A method for preparing a fat-soluble vitamin E powder

Abstract

This invention discloses a method for preparing fat-soluble vitamin E powder. The specific operation process is as follows: after preparing a powdered drug cocrystal product using ball milling, a more efficient, green, and sustainable mechanochemical method is employed to improve the preparation process, resulting in better uniform dispersion of the drug and carrier. Solubility is used as the evaluation target to screen vitamin E inclusion materials and excipients, and the optimal formulation is selected for preparing the vitamin E cocrystal inclusion complex. Results show that the method of this invention effectively improves the solubility and other physicochemical properties of fat-soluble vitamin E. Its low energy consumption and minimal use of toxic and harmful reagents give it multiple advantages for large-scale production. Therefore, it has broad application potential and is of great significance for the formulation of vitamin drugs.

Description

Technical Field

[0001] This invention belongs to the field of solubilization technology for poorly soluble drugs, and specifically relates to a method for preparing fat-soluble vitamin E powder. Background Technology

[0002] Vitamins are essential micronutrients that organisms cannot synthesize themselves and must obtain from external sources. Many vitamins are known to be effective coenzyme components of enzymes, playing an indispensable role in human growth, metabolism, and development. Vitamin E, also known as tocopherol, is a fat-soluble vitamin. Natural vitamin E is a colorless or pale yellow transparent oily liquid, easily oxidized in air and losing its activity; therefore, it is often esterified. With the deepening research into the physicochemical properties of vitamins, vitamins and their derivatives are receiving increasing attention in food, animal feed (approximately 200-300g of vitamin E is required per kilogram of feed), cosmetics (antioxidant effects), chemical industry, nutritional supplements, and pharmaceuticals.

[0003] However, most vitamins are unstable and easily lose their activity under the catalysis of light, pH, temperature, metal ions, oxygen, and other conditions. They are also prone to degradation during processing and storage, especially fat-soluble vitamins, which typically have poor water solubility during digestion, further limiting their clinical application. Therefore, vitamins are often encapsulated to obtain products with excellent physicochemical properties, such as powders, injections, tablets, microcapsules, and liposomes. Preparation methods include spray drying, thin-layer dispersion, emulsification, ultrasound, and high-pressure homogenization, etc. However, the above-mentioned preparation technologies and processes all have many limitations in terms of cost or large-scale production. The emergence of cocrystallization technology has broken through the barrier that fat-soluble vitamins usually require a first step of esterification to improve stability. It prioritizes the use of low-cost small molecules such as amino acids to form drug cocrystallization products, realizing the transformation of oily substances into powder. Powdered products are limited in continuous production due to their inability to be used with heat-sensitive raw materials. Therefore, the prepared cocrystallization products can be prepared as inclusion complexes, which provides the possibility of further expanding the physicochemical properties of drugs, such as solubility, stability, and bioavailability. In terms of preparation process, mechanochemical technology is preferred, as it not only saves costs but also has advantages in terms of sustainability and scalability.

[0004] Patent CN118716499A discloses a method for preparing water-soluble vitamin E. This method involves dissolving vitamin E and β-cyclodextrin separately in xylitol aqueous solution and choline chloride aqueous solution, respectively. After inclusion complexation to obtain a vitamin E-β-cyclodextrin inclusion complex, the mixture is electrospun to obtain water-soluble vitamin E. The xylitol aqueous solution can form a eutectic solvent with choline chloride to promote the inclusion of vitamin E by β-cyclodextrin. Simultaneously, choline chloride acts as a hydrogen bond acceptor, binding to both β-cyclodextrin and xylitol, effectively weakening intramolecular hydrogen bonds and lowering lattice energy, thereby further improving the solubility of vitamin E. However, this formulation method is suitable for small-scale laboratory trials and may encounter technical and economic challenges in industrial-scale production.

[0005] Patent CN114886122B discloses a method for preparing vitamin E powder. This method involves adding DL-α-tocopherol acetate, silica, PEG4000, and PVP K90 in a ball mill jar at a mass ratio of 50:45:3:2, and then sieving to obtain the powder. However, this method does not significantly improve the water solubility of vitamin E, and the esterification process incurs additional costs.

