ammonium nitrate solution at 35° C. for 0.5 h;

[0120] (5) Continue cooling to 5°C at a rate of 5°C / h;

[0121] (6) Keep at 5°C for 1-2 h, filter, wash with ethanol, and dry in vacuo at 50°C to obtain 97 g of thiamine nitrate solid.

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

[0123] Example 3

[0124] (1) Add 100 g of thiamine nitrate powder and 1000 ml of water to a reaction kettle, heat to 65° C. to dissolve, then cool to 50° C., add 0.5 g of seed crystals (D10: 87 um; D50: 207 um; D90: 487 um), and grow the crystals for 1 hour;

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

[0126] (3) After wet grinding, the temperature was raised to 45°C at a rate of 10°C / h, maintained for 1 h, and then lowered to 35°C at a rate of 5°C / h;

[0127] (4) Continue cooling to 5°C at a rate of 5°C / h;

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

[0129] The polarizing microscope photo of the obtained product is as follows Figure 5 The particle size of the sample 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 100 g of thiamine nitrate powder and 1400 ml of water to a reaction kettle, heat to 55° C. to dissolve, then cool to 45° C., add 2.5 g of seed crystals (D10: 87 um; D50: 207 um; D90: 487 um), and grow the crystals for 2 hours;

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

[0133] (3) After wet grinding, the temperature was raised to 40°C at a rate of 10°C / h, maintained for 0.5h, and then cooled to 35°C at a rate of 10°C / h;

[0134] (4) Slowly add 100 ml of 50 wt% ammonium nitrate solution at 35° C. for 1 h;

[0135] (5) Continue cooling to 5°C at a rate of 10°C / h;

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

[0137] The polarizing microscope photo of the obtained product is as follows Fig. 9 The obtained particles are relatively slender, with an angle of repose of 33 degrees, a bulk density of 0.77 g / ml, and an aspect ratio of 8:1.

[0138] Comparative Example 1

[0139] (1) Add 100 g of thiamine nitrate powder and 1400 ml of water to a reactor, 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), grow the crystals for 1 hour, and obtain a liquid particle size distribution of D10: 90 um, D50: 250 um, and D90: 690 um.

[0140] (2) Slowly add 150 ml of 40 wt% ammonium nitrate solution at 35 °C for 0.5 h

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

[0142] (4) Keep at 5°C for 1-2 hours, filter, wash with ethanol, and dry in vacuo at 50°C to obtain 96.5 g of thiamine nitrate solid.

[0143] The polarizing microscope photo of the obtained product is as follows Figure 4 The angle of repose is 40 degrees, and the bulk density is 0.67 g / ml. It can be seen that the particles of Comparative Example 1 are in the shape of long rods, 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] The crystallization of thiamine nitrate was carried out according to the method disclosed in CN107652281 A:

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

[0147] (2) pumping the mixed oxidizing liquid and ammonia water with a mass concentration of 14% to control the flow rate so that the pH value is between 6.5 and 7.0 into a static mixing crystallizer;

[0148] (3) The material obtained in step (2) is passed through a static mixing crystallizer, and after reaction and crystallization, it flows into a cooling centrifugal kettle for thiamine nitrate. During the crystallization process, the temperature of the material in the reactor is controlled to be around 30° C. After all the reaction and crystallization of a batch of materials in the static mixing crystallizer are completed, the crystallized material is cooled to below 10° C., filtered, washed, and dried.

[0149] The polarizing microscope photo of the obtained product is as follows 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 the particles in Comparative Example 2 is very small and the fluidity is poor.

[0150] Comparative Example 3

[0151] (1) Add 100 g of thiamine nitrate powder and 1400 ml of water to a reaction kettle, heat to 55° C. to dissolve, then cool to 45° C., add 0.1 g of seed crystals (D10: 16 um, D50: 62 um, D90: 183 um, from Comparative Example 2), and grow the crystals for 1 hour;

[0152] (2) After cooling to 25°C at 10°C / h, the particle size distribution of the slurry was: D10: 72um, D50: 189um, D90: 411um. The slurry was wet-milled at 25°C for 0.5h to obtain a particle size distribution of D10: 63um, D50: 132um, D90: 327um.

