A method for optimizing the crystallization process of thiamine nitrate

Abstract

This invention discloses an optimized method for the crystallization process of thiamine nitrate. Using thiothiamine as the starting material, the reaction solution is obtained by oxidation with hydrogen peroxide followed by decolorization with activated carbon. An aqueous solution of ammonium nitrate is added to the reaction solution, and ammonia is added dropwise using an intermittent feeding and crystal growth method to adjust the pH of the reaction solution to 6.8–7.2. The reaction solution is then cooled, filtered, and vacuum dried to obtain thiamine nitrate crystals. This invention, by using an intermittent feeding method during the ammonia addition process, provides an appropriate crystal growth time, effectively controls the supersaturation of the solution, making the process easier to control. The resulting crystals have a more complete morphology, exhibiting a coarse rod shape with higher regularity. The produced powder product has an angle of repose of 36–39°, a bulk density of 0.62–0.68 g / mL, and a Hauss-Na ratio of 1.20–1.32, improving product flowability and benefiting subsequent formulation processes and industrial production.

Description

Technical Field

[0001] This invention belongs to the field of crystallization technology, specifically relating to a method for optimizing the crystallization process of thiamine nitrate. Background Technology

[0002] Thiamine nitrate is the nitrate of vitamin B1. Its chemical name is 4-methyl-3-[(2-methyl-4-amino-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)thiazolyl nitrate, and its molecular formula is C1. 12 H 17 N5O4S, with a molecular weight of 327.36, has the structural formula shown in formula (Ⅰ). Thiamine nitrate has a melting point of 196–200℃ (decomposes), low hygroscopicity, and is stable in air. Its solubility in alkaline solutions is much lower than in acidic solutions (pH 3.0–5.0). Therefore, this property is utilized by adding an alkaline reagent to an acidic thiamine nitrate solution to reduce its solubility, thereby precipitating thiamine nitrate crystals.

[0003]

[0004] Vitamin B1 is found in foods such as the outer husks and germ of grains, lean meat, and peanuts. Pure vitamin B1 is usually obtained through chemical synthesis and is an essential vitamin for humans and animals. Clinically, thiamine nitrate is mainly used to prevent beriberi caused by vitamin B1 deficiency and is also used as an adjunct treatment for various diseases, such as neuritis, myocarditis, and indigestion. In recent years, with the continuous development of clinical pharmacology research, it has been found that neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are also related to vitamin B1 deficiency.

[0005] There are numerous domestic manufacturers of thiamine nitrate, but the thiamine nitrate crystals they produce are mostly rod-shaped or needle-shaped with small particle sizes. This results in low powder bulk density and poor flowability, making it difficult to meet the requirements for tablet production using the compression method, thus restricting downstream production. Generally, it is considered that when the powder's angle of repose is <40° and the Hausner ratio (the ratio of tapped density to loose packing density) is <1.35, the flowability is good and can meet the requirements of the formulation production process.

[0006] CN 106588907 discloses a method for crystallizing thiamine nitrate by adjusting the mixing order of thiamine sulfate solution, ammonium nitrate solution, and ammonia. First, the thiamine sulfate solution and ammonium nitrate are mixed evenly, then simultaneously and uniformly added to a refining reactor with the required amount of ammonia for crystallization, finally obtaining rod-shaped particles with a bulk density of 0.35–0.4 g / mL. This crystallization method directly adds ammonia and the reaction solution to the refining reactor simultaneously. The amount of ammonia added is calculated based on a ratio beforehand, which may lead to excess ammonia causing a weakly alkaline pH, resulting in degradation of the thiamine nitrate. This invention does not significantly improve the bulk density compared to conventional crystallization methods, and the invention does not disclose data on the angle of repose. CN 109942568 discloses a method for preparing thiamine nitrate, using nitric acid instead of ammonium nitrate aqueous solution, mixing it with thiamine sulfate solution, adding ammonia to adjust the pH, controlling the feeding time to 3–6 hours, finally obtaining rod-shaped crystals with a bulk density of 0.43–0.61 g / mL. This crystallization method significantly improves the bulk density, but the final wastewater contains nitric acid, a strong acid that must be treated to meet national emission standards before discharge, undoubtedly increasing treatment costs. CN 105384735 discloses a method for preparing thiamine nitrate block crystals, which involves mixing thiamine sulfate solution and ammonium nitrate solution, adding additives, adjusting the pH to 3.9–4.3 with ammonia, adding seed crystals, cultivating crystals, further adjusting the pH to 6.80–7.05, followed by cooling, filtration, and washing to obtain thiamine nitrate crystals. The thiamine nitrate crystals obtained by this crystallization method are blocky with an angle of repose of 30–38° and a bulk density of 0.8–0.93 g / mL, showing significantly improved flowability. However, this method uses additives such as sodium alkyl sulfate, sodium alkyl sulfonate, and sodium stearate, and the residue of these additives may increase the difficulty of post-processing and introduce toxicity. Therefore, developing a method that is low-cost and time-consuming, does not require the addition of additives or seed crystals, and directly optimizes the thiamine nitrate crystallization process to improve powder flowability would greatly enhance the product's market competitiveness. Summary of the Invention

