Selenium dioxide crystal and method for preparing the same
The characteristics of selenite crystals were determined by Cu-Kα radiation measurement and DSC spectroscopy. Selenite crystals were prepared by using anhydrous ethanol suspension and crystallization solvent, which solved the problems of high cost, low purity and safety hazards in the existing technology. It achieved the preparation of selenite with high yield and stable crystal form, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGSU YUTIAN PHARM CO LTD
- Filing Date
- 2026-02-28
- Publication Date
- 2026-05-29
AI Technical Summary
Existing methods for preparing selenite acid suffer from high production costs, low purity, and are unsuitable for industrial production. Furthermore, they pose safety risks or have byproduct impurities that are difficult to remove.
The characteristics of selenite crystals were determined by X-ray powder diffraction peaks measured by Cu-Kα radiation and differential scanning calorimetry (DSC) patterns. Stable selenite crystals were prepared by adding selenium dioxide suspension to anhydrous ethanol and slowly adding purified water, followed by adding a crystallization solvent such as ethyl acetate. Combined with nitrogen protection and drying treatment, stable selenite crystals were prepared.
The prepared selenite crystals have a yield of up to 75%–79%, stable crystal form, are suitable for industrial production, are simple to operate, safe, low in cost, and the product meets pharmacopoeia standards.
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Figure CN122102064A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of crystal preparation of pharmaceutical intermediates, and more particularly to a crystallization-stable selenite crystal and its preparation method. Background Technology
[0002] Selenous acid is a pharmaceutical supplement with the molecular formula H₂O₃Se, a molecular weight of 128.97, and CAS number 7783-00-8. It is a colorless or white hexagonal prismatic crystal. Its structural formula is shown in Formula I.
[0003] ; Formula I.
[0004] Selenium is a trace but essential nutrient for the human body, with functions encompassing antioxidation, thyroid regulation, immune enhancement, cardiovascular protection, liver detoxification, and male reproductive health. It is a key factor in maintaining the normal function of multiple systems. Since the soil in most parts of China is selenium-deficient, it is necessary to obtain sufficient selenium through daily consumption of selenium-rich foods (such as animal organs, seafood, nuts, and garlic). If necessary, selenium supplements should be used under the guidance of a doctor / nutritionist to avoid both deficiency and excess, thus maximizing its health benefits.
[0005] The core medicinal value of selenite (and its practical forms such as sodium selenite and potassium selenite, which are mostly used in clinical practice as salts) revolves around the physiological functions of selenium. Selenium is an essential trace element for the human body, participating in the synthesis and metabolism of various enzymes. When the human body is deficient in selenium due to insufficient selenium intake or absorption disorders, selenite preparations can be used as supplements to correct the selenium deficiency and improve related pathological problems.
[0006] Currently, the preparation methods of selenite can be divided into the following three categories according to the different starting materials: preparation methods using elemental selenium as the starting material, preparation methods using sodium selenite as the starting material, and preparation methods using selenium dioxide as the starting material.
[0007] Route 1: This method uses elemental selenium as the starting material. Elemental selenium (Se) is dissolved in concentrated nitric acid (HNO3), heated until completely dissolved, and excess nitric acid is evaporated to obtain selenite crystals. Advantages: The raw materials (Se, HNO3) are readily available and the cost is low. The reaction is fast, suitable for small-scale laboratory preparation. Disadvantages: Toxic NO gas may be generated, requiring a fume hood. If the temperature is too high or there is excess nitric acid, over-oxidation may occur, producing selenic acid (H2SeO4), requiring purification to remove residual nitric acid, which is not conducive to producing high-purity selenite.
[0008] Route 2: This method uses selenium dioxide as the starting material. Selenium dioxide (SeO2) is dissolved in deionized water (stirred at room temperature), the solution is evaporated and concentrated, and selenite crystals precipitate upon cooling. Advantages: Simple reaction, few byproducts, high product purity, no toxic gas generation, safer operation, suitable for the preparation of high-purity selenite. Disadvantages: The evaporation and concentration process is easily reduced to elemental selenium by reducing dust in the air, and the evaporation temperature must be controlled to avoid decomposition. Therefore, this route is not chosen for scale-up production.