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

[0154] (4) Slowly add 100 ml of 50 wt% ammonium nitrate solution at 35° C. for 1 h;

[0155] (5) Continue cooling to 5°C at a rate of 10°C / h;

[0156] (6) Keep at 5°C for 1-2 h, filter, wash with methanol, and dry in vacuo at 40°C to obtain 92 g of thiamine nitrate solid.

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

[0158] Comparative Example 4

[0159] (1) Add 100 g of thiamine nitrate powder and 1400 ml of water to a reaction kettle, heat to 55°C to dissolve, then cool to 45°C, add 5 g of small particle seed crystals (D10: 16 um, D50: 62 um, D90: 183 um), and grow the crystals for 2 hours;

[0160] (2) After cooling to 25°C at 10°C / h, the particle size distribution of the slurry was: D10: 36um, D50: 95um, D90: 239um, and wet grinding was performed at 25°C for 0.5h with wet grinding parameters of 2P4M and 3000rpm, and the particle size distribution of the slurry was: D10: 27um, D50: 72um, D90: 184um;

[0161] (3) After wet grinding, the temperature was raised to 40°C at a rate of 10°C / h, maintained for 0.5h, and then cooled 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. for 1 h;

[0163] (5) Continue cooling to 5°C at a rate of 10°C / h;

[0164] (6) Keep at 5°C for 1-2 h, filter, wash with methanol, and dry in vacuo 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 . Purity 99.4%. The sample particle size was tested using a Malvern particle size distribution tester, D10: 80, D50: 190, D90: 475um. The angle of repose was 42 degrees, and the bulk density was 0.63g / ml. The use of small particle seeds made the product particle size smaller and the fluidity worse.

[0166] Comparative Example 5:

[0167] (1) Add 100 g of thiamine nitrate powder and 1400 ml of water to a reaction kettle, heat to 55° C. to dissolve, then cool to 45° C., add 2.5 g of seed crystals (D10: 87 um; D50: 207 um; D90: 487 um), and grow the crystals for 2 hours;

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

[0169] (3) After wet grinding, the temperature was raised to 40°C at a rate of 10°C / h, maintained for 0.5h, and then cooled 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. for 1 h;

[0171] (5) Continue cooling to 5°C at a rate of 10°C / h;

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

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

Claims

1. A method for preparing thiamine nitrate crystals, characterized in that: It includes the following steps: Step (1): wet-grinding a suspension containing thiamine nitrate particles at 5-30° C. to obtain a wet-grinding liquid, wherein the particle size distribution of thiamine nitrate in the wet-grinding liquid is: D10: 10-100 μm, D50: 100-270 μm, and D90: 350-720 μm; Step (2): heating to 35-50°C, and cooling to 20-40°C for a heating and cooling cycle; Step (3): cooling and crystallizing to obtain thiamine nitrate crystals.