[0007] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for optimizing the crystallization process of thiamine nitrate. This invention adopts an intermittent feeding and intermittent crystal growth operation method during the ammonia water droplet addition process, which can obtain thiamine nitrate crystal products with better flowability, which is beneficial to downstream operations.

[0008] The technical solution of this invention is as follows: A method for optimizing the crystallization process of thiamine nitrate, comprising the following steps:

[0009] Using thioamine as the starting material, the thioamine sulfate reaction solution was obtained by oxidation with hydrogen peroxide and decolorization with activated carbon. The obtained thioamine sulfate reaction solution was added to a reactor, and ammonium nitrate aqueous solution was added under stirring. Then, ammonia water was added dropwise to adjust the pH value for neutralization reaction by intermittent feeding and intermittent crystal growth. After crystal growth, the solution was cooled, filtered, washed and dried to obtain thioamine nitrate crystals.

[0010] Furthermore, the present invention further specifies the specific operation of the intermittent feeding and intermittent crystal growth method as follows: first, add ammonia water dropwise to adjust the pH of the reaction solution to 4.5-4.7 and then stop adding the ammonia water; grow crystals for 10-20 minutes; after crystal growth is completed, add ammonia water dropwise again to adjust the pH of the reaction solution to 5.8-6.0 and then stop adding the ammonia water; grow crystals for 10-20 minutes; after crystal growth is completed, add ammonia water dropwise again to adjust the pH of the reaction solution to 6.8-7.2 to complete the neutralization reaction.

[0011] Furthermore, the present invention also specifies that the ammonia droplet acceleration rate is 1.0 to 1.5 mL / min.

[0012] Furthermore, the present invention also specifies that the stirring rate during the ammonia water droplet addition process is 100-150 r / min.

[0013] Furthermore, the present invention also specifies that the reaction solution is cooled to 5-8°C after the crystal growth is completed.

[0014] Furthermore, the present invention also specifies a cooling rate of 0.4 to 0.7 °C / min.

[0015] Furthermore, the present invention further specifies that the thiamine nitrate crystals obtained by the specified method are coarse rod-shaped, with high regularity of crystal morphology, an angle of repose of 36–39°, a bulk density of 0.62–0.68 g / mL, and a Hausner ratio of 1.20–1.32.

[0016] By employing the above-described technology, compared with the prior art, the present invention has the following advantages and...

[0017] Beneficial effects:

[0018] 1. This invention controls the ammonia water droplet addition process by adopting an intermittent feeding and intermittent crystal growth operation method. That is, during the ammonia water droplet addition process, the pH value of the reaction solution and the crystal growth time are controlled by controlling the droplet rate and the amount of droplet added, so that thiamine nitrate crystals that meet the requirements can be obtained. The process conditions are simple, easy to control, and do not require the introduction of additional additives, which is conducive to industrial production.

[0019] 2. The thiamine nitrate crystals obtained by the method of this invention are coarse rod-shaped with high regularity of crystal morphology. The product has an angle of repose of 36-39°, a bulk density of 0.62-0.68 g / mL, and a Hauss-Na ratio of 1.20-1.32, which improves the product's flowability and can meet the special process requirements of downstream applications. Attached Figure Description

[0020] Figure 1 This is a polarized light microscope image of the thiamine nitrate crystals prepared in Example 1. Detailed Implementation

[0021] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, which will enable those skilled in the art to more fully understand the present invention, but the scope of protection of the present invention is not limited thereto. The raw materials and reagents used in the embodiments can all be obtained from conventional commercial channels.