[0009] Route 3: This method uses sodium selenite as the starting material. Na₂SeO₃ is dissolved in water, and hydrochloric acid (HCl) or sulfuric acid (H₂SO₄) is slowly added dropwise. NaCl (or Na₂SO₄) is removed by filtration, and the filtrate is evaporated to obtain H₂SeO₃. Advantages: The reaction is mild and conditions are easily controlled. It is suitable for systems where strong oxidants need to be avoided. Disadvantages: The product may contain sodium salts, requiring multiple recrystallization purifications. If H₂SO₄ is used, sulfate impurities may be introduced, failing to meet the quality standards for selenite raw materials. Summary of the Invention
[0010] To address the aforementioned problems, the present invention aims to provide a stable selenite crystal suitable for industrial production and its preparation method.
[0011] To achieve the above objectives, the present invention employs the following technical solution: a selenite crystal, wherein the selenite crystal, measured by Cu-Kα radiation, exhibits X-ray powder diffraction at diffraction angles expressed in 2θ at 17.7°±0.2°, 19.5°±0.2°, 20.0°±0.2°, 22.9°±0.2°, 24.5°±0.2°, 24.9°±0.2°, 26.2°±0.2°, and 2... Characteristic peaks are observed at 9.8°±0.2°, 30.2°±0.2°, 31.4°±0.2°, 33.0°±0.2°, 34.3°±0.2°, 35.8°±0.2°, 36.6°±0.2°, 37.4°±0.2°, 37.5°±0.2°, and 38.4°±0.2°. The differential scanning calorimetry (DSC) spectrum of the selenite crystal shows a characteristic endothermic peak at 73.4°C. The selenite crystal of this invention possesses the following characteristics: Figure 1 The X-ray diffraction pattern and diffraction peaks shown have the following characteristics: Figure 3 The DSC spectrum shown.
[0012] The present invention provides a method for preparing selenite crystals, comprising the following steps:
[0013] 1) Add anhydrous ethanol to the reaction vessel, then add selenium dioxide while stirring to form an ethanol suspension of selenium dioxide; then slowly add purified water, and react for 1-2 hours after the addition is complete; filter under nitrogen pressure to obtain a selenite ethanol solution.
[0014] 2) Slowly add the crystallization solvent to the selenite ethanol solution in step 1), stir and crystallize for 2-3 hours; filter under nitrogen pressure, and dry the wet product under nitrogen flow at a temperature of 10-40℃ and a pressure of 0.03-0.05MPa for 4-6 hours; collect the material to obtain selenite crystals.
[0015] The specific reaction formula is as follows:
[0016] .
[0017] In step 1) of this invention, the mass ratio of selenium dioxide, anhydrous ethanol, and purified water is 1:1 to 2:0.2 to 0.4. If the water content is less than 0.2, the selenium dioxide reaction is incomplete, and selenium dioxide will be present in the product; if the water content is more than 0.4, it will affect subsequent crystallization, and the water content of the product will increase, making it impossible to obtain the target crystal form.
[0018] In step 2) of this invention, the crystallization solvent is selected from any one of ethyl acetate, n-hexane, or n-heptane. Ethyl acetate is preferred as the crystallization solvent, and the volume ratio of ethyl acetate to anhydrous ethanol in step 1) is 3-5:1. If the volume of ethyl acetate is lower or exceeds this range, the crystal form will change.
[0019] The reactions in step 1) are all carried out under heat preservation conditions, with a reaction temperature of 20–40℃. Below 20℃, the selenium dioxide reaction is incomplete, and above 40℃, selenite is reduced to elemental selenium.
[0020] The reaction temperature for stirring and crystallization in step 2) is 20–30°C; the drying temperature of the nitrogen gas flow is preferably 20–30°C. At temperatures above 30°C, selenite loses water to form selenium dioxide.
[0021] The advantages of this invention are: the yield of stable crystals prepared by the method of this invention reaches 75% to 79%, the overall preparation route is simple, the reaction conditions are mild, the operation is convenient, the cost is low, and the process reproducibility is good; the prepared selenite acid has a stable crystal form, and after being stored for 6 months under accelerated conditions of 40℃±2℃ and 75%±5%RH, the crystal form of the sample did not change; it is suitable for large-scale industrial production of raw materials. Attached Figure Description
[0022] Figure 1 The IR spectrum of selenite is shown in Example 1 of the invention.