2. The method for preparing thiamine nitrate crystals according to claim 1, characterized in that: It meets one or more of the following conditions: (1) In the step (1), the suspension is a suspension of thiamine nitrate particles and water; (2) In the step (1), in the wet grinding liquid, the particle size distribution D10 of the thiamine nitrate is 50-100 um; (3) In the step (1), the particle size distribution D50 of the thiamine nitrate in the wet grinding liquid is 150-270 μm; (4) In the step (1), in the wet grinding solution, the particle size distribution D90 of the thiamine nitrate is 380-720 μm; (5) In the step (1), the particle size of thiamine nitrate in the wet grinding solution is smaller than the particle size of thiamine nitrate particles in the suspension; (6) In the step (1), the particle size distribution of the thiamine nitrate particles in the suspension is D10: 10-100 um, D50: 100-300 um, and D90: 500-800 um; (7) In step (1), the temperature of the wet grinding is 5-25°C; (8) In step (1), the wet grinding is performed by using a machine that provides shear force; (9) In step (1), the wet grinding time is 0.3-1.5 hours; (10) In step (2), the temperature is raised to 40-50° C.; (11) In step (2), the temperature is lowered to 30-38°C; (12) In step (2), the temperature difference between the heating and cooling is 3-12°C; (13) In step (2), the number of heating and cooling cycles is 1; (14) In step (2), the heating rate is 3 to 20°C / h; (15) In step (2), the cooling rate is 5 to 15°C / h; (16) In step (2), after the heating is completed, the temperature is maintained and then cooled; (17) In step (2), an aqueous solution of ammonium nitrate is added after cooling; (18) In the step (2), the volume mass ratio of the aqueous ammonium nitrate solution to the thiamine nitrate is (0.5-5): 1 mL / g; (19) In step (2), the rate of adding the aqueous ammonium nitrate solution is 1-5 mL / g / h, wherein mL / g is the volume mass ratio of the aqueous ammonium nitrate solution to the thiamine nitrate; (20) In step (2), the aqueous ammonium nitrate solution is added dropwise; (21) In step (2), the aqueous ammonium nitrate solution is added at the cooling end point temperature of step (2); (22) In the step (3), the cooling and crystallization is performed by cooling to 0-10°C for crystallization; (23) In step (3), the cooling rate of the cooling crystallization is 5-15°C / h; (24) The step (3) further comprises the following post-treatment steps: filtering, washing and drying to obtain the thiamine nitrate crystals; (25) In step (3), the thiamine nitrate crystals satisfy the following particle size distribution conditions: D10: 80-200 μm, D50: 200-500 μm, D90: 800-1200 μm; (26) In step (3), the angle of repose of the thiamine nitrate crystals is 30-35°; (27) In step (3), the bulk density of the thiamine nitrate crystals is 0.7-0.9 g / mL; (28) In step (3), the aspect ratio of the thiamine nitrate crystals is 2:1-10:

1.

3. The method for preparing thiamine nitrate crystals according to claim 2, characterized in that: It meets one or more of the following conditions: (1) In the step (1), in the suspension, the mass ratio of thiamine nitrate to water is 1:(8-20) based on total thiamine nitrate, where total thiamine nitrate refers to the sum of thiamine nitrate particles and thiamine nitrate dissolved in water; (2) In the step (1), the particle size distribution D50 of the thiamine nitrate in the wet grinding liquid is 150-250 μm; (3) In the step (1), in the wet grinding solution, the particle size distribution D90 of the thiamine nitrate is 380-510 μm; (4) In the step (1), in the suspension, the particle size distribution D10 of the thiamine nitrate particles is 60-100 um; (5) In the step (1), the particle size distribution D50 of the thiamine nitrate particles in the suspension is 200-300 μm; (6) In the step (1), the particle size distribution D90 of the thiamine nitrate particles in the suspension is 550-800 um; (7) In step (1), the temperature of the wet grinding is 25°C; (8) In step (1), the wet grinding is performed by using a wet grinder, an emulsifier or ultrasonic treatment; (9) In the step (1), when the wet grinding is performed by a wet grinder, the speed of the wet grinder is 1000-15000 rpm; (10) In step (1), the wet grinding time is 0.5 h or 1 h; (11) In step (2), the temperature is raised to 40° C. or 45° C.; (12) In step (2), the temperature is lowered to 35° C. (13) In step (2), the temperature difference between the heating and cooling is 5°C or 10°C; (14) In step (2), the heating rate is 10°C / h; (15) In step (2), the cooling rate is 10°C / h or 5°C / h; (16) In step (2), after the heating is completed, the temperature is maintained for 0.3-2 hours and then cooled; (17) In step (2), after cooling, a 40% to 60% by weight aqueous solution of ammonium nitrate is added; (18) In the step (2), the volume mass ratio of the aqueous ammonium nitrate solution to the thiamine nitrate is (1-5): 1 mL / g; (19) In step (2), the rate of adding the aqueous ammonium nitrate solution is 1 or 3 mL / g / h, wherein mL / g is the volume mass ratio of the aqueous ammonium nitrate solution to the thiamine nitrate; (20) In step (2), the dropwise addition time of the aqueous ammonium nitrate solution is 1 h or 0.5 h; (21) In the step (3), the cooling and crystallization is performed by cooling to 5°C; (22) In the step (3), the cooling rate of the cooling crystallization is 5 or 10°C / h; (23) In the step (3), in the post-treatment step, the washing is performed using an alcohol solvent; (24) In step (3), in the post-treatment step, the drying is vacuum drying; (25) In step (3), the particle size distribution D10 of the thiamine nitrate crystals is 100-150 μm (26) In step (3), the particle size distribution D50 of the thiamine nitrate crystal is 300-400 μm. (27) In step (3), the particle size distribution D90 of the thiamine nitrate crystals is 850-1100 um.