[0006] Since most vitamins are first converted into a free form in the body before digestion and absorption, cocrystallization technology, which associates active pharmaceutical ingredients with adjuvants using only weak interactions such as hydrogen bonds without altering the original covalent structure of the drug, has come into the researchers' view. Because APIs and CCFs are bound together by weak interactions such as hydrogen bonds, they are easily broken down into a free form by digestive enzymes after oral administration, making them readily absorbed. Numerous studies have also shown that in vitro assessments based on dissolution and / or solubility are sufficient to demonstrate that APIs dissociate from CCFs before reaching their pharmacologically active sites (Cryst. Growth Des. 2023, 23, 1-5) and are digested and absorbed in a free form. Therefore, the development of vitamin cocrystallization drugs is essential. However, the currently described hot-melt extrusion technology, which can continuously produce drug cocrystallization products, is limited by its inability to be applied to heat-sensitive raw materials, resulting in the current predominantly intermittent production of cocrystallizations. To address this issue, eutectic inclusion compounds can be prepared, which not only solves the problem of continuous production but also promises to further improve drug solubility, bioavailability, and stability through the combination of these two technologies. Inclusion technology refers to inclusion compounds formed by a guest molecule being embedded within the cavity structure of another host molecule. Common host molecules include cyclodextrins, calixarenes, cucurbitacins, and columnar aromatics, which possess a relatively hydrophobic central cavity and a hydrophilic outer surface (Pharmaceuticals 2023, 16, 1074). This unique cavity structure allows for the embedding of hydrophobic molecules of appropriate size.

[0007] Mechanochemical milling, as a more environmentally friendly, greener, and sustainable technology, has been named by the International Union of Pure and Applied Chemistry (IUPAC) as one of the innovative technologies with the potential to change the world. Studies by Etter et al. have shown that a large amount of solvent is not necessary for the formation of cocrystals (Physical Chemistry, 1991, 95(12):4601-4610), which paves the way for the application of mechanochemistry in pharmaceutical cocrystals. Similarly, inclusion complexes of cocrystals can also be prepared using mechanochemical methods. Summary of the Invention

[0008] To address the aforementioned problems, the present invention aims to provide a method for preparing fat-soluble vitamin E powder. This method firstly addresses the research objective by combining eutectic and inclusion technologies to achieve the synergistic effect of both methods; secondly, it selects low-cost eutectic formants and encapsulating materials; and finally, in terms of the preparation process, it employs a mechanochemical method that is more suitable for scalable and sustainable production compared to solution methods.

[0009] The specific technical solution is as follows:

[0010] A method for preparing fat-soluble vitamin E powder includes the following steps:

[0011] 1) Add vitamin E and cocrystallizing agent to a ball milling jar, add a small amount of methanol, add zirconium oxide beads as the ball milling medium, seal and place on a planetary ball mill for ball milling to obtain vitamin E-proline drug cocrystallization product;

[0012] 2) Add the vitamin E-proline drug cocrystal product prepared in step 1), surfactant, flow aid and polymer material to the ball mill jar, then add zirconia beads as the ball milling medium, seal and place on a planetary ball mill for ball milling to obtain vitamin E powder product.

[0013] Further, the eutectic forming agent is proline, betaine, glutamic acid, nicotinamide, gallic acid, malonic acid, or nicotinic acid, preferably proline or betaine; the surfactant is Tween-80, Span 60, poloxamer 188, monoglyceride, povidone K90, or sodium dodecyl sulfate, preferably poloxamer 188; the glidant is talc, silica, or magnesium stearate, preferably silica; and the polymer is one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and hydroxypropyl-β-cyclodextrin, preferably hydroxypropyl-β-cyclodextrin.

[0014] Furthermore, in step 2), the mass ratio of vitamin E, eutectic forming agent, surfactant, flow aid and polymer material is 25%:3%:2%:2%:18%.

[0015] Furthermore, in step 2), the ball mill speed is 100-300 rpm, preferably 250 rpm; the ball milling time is 0.5-4 h, preferably 2 h.

[0016] Furthermore, the mass ratio of zirconia beads to the total added material is 5-30:1, and the filler material of the ball mill is 10-30%, preferably 20%.