[0023] Figure 2 MS spectrum of selenite in Invention Example 1.
[0024] Figure 3 The X-ray powder diffraction pattern of selenite crystals on day 0 in Example 1 of the present invention is shown.
[0025] Figure 4This is the TGA spectrum of selenite crystals in Example 1 of the present invention.
[0026] Figure 5 This is the DSC spectrum of selenite crystals in Example 1 of the present invention.
[0027] Figure 6 The X-ray powder diffraction pattern of selenite crystals obtained after 6 months of accelerated processing in Example 4 of this invention is shown.
[0028] in, Figure 3 and Figure 6 The horizontal tables in the table are data tables for X-ray powder diffraction patterns, and the vertical tables are detailed X-ray powder diffraction patterns. Detailed Implementation
[0029] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.
[0030] Example 1: A method for preparing selenite crystals, comprising the following steps.
[0031] 1) Add 100g of anhydrous ethanol to a 1L glass bottle, and add 100g of selenium dioxide while stirring to form an ethanol suspension of selenium dioxide. Control the reaction temperature at 20~30℃, and slowly add 20g of purified water. After the addition is complete, keep the temperature at 20~30℃ for 1~2 hours. Filter under nitrogen pressure to obtain a selenite ethanol solution.
[0032] 2) Controlling the reaction temperature at 20-30℃, slowly add 400g of ethyl acetate. After the addition is complete, maintain the temperature at 10-30℃ and stir to induce crystallization for 2-3 hours. Filter under nitrogen pressure. Dry the wet product under a nitrogen stream at 20-30℃ and 0.03-0.05MPa for 4-6 hours. 92.0g of selenite crystals were obtained, with a purity of 97.2%, a yield of 79.2%, and a residue on ignition of 0.003%. The IR and MS data are consistent with the structure of selenite. Physicochemical and elemental impurity test results all meet the standards of the United States Pharmacopeia.
[0033] The infrared absorption spectrum of selenite is shown below. Figure 1 As shown;
[0034] The mass spectrum of selenite is as follows: Figure 2 As shown;
[0035] X-ray powder diffraction pattern of stable crystal form of selenite as follows Figure 3 As shown, the testing date was November 11, 2024.
[0036] TGA spectra of the stable crystal form of selenite are as follows: Figure 4 As shown, the testing date was November 13, 2024.
[0037] DSC spectrum of stable crystal form of selenite as follows Figure 5 As shown, the testing date was November 14, 2024.
[0038] Example 2: A selenite crystal and its preparation method, comprising the following steps:
[0039] 1) Add 100g of anhydrous ethanol to a 1L glass bottle, and add 100g of selenium dioxide while stirring to form an ethanol suspension of selenium dioxide. Control the reaction temperature at 30~40℃, and slowly add 20g of purified water. After the addition is complete, keep the temperature at 30~40℃ for 1~2 hours. Filter under nitrogen pressure to obtain a selenite ethanol solution.
[0040] 2) Control the reaction temperature at 20-30℃, slowly add 400g of n-hexane. After the addition is complete, maintain the temperature at 10-30℃ and stir to induce crystallization for 2-3 hours. Filter under nitrogen pressure. Dry the wet product under a nitrogen stream at 30-40℃ and 0.03-0.05MPa for 4-6 hours. Collect 87.2g of selenite crystals with a purity of 96.6% and a yield of 75.0%.
[0041] Example 3: A selenite crystal and its preparation method, comprising the following steps.
[0042] 1) Add 100g of anhydrous ethanol to a 1L glass bottle, and add 100g of selenium dioxide while stirring to form an ethanol suspension of selenium dioxide. Control the reaction temperature at 20~30℃, and slowly add 20g of purified water. After the addition is complete, keep the temperature at 20~30℃ for 1~2 hours. Filter under nitrogen pressure to obtain a selenite ethanol solution.
[0043] 2) Control the reaction temperature at 20-30℃, slowly add 400g of n-heptane. After the addition is complete, maintain the temperature at 10-30℃ and stir to induce crystallization for 2-3 hours. Filter under nitrogen pressure. Dry the wet product under a nitrogen stream at 10-20℃ and 0.03-0.05MPa for 4-6 hours. Collect 89.2g of selenite crystals with a purity of 96.1% and a yield of 76.8%.