4. The method for preparing thiamine nitrate crystals according to any one of claims 1 to 3, characterized in that: It meets one or more of the following conditions: (1) In the step (1), in the wet grinding liquid, the particle size distribution D10 of the thiamine nitrate is 61um, 69um, 67um or 87um; (2) In the step (1), in the wet grinding solution, the particle size distribution D50 of the thiamine nitrate is 198 um, 200 um, 202 um or 264 um; (3) In the step (1), in the wet grinding solution, the particle size distribution D90 of the thiamine nitrate is 412 um, 430 um, 500 um, 495 um or 695 um; (4) In the step (1), in the suspension, the particle size distribution D10 of the thiamine nitrate particles is 79 um, 90 um, 93 um or 95 um; (5) In the step (1), in the suspension, the particle size distribution D50 of the thiamine nitrate particles is 220 um, 250 um, 284 um or 290 um; (6) In the step (1), in the suspension, the particle size distribution D90 of the thiamine nitrate particles is 602 um, 690 um, 737 um or 750 um; (7) In step (1), the mass ratio of thiamine nitrate to water in the suspension is 1:14, 1.005:14, 1.025:10, 1:10 or 1.005:10; (8) In step (1), the wet grinding is carried out using a wet grinder; (9) In the step (1), when the wet grinding is performed by a wet grinder, the speed of the wet grinder is 1000-5000 rpm; (10) In the step (1), the wet grinding is carried out using a wet grinder at 1000-3000 rpm, and the wet grinding time is 0.5-1 h; (11) In step (2), after the heating is completed, the temperature is maintained for 0.5 h or 1 h, and then cooled; (12) In step (2), after cooling, a 50% or 40% by weight aqueous solution of ammonium nitrate is added; (13) In step (2), the volume mass ratio of the aqueous ammonium nitrate solution to the thiamine nitrate is 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; (14) In step (3), in the post-treatment step, the alcohol solvent is methanol and / or ethanol; (15) In the step (3), in the post-treatment step, the drying is performed under vacuum at 40-70°C; (16) The particle size distribution D10 of the thiamine nitrate crystals is 128 um, 108 um or 112 um; (17) The D50 of the thiamine nitrate crystal particle size distribution is 313 um, 327 um or 371 um; (18) The D90 of the particle size distribution of the thiamine nitrate crystals is 870 um, 893 um or 1010 um.

5. The method for preparing thiamine nitrate crystals according to claim 4, characterized in that: 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: 69um, D50: 202um, D90: 495um, or D10: 67um, D50: 202um, D90: 430um, or D10: 61um, D50: 198um, D90: 412um, or D10: 87um, D50: 264um, D90: 695um; (2) In the step (1), in the suspension, the particle size distribution of the thiamine nitrate particles is: D10: 95um, D50: 290um, D90: 750um, or D10: 90um, D50: 250um, D90: 690um, or D10: 79um, D50: 220um, D90: 602um, or D10: 93um, D50: 284um, D90: 737um; (3) In step (3), the thiamine nitrate crystals satisfy 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 step (3), the repose angle of the thiamine nitrate crystals is 30°, 33° or 35° (5) In step (3), the bulk density of the thiamine nitrate crystals is 0.83 g / mL, 0.81 g / mL, 0.77 g / mL or 0.79 g / mL; (6) In step (3), the aspect ratio of the thiamine nitrate crystals is 5:1, 4:1, 6:1 or 8:1; (7) In the step (1), when the wet grinding is carried out using a wet grinder, the rotation speed of the wet grinder is 3000 rpm, 1000 rpm, 2000 rpm or 1500 rpm.