[0017] By employing the above-described technology, the beneficial effects of this invention compared to existing technologies are as follows:

[0018] 1) This invention utilizes polymer materials as carriers to increase the solubility of drugs, while using surfactants and flow aids to improve their dissolution rate, which is beneficial to improving the bioavailability of fat-soluble vitamin E in vivo.

[0019] 2) This invention prepares 50% fat-soluble vitamin E powder through a defined preparation method. The operation is simple and, compared with traditional preparations, avoids the use of toxic and harmful organic solvents, making it more green and environmentally friendly. It has the advantages of simple operation, low production cost, large-scale production capability, and environmental friendliness and pollution-free production. It is a preparation method with broad application prospects.

[0020] 3) This invention prepares 50% fat-soluble vitamin E powder by mechanical force. The preparation of vitamin E and L-proline into drug cocrystals and ball milling with a polymer carrier can significantly improve the water solubility of fat-soluble vitamin E, providing a new idea and method for the formulation development of feed powder.

[0021] 4) This invention innovatively combines eutectic technology with inclusion technology, which is expected to achieve the combined effect of the two methods. Attached Figure Description

[0022] Figure 1 Solubility diagrams of vitamin E powders prepared with different excipients and carrier formulations;

[0023] Figure 2 Solubility graph of vitamin E powder with different ball-to-powder ratios;

[0024] Figure 3 Solubility graph of vitamin E powder at different ball milling times;

[0025] Figure 4 Solubility graph of vitamin E powder at different rotation speeds;

[0026] Figure 5 Solubility graph of vitamin E powder with different filling ratios. Detailed Implementation

[0027] The present invention will be further described below with reference to specific embodiments and accompanying drawings, but the scope of protection of the present invention is not limited thereto.

[0028] Example 1: Preparation of Vitamin E Drug Cocrystal Products Using Proline as a Vitamin E Cocrystal Formulator

[0029] Vitamin E (4.8g), L-proline (0.575g), and methanol (4ml) were added to a 50ml tetrafluoroethylene ball mill jar. 36g of 15mm diameter zirconia beads were added as grinding media. After mixing thoroughly, the mixture was placed in a planetary ball mill and the mill was set to 250 rpm for 2 hours. A highly free-flowing, white powder was obtained.

[0030] Example 2: Preparation of 50% Vitamin E powder with hydroxypropyl-β-cyclodextrin and Tween-80 as carriers (Vitamin E: L-proline: Tween-80: Silica: Hydroxypropyl-β-cyclodextrin = 25%: 3%: 2%: 2%: 18%)

[0031] In a 300ml tetrafluoroethylene ball mill jar, add 14g of vitamin E-proline cocrystal, 1g of Tween-80, 1g of silica, and 9g of hydroxypropyl-β-cyclodextrin. Add 380g of 15mm diameter zirconia beads as the grinding medium, mix thoroughly, and then place in a planetary ball mill. Set the speed to 250 rpm for 2 hours. After the process, take an appropriate amount of product into a 50ml centrifuge tube, add 10ml of distilled water, cap the tube, and place it in a constant temperature water bath shaker at 37℃. Shake at 150 rpm for 24 hours. Analyze the supernatant using high-performance liquid chromatography (HPLC) after filtering through a 0.45μm syringe filter. The results show that the solubility of vitamin E in this component is 154.37μg / mL.

[0032] Example 3: Preparation of 50% Vitamin E powder with hydroxypropyl-β-cyclodextrin and poloxamer 188 as carriers (Vitamin E: L-proline: poloxamer 188: silica: hydroxypropyl-β-cyclodextrin = 25%: 3%: 2%: 2%: 18%)

[0033] In a 300ml tetrafluoroethylene ball mill jar, add 14g of vitamin E-proline cocrystal, 1g of poloxamer 188, 1g of silica, and 9g of hydroxypropyl-β-cyclodextrin. Add 380g of 15mm diameter zirconia beads as the grinding medium, mix thoroughly, and then place in a planetary ball mill. Set the speed to 250 rpm for 2 hours. After the process, take an appropriate amount of product into a 50ml centrifuge tube, add 10ml of distilled water, cap the tube, and place it in a constant temperature water bath shaker at 37℃. Shake at 150 rpm for 24 hours. Analyze the supernatant using high-performance liquid chromatography (HPLC) after filtering through a 0.45μm syringe filter. The results show that the solubility of vitamin E in this component is 178.35μg / mL.