[0044] Example 4: Stability Comparison Example
[0045] The stable crystalline form of selenite prepared in Example 1 was placed under accelerated conditions (40℃±2℃, 75%±5%RH) to investigate the stability of the selenite sample. The sampling period was 6 months.
[0046] Stability study results showed that the crystal form of selenite remained unchanged after 6 months of accelerated storage at 40℃±2℃ and 75%±5%RH. This indicates that the crystal form of selenite is stable under accelerated storage conditions (40℃±2℃, 75%±5%RH).
[0047] X-ray powder diffraction pattern of selenite stable crystal form after 6 months of accelerated crystallization is shown below. Figure 6 As shown, the testing date was May 19, 2025.
[0048] Example 5: Comparative Example
[0049] A selenite crystal and its preparation method, comprising the following steps:
[0050] Add 100g of anhydrous ethanol to a 1L glass bottle, then add 100g of selenium dioxide while stirring to form an ethanol suspension of selenium dioxide. Control the reaction temperature at 40-50℃, and slowly add 20g of purified water. After the addition is complete, maintain the temperature at 40-50℃ for 1-2 hours. Filter under nitrogen pressure to obtain a selenite ethanol solution. The ethanol solution turns red. If the temperature is too high, the selenite acid will be reduced to elemental selenium, and a qualified product cannot be obtained.
[0051] It should be noted that the above are merely preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any combination or equivalent transformation made based on the above embodiments shall fall within the scope of protection of the present invention.
Claims
1. A type of selenite crystal, characterized in that, The X-ray powder diffraction of the selenite crystal, measured using Cu-Kα radiation, showed diffraction angles (expressed as 2θ) of 17.7°±0.2°, 19.5°±0.2°, 20.0°±0.2°, 22.9°±0.2°, 24.5°±0.2°, 24.9°±0.2°, 26.2°±0.2°, 29.8°±0.2°, and 30.2°. Characteristic peaks are observed at ±0.2°, 31.4°±0.2°, 33.0°±0.2°, 34.3°±0.2°, 35.8°±0.2°, 36.6°±0.2°, 37.4°±0.2°, 37.5°±0.2°, and 38.4°±0.2°; the differential scanning calorimetry (DSC) spectrum of the selenite crystals shows a characteristic endothermic peak at 73.4°C.
2. The crystal as described in claim 1, characterized in that, The selenite crystal has an X-ray diffraction pattern and diffraction peaks as shown in Figure 1, and a DSC pattern as shown in Figure 3.
3. A method for preparing selenite crystals as described in claim 1 or 2, characterized in that, The preparation method includes the following steps: 1) Add anhydrous ethanol to the reaction vessel, then add selenium dioxide while stirring to form an ethanol suspension of selenium dioxide; then slowly add purified water, and react for 1-2 hours after the addition is complete; filter under nitrogen pressure to obtain a selenite ethanol solution. 2) Slowly add the crystallization solvent to the selenite ethanol solution in step 1), stir and crystallize for 2-3 hours; filter under nitrogen pressure, and dry the wet product under nitrogen flow at a temperature of 10-40℃ and a pressure of 0.03-0.05MPa for 4-6 hours; collect the material to obtain selenite crystals.
4. The preparation method according to claim 3, characterized in that, In step 1), the mass ratio of selenium dioxide, anhydrous ethanol, and purified water is 1:1 to 2:0.2 to 0.
4.
5. The preparation method according to claim 3, characterized in that, In step 2), the crystallization solvent is selected from any one of ethyl acetate, n-hexane, or n-heptane.
6. The preparation method according to claim 5, characterized in that, In step 2), the crystallization solvent is ethyl acetate, and the volume ratio of ethyl acetate to anhydrous ethanol in step 1) is 3-5:
1.
7. The preparation method according to claim 3, characterized in that, The reactions in step 1) are all carried out under heat preservation conditions, with a reaction temperature of 20–40°C.
8. The preparation method according to claim 3, characterized in that, The reaction temperature for stirring and crystallization in step 2) is 20-30°C; the drying temperature for the nitrogen gas flow is 20-30°C.