6. The preparation method according to claim 1, characterized in that: The preparation method further comprises the following steps: Mixing a mixture A of thiamine nitrate and water with seed crystals at 40-60° C. and crystallizing to obtain a suspension containing thiamine nitrate particles; Preferably, 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), for example, 1:14 or 1:10; (2) The mixing is performed at 40-50° C., for example, 45° C. or 50° C.; (3) The seed crystals are thiamine nitrate particles with a particle size distribution of D90: 400-600 um, D50: 150-250 um, and D10: 50-100 um; (3) the mass ratio of the seed crystal to the thiamine nitrate is (0.3-10):100, for example (0.3-3):100, preferably 0.5:100 or 2.5:100; (4) The crystallization step comprises two stages; the first stage is carried out at 40-50° C., and the crystallization time of the first stage is, for example, 1-2 hours; the second stage is cooling crystallization; for example, the cooling crystallization is cooling 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; Further preferably, the preparation method satisfies one or more of the following conditions: (1) The particle size distribution D10 of the seed crystal is 80-100 um, for example 87 um; (2) The particle size distribution D50 of the seed crystal is 200-220 μm, for example 207 μm; (3) The particle size distribution D90 of the seed crystal is 480-50 μm, for example 487 μm; More preferably, the seed crystals have a particle size distribution of: D10: 87 um, D50: 207 um, D90: 487 um.

7. The preparation method according to claim 6, characterized in that: The preparation method further comprises the following steps: At 50-70° C., thiamine nitrate and water are mixed and dissolved to obtain a mixture A of thiamine nitrate and water; Preferably, the preparation method meets one or more of the following conditions: (1) The amounts of thiamine nitrate and water are as described in any one of claims 1 to 6; (2) The mixing temperature is 50-60°C, for example 55°C or 65°C; Further preferably, the preparation method comprises the following steps: Step (s1) mixing and dissolving thiamine nitrate and water at 50-70° C. to obtain a mixture A of thiamine nitrate and water; Step (s2) mixing a mixture A of thiamine nitrate and water with seed crystals at 40-60° C., and crystallizing to obtain a mixture of thiamine nitrate particles and water; Step (1) wet-grinding a mixture of thiamine nitrate particles and water at 5-30° C. to obtain a wet-grinding liquid, wherein the particle size distribution of thiamine nitrate is: D10: 10-100 um, D50: 100-270 um, D90: 350-720 um; Step (2) heating to 35-50°C, cooling to 20-40°C and performing a heating and cooling cycle; Step (3) cooling and crystallizing to obtain thiamine nitrate crystals.

8. An aqueous suspension containing thiamine nitrate particles, characterized in that: The particle size distribution of thiamine nitrate is: D10: 10-100um, D50: 100-270um, D90: 350-720um; Preferably, the aqueous suspension containing thiamine nitrate particles satisfies one or more of the following conditions: (1) The aqueous suspension containing thiamine nitrate particles is a suspension of thiamine nitrate crystals obtained by wet grinding; (2) In the suspension, the mass ratio of thiamine nitrate to water is 1:(8-20), for example, 1:14, 1.005:14, 1.025:10, 1:10 or 1.005:10; (3) In the aqueous suspension containing thiamine nitrate particles, the particle size distribution of thiamine nitrate is as described in any one of claims 1 to 7.

9. Use of the aqueous suspension containing thiamine nitrate particles as claimed in claim 8 in preparing thiamine nitrate crystals by cooling and crystallizing; Preferably, the thiamine nitrate crystals and the cooling crystallization are as described in any one of claims 1-7.

10. A thiamine nitrate crystal, characterized in that: It is a rod-shaped crystal with a particle size distribution of D10: 80-200um, D50: 200-500um, D90: 800-1200m; Preferably, the thiamine nitrate crystal is as described in any one of claims 2-5; Further preferably, the thiamine nitrate crystals are prepared by the preparation method according to any one of claims 1-7.

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