[0034] Example 4: Preparation of 50% Vitamin E powder with hydroxypropyl-β-cyclodextrin and Span 60 as carriers (Vitamin E: L-proline: Span 60: Silica: Hydroxypropyl-β-cyclodextrin = 25%: 3%: 2%: 2%: 18%)

[0035] In a 300ml tetrafluoroethylene ball mill jar, add 14g of vitamin E-proline cocrystal, 1g of Span 60, 1g of silica, and 9g of hydroxypropyl-β-cyclodextrin. Add 380g of 15mm diameter zirconia beads as the grinding medium, mix thoroughly, and then place in a planetary ball mill. Set the speed to 250 rpm for 2 hours. After the process, transfer an appropriate amount of product to a 50ml centrifuge tube, add 10ml of distilled water, cap, and place in a constant temperature water bath shaker at 37℃. Shake at 150 rpm for 24 hours. Analyze the supernatant using high-performance liquid chromatography (HPLC) after filtering through a 0.45μm syringe filter. The results show that the solubility of vitamin E in this component is 116.96μg / mL.

[0036] Example 5: Preparation of 50% Vitamin E powder with hydroxypropyl-β-cyclodextrin and povidone K90 as carriers (Vitamin E: L-proline: povidone K90: silica: hydroxypropyl-β-cyclodextrin = 25%: 3%: 2%: 2%: 18%)

[0037] In a 300ml tetrafluoroethylene ball mill jar, add 14g of vitamin E-proline cocrystal, 1g of povidone K90, 1g of silica, and 9g of hydroxypropyl-β-cyclodextrin. Add 380g of 15mm diameter zirconia beads as the grinding medium, mix thoroughly, and then place in a planetary ball mill. Set the speed to 250 rpm for 2 hours. After the process, take an appropriate amount of product into a 50ml centrifuge tube, add 10ml of distilled water, cap the tube, and place it in a constant temperature water bath shaker at 37℃. Shake at 150 rpm for 24 hours. Analyze the supernatant using high-performance liquid chromatography (HPLC) after filtering through a 0.45μm syringe filter. The results show that the solubility of vitamin E in this component is 45.93μg / mL.

[0038] Example 6: Preparation of 50% Vitamin E powder with hydroxypropyl-β-cyclodextrin and monoglyceride as carriers (Vitamin E: L-proline: monoglyceride: silicon dioxide: hydroxypropyl-β-cyclodextrin = 25%: 3%: 2%: 2%: 18%)

[0039] In a 300ml tetrafluoroethylene ball mill jar, add 14g of vitamin E E-proline cocrystal, 1g of monoglyceride, 1g of silica, and 9g of hydroxypropyl-β-cyclodextrin. Add 380g of 15mm diameter zirconia beads as the grinding medium, mix thoroughly, and then place in a planetary ball mill. Set the speed to 250 rpm for 2 hours. After the process, transfer an appropriate amount of product to a 50ml centrifuge tube, add 10ml of distilled water, cap, and place in a constant temperature water bath shaker at 37℃. Shake at 150 rpm for 24 hours. Analyze the supernatant using high-performance liquid chromatography (HPLC) after filtering through a 0.45μm syringe filter. The results show that the solubility of vitamin E in this component is 70.31μg / mL.

[0040] Example 7: Preparation of 50% Vitamin E powder with hydroxypropyl-β-cyclodextrin and sodium lauryl sulfate as carriers (Vitamin E: L-proline: Sodium lauryl sulfate: Silicon dioxide: Hydroxypropyl-β-cyclodextrin = 25%: 3%: 2%: 2%: 18%)

[0041] In a 300ml tetrafluoroethylene ball mill jar, add 14g of vitamin E E-proline cocrystal, 1g of sodium dodecyl sulfate, 1g of silica, and 9g of hydroxypropyl-β-cyclodextrin. Add 380g of 15mm diameter zirconia beads as the grinding medium, mix thoroughly, and then place in a planetary ball mill. Set the speed to 250 rpm for 2 hours. After the process, transfer an appropriate amount of product to a 50ml centrifuge tube, add 10ml of distilled water, cap, and place in a constant temperature water bath shaker at 37℃. Shake at 150 rpm for 24 hours. Analyze the supernatant using high-performance liquid chromatography (HPLC) after filtering through a 0.45μm syringe filter. The results show that the solubility of vitamin E in this component is 62.28μg / mL.