[0022] Example 1

[0023] Starting with 50g of thioamine, the reaction solution was oxidized with 57mL of 30% hydrogen peroxide and then decolorized with 2g of activated carbon to obtain thioamine sulfate reaction solution. This reaction solution was added to a reactor, and the temperature was controlled at 20℃ with a stirring rate of 100r / min. A 50% ammonium nitrate aqueous solution was added, and the pH was adjusted with 25% ammonia solution at a feeding rate of 1.2mL / min. The ammonia addition was stopped after adjusting the pH to 4.5, and crystallization was allowed to continue for 10min. After crystallization, ammonia was added again to adjust the pH to 5.8, and the addition was stopped. Crystallization was allowed to continue for 10min, and finally, ammonia was added until the pH reached 6.8 to complete the neutralization reaction. The solution was then cooled to 5℃ at a rate of 0.5℃ / min, filtered, washed with 20mL of methanol and 20mL of pure water, and dried under vacuum at 60℃ to obtain 53.38g of thioamine nitrate crystals, with a yield of 96.67%.

[0024] The obtained product is a coarse rod-shaped crystal, and its polarized light microscope image is as follows. Figure 1 As shown.

[0025] Example 2.

[0026] Starting with 50g of thioamine, the reaction solution was oxidized with 57mL of 30% hydrogen peroxide and then decolorized with 2g of activated carbon to obtain thioamine sulfate reaction solution. This reaction solution was added to a reactor, and the solution temperature was controlled at 20℃. The stirring speed was 150r / min. A 50% ammonium nitrate aqueous solution was added, and the pH was adjusted with 25% ammonia solution at a rate of 1.3mL / min. The ammonia addition was stopped after adjusting the pH to 4.6, and crystallization was allowed to continue for 20min. After crystallization, ammonia solution was added again to adjust the pH to 6.0, and the addition was stopped again. Crystallization was allowed to continue for another 20min, and finally, ammonia solution was added until the pH reached 7.0 to complete the neutralization reaction. The solution was then cooled to 6℃ at a rate of 0.4℃ / min. After filtration, the solution was washed with 20mL of methanol and 20mL of pure water, respectively, and dried under vacuum at 60℃ to obtain 52.32g of thioamine nitrate crystals, with a yield of 94.76%.

[0027] Example 3.

[0028] Starting with 50g of thioamine, the reaction solution was oxidized with 57mL of 30% hydrogen peroxide and then decolorized with 2g of activated carbon to obtain thioamine sulfate reaction solution. This reaction solution was added to a reactor, and the solution temperature was controlled at 20℃. The stirring speed was 100r / min. A 50% ammonium nitrate aqueous solution was added, and the pH was adjusted with 25% ammonia solution at a rate of 1.0mL / min. The ammonia addition was stopped after adjusting the pH to 4.7, and crystallization was allowed to continue for 10min. After crystallization, ammonia solution was added again to adjust the pH to 5.9, and the addition was stopped again. Crystallization was allowed to continue for 10min, and finally, ammonia solution was added until the pH reached 6.9 to complete the neutralization reaction. The solution was then cooled to 7℃ at a rate of 0.7℃ / min. After filtration, the solution was washed with 20mL of methanol and 20mL of pure water, respectively, and dried under vacuum at 60℃ to obtain 51.30g of thioamine nitrate crystals, with a yield of 92.91%.

[0029] Example 4.

[0030] Starting with 50g of thioamine, the reaction solution was oxidized with 57mL of 30% hydrogen peroxide and then decolorized with 2g of activated carbon to obtain thioamine sulfate reaction solution. This reaction solution was added to a reactor, and the solution temperature was controlled at 20℃. The stirring speed was 130r / min. A 50% ammonium nitrate aqueous solution was added, and the pH was adjusted with 25% ammonia solution at a rate of 1.4mL / min. The ammonia addition was stopped after adjusting the pH to 4.5, and crystallization was allowed to continue for 15min. After crystallization, ammonia solution was added again to adjust the pH to 5.8, and then stopped. Crystallization was allowed to continue for another 15min. Finally, ammonia solution was added until the pH reached 7.1, completing the neutralization reaction. The solution was then cooled to 5℃ at a rate of 0.5℃ / min. After filtration, the solution was washed with 20mL of methanol and 20mL of pure water, respectively, and dried under vacuum at 60℃ to obtain 52.91g of thioamine nitrate crystals, with a yield of 95.83%.

[0031] Example 5.