[0042] Example 8: Preparation of 50% Vitamin E powder with β-cyclodextrin and poloxamer 188 as carriers (Vitamin E: L-proline: poloxamer 188: silica: β-cyclodextrin = 25%: 3%: 2%: 2%: 18%)

[0043] In a 300ml tetrafluoroethylene ball mill jar, add vitamin E EL-proline cocrystal (14g), poloxamer 188 (1g), silica (1g), and β-cyclodextrin (9g). Add 380g of 15mm diameter zirconia beads as the grinding medium, mix thoroughly, and then place in a planetary ball mill. Set the speed to 250 rpm for 2 hours. After the process, take an appropriate amount of product into a 50ml centrifuge tube, add 10ml of distilled water, cap the tube, and place it in a constant temperature water bath shaker at 37℃. Shake at 150 rpm for 24 hours. Analyze the supernatant using high performance liquid chromatography (HPLC) after filtering through a 0.45μm syringe filter. The results show that the solubility of vitamin E in this component is 1.78μg / mL.

[0044] Examples 2-8 selected Tween 80, poloxamer 188, Span 60, povidone K90, monoglyceride, and sodium lauryl sulfate as surfactants, and hydroxypropyl-β-cyclodextrin or β-cyclodextrin as polymers to prepare 50% vitamin E powders with different excipients (50% refers to vitamin E content accounting for 50% of the total material). The solubility of vitamin E in each powder was plotted as a curve, such as... Figure 1 As shown, hydroxypropyl-β-cyclodextrin and poloxamer were preferred, and the powder prepared with these compounds showed the highest solubility of vitamin E, at 178.35 μg / mL.

[0045] Example 9: Ball-to-material ratio screening

[0046] Using the powder formulation in Example 3, the following mixture was added to a 300ml tetrafluoroethylene ball mill jar at a ratio of 25%:3%:2%:2%:18% for vitamin E1-proline cocrystal: poloxamer 188: silica:hydroxypropyl-β-cyclodextrin:=25%:3%:2%:2%:18%. Zirconia beads with a diameter of 15mm were added sequentially as grinding media at ball-to-particle ratios of 5:1, 10:1, 15:1, 20:1, and 30:1. After thorough mixing, the mixture was placed in a planetary ball mill at 250 rpm for 2 hours. Afterward, an appropriate amount of product was transferred to a 50ml centrifuge tube, 10ml of distilled water was added, the tube was capped, and the tube was placed in a constant temperature water bath shaker at 37°C and shaken at 150 rpm for 24 hours. The supernatant was filtered through a 0.45μm syringe filter and analyzed by high-performance liquid chromatography (HPLC). Figure 2 The experimental results showed that the vitamin E solubility of this component was the highest at a ball-to-material ratio of 15:1, which was 170.21 μg / mL.

[0047] Example 10: Ball Milling Time Screening

[0048] Using the powder formulation from Example 3, vitamin E1-proline cocrystal (14g), poloxamer 188 (1g), silica (1g), and hydroxypropyl-β-cyclodextrin (9g) were added to a 300ml tetrafluoroethylene ball mill jar. 380g of 15mm diameter zirconia beads were added as the grinding medium. After thorough mixing, the mixture was placed in a planetary ball mill. Five experimental groups were set for 30min, 1h, 2h, 3h, and 4h at a speed of 250rpm. After completion, an appropriate amount of product was placed in a 50ml centrifuge tube, 10ml of distilled water was added, the tube was capped, and the tube was placed in a constant temperature water bath shaker at 37℃ and shaken at 150rpm for 24 hours. The supernatant was filtered through a 0.45μm syringe filter and analyzed by high-performance liquid chromatography (HPLC). Figure 3 The experimental results showed that the vitamin E solubility of this component was the highest at 177.41 μg / mL after 2 hours of reaction.

[0049] Example 11: Ball Mill Speed ​​Screening

[0050] Using the powder formulation from Example 3, vitamin E1-proline cocrystal (14g), poloxamer 188 (1g), silica (1g), and hydroxypropyl-β-cyclodextrin (9g) were added to a 300ml tetrafluoroethylene ball mill jar. 380g of 15mm diameter zirconia beads were added as the grinding medium. After thorough mixing, the mixture was placed in a planetary ball mill. Five experimental groups were set at rotation speeds of 100rpm, 150rpm, 200rpm, 250rpm, and 300rpm for 2 hours. After completion, an appropriate amount of product was placed in a 50ml centrifuge tube, 10ml of distilled water was added, the tube was capped, and the tube was placed in a constant temperature water bath shaker at 37°C and shaken at 150rpm for 24 hours. The supernatant was filtered through a 0.45μm syringe filter and analyzed by high-performance liquid chromatography (HPLC). Figure 4 The experimental results showed that the vitamin E solubility of this component was the highest at a rotation speed of 250 rpm, which was 185.41 μg / mL.

[0051] Example 12: Screening of ball mill filling rate

[0052] Using the powder formulation in Example 3, the following mixture was added to a 300ml tetrafluoroethylene ball mill jar at a ratio of 25%:3%:2%:2%:18% for vitamin E1-proline cocrystal, poloxamer 188, silica, and hydroxypropyl-β-cyclodextrin. Zirconia beads with a diameter of 15mm were added as grinding media at filling rates of 10%, 15%, 20%, 25%, and 30%, respectively. After thorough mixing, the mixture was placed in a planetary ball mill at 250 rpm for 2 hours. After the reaction, an appropriate amount of product was transferred to a 50ml centrifuge tube, 10ml of distilled water was added, the tube was capped, and the tube was placed in a constant temperature water bath shaker at 37°C and shaken at 150 rpm for 24 hours. The supernatant was filtered through a 0.45μm syringe filter and analyzed by high-performance liquid chromatography (HPLC). Figure 5 The experimental results showed that the vitamin E solubility of this component was the highest when the filling rate was 20%, which was 209.1 μg / mL.

[0053] Examples 9-12 selected different ball milling parameters to screen for optimal solubility and prepared 50% vitamin E powder with different excipients. The optimal ball milling conditions were found to be: ball milling speed of 250 rpm, reaction time of 2 h, filling rate of 20%, and ball-to-material ratio of 15:1.

Claims

1. A method for preparing fat-soluble vitamin E powder, characterized in that, Includes the following steps: 1) Add vitamin E and cocrystallizing agent to a ball milling jar, add a small amount of methanol, add zirconium oxide beads as the ball milling medium, seal and place on a planetary ball mill for ball milling to obtain vitamin E-proline drug cocrystallization product; 2) Add the vitamin E-proline drug cocrystal product, surfactant, flow aid and polymer material prepared in step 1) to the ball mill jar, then add zirconia beads as the ball milling medium, seal and place on a planetary ball mill for ball milling to obtain vitamin E powder product. The eutectic forming agent is proline, the surfactant is poloxamer 188, the polymer material is hydroxypropyl-β-cyclodextrin, the flow aid is silica, the ball mill speed in step 2) is 100-300 rpm, the ball milling time is 0.5-4 h, the ball-to-material mass ratio of zirconia beads to total added material is 5-30:1, and the ball mill filler is 10-30%.

2. The method for preparing fat-soluble vitamin E powder as described in claim 1, characterized in that, In step 2), the mass ratio of vitamin E, eutectic forming agent, surfactant, flow aid and polymer material is 25%:3%:2%:2%:18%.

3. The method for preparing fat-soluble vitamin E powder as described in claim 1, characterized in that, In step 2), the ball mill speed is 250 rpm and the ball milling time is 2 hours.

4. The method for preparing fat-soluble vitamin E powder as described in claim 1, characterized in that, The mass ratio of zirconia beads to the total added material is 15:1, and the ball mill filler is 20%.

Images