[0032] Starting with 50g of thioamine, the reaction solution was oxidized with 57mL of 30% hydrogen peroxide and then decolorized with 2g of activated carbon to obtain thioamine sulfate reaction solution. This reaction solution was added to a reactor, and the solution temperature was controlled at 20℃. The stirring speed was 150r / min. A 50% ammonium nitrate aqueous solution was added, and the pH was adjusted with 25% ammonia solution at a rate of 1.5mL / min. The ammonia addition was stopped after the pH of the reaction solution was adjusted to 4.7, and crystallization was allowed to continue for 20min. After crystallization, ammonia solution was added again to adjust the pH to 6.0, and then the addition was stopped. Crystallization was allowed to continue for another 20min. Finally, ammonia solution was added until the pH reached 7.2 to complete the neutralization reaction. The solution was then cooled to 8℃ at a rate of 0.6℃ / min. After filtration, the solution was washed with 20mL of methanol and 20mL of pure water, respectively, and dried under vacuum at 60℃ to obtain 50.98g of thioamine nitrate crystals, with a yield of 92.32%.

[0033] Example 6.

[0034] Starting with 50g of thioamine, the reaction solution was oxidized with 57mL of 30% hydrogen peroxide and then decolorized with 2g of activated carbon to obtain thioamine sulfate reaction solution. This reaction solution was added to a reactor, and the solution temperature was controlled at 20℃. The stirring speed was 130r / min. A 50% ammonium nitrate aqueous solution was added, and the pH was adjusted with 25% ammonia solution at a rate of 1.0mL / min. The ammonia addition was stopped after adjusting the pH to 4.6, and crystallization was allowed to continue for 15min. After crystallization, ammonia solution was added again to adjust the pH to 5.9, and the addition was stopped again. Crystallization was allowed to continue for 15min, and finally, ammonia solution was added until the pH reached 7.0 to complete the neutralization reaction. The solution was then cooled to 6℃ at a rate of 0.4℃ / min. After filtration, the solution was washed with 20mL of methanol and 20mL of pure water, respectively, and dried under vacuum at 60℃ to obtain 52.55g of thioamine nitrate crystals, with a yield of 95.17%.

[0035] The flowability tests of the thiamine nitrate products obtained in Examples 1-6 were performed using a BT-1000 powder comprehensive property tester. The results are shown in the table below:

[0036]

[0037]

[0038] As can be seen from the table above, the thiamine nitrate products obtained in Examples 1 to 6 have an angle of repose of 36 to 39°, a bulk density of 0.62 to 0.68 g / mL, and a Hausner ratio of 1.20 to 1.32. The flowability of the powder has been significantly improved, which is beneficial for subsequent tablet compression.

[0039] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. All other technical solutions formed by equivalent transformations or equivalent transformations fall within the protection scope of the present invention.

Claims

1. A method for optimizing the crystallization process of thiamine nitrate, characterized in that... It includes the following steps: Using thiothiamine as the starting material, the reaction solution was oxidized with hydrogen peroxide and then decolorized with activated carbon to obtain thiamine sulfate reaction solution. The obtained thiamine sulfate reaction solution was added to a reactor, and ammonium nitrate aqueous solution was added under stirring. Then, ammonia water was added dropwise to adjust the pH value for neutralization reaction by intermittent feeding and intermittent crystal growth. After crystal growth, the solution was cooled, filtered, washed, and dried to obtain thiamine nitrate crystals. The specific operation of the intermittent feeding and intermittent crystal growth method is as follows: first, ammonia water was added dropwise to adjust the pH of the reaction solution to 4.5~4.7 and then the addition was stopped. Crystal growth was carried out for 10~20 minutes. After crystal growth, ammonia water was added dropwise again to adjust the pH of the reaction solution to 5.8~6.0 and then the addition was stopped. Crystal growth was carried out for 10~20 minutes. After crystal growth, ammonia water was added dropwise again to adjust the pH of the reaction solution to 6.8~7.2 to complete the neutralization reaction. The ammonia droplet acceleration rate was 1.0~1.5 mL / min; The stirring rate during the ammonia water droplet addition process is 100~150 r / min.

2. The method for optimizing the crystallization process of thiamine nitrate according to claim 1, characterized in that... After crystal growth is complete, cool the reaction solution to 5-8℃.

3. The method for optimizing the crystallization process of thiamine nitrate according to claim 1, characterized in that... Cooling rate: 0.4~0.7℃ / min.

4. The method for optimizing the crystallization process of thiamine nitrate according to claim 1, characterized in that... The obtained thiamine nitrate crystals are coarse rod-shaped with high regularity of crystal morphology. The product has an angle of repose of 36~39°, a bulk density of 0.62~0.68 g / mL, and a Hausner ratio of 1.20~1.32.

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