CN109045302B - Polyethylene glycol vitamin E succinate powder and preparation method and application thereof - Google Patents
Polyethylene glycol vitamin E succinate powder and preparation method and application thereof Download PDFInfo
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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Abstract
The invention discloses polyethylene glycol vitamin E succinate powder and a preparation method and application thereof, belonging to the technical field of medicine raw materials. The preparation method comprises the following steps: (1) melting: heating the raw material waxy polyethylene glycol vitamin E succinate to 30-60 ℃ to melt; (2) dissolving with a nonpolar solvent: stirring the melted raw materials and the nonpolar solvent uniformly at the temperature of 30-60 ℃; (3) vacuum pumping: vacuum-pumping at 10-30 deg.C and vacuum degree of-0.06 MPa-0.098 MPa, and drying to obtain polyethylene glycol vitamin E succinate powder. The polyethylene glycol vitamin E succinate powder obtained by the invention has consistent and uniform particle size and excellent fluidity. It is more convenient to use than the waxy product and has broader application in practical applications, particularly advantageous in terms of drug solubilization, and particularly advantageous in terms of capsule filling.
Description
Technical Field
The invention belongs to the technical field of medicine raw materials, and particularly discloses polyethylene glycol vitamin E succinate powder as well as a preparation method and application thereof.
Background
Polyethylene glycol vitamin E succinate is a water-soluble tocopherol derivative, has certain surfactant properties, and can be used as a solubilizer, an absorption enhancer, an emulsifier, a plasticizer and a carrier of a fat-soluble drug delivery system. In addition, it can be used as nutritional supplement for tocopherol to treat some tocopherol malabsorption.
In the synthesis process of the polyethylene glycol vitamin E succinate, most of products are waxy solids, so that the requirements of uniformly mixing all components can be met only by taking a large amount of time for dissolving and uniformly mixing the products in subsequent application. The waxy solid itself cannot be simply mechanically comminuted to give a powder product. The preparation method has the advantages that the preparation method is a wax-like product, so that the application convenience is greatly limited, the formulations of the polyethylene glycol vitamin E succinate products on the market are mainly liquid and wax-like solids, and have certain limitations, and the preparation method is used for preparing water-soluble liquid products and needs a large amount of time. The waxy solid is difficult to prepare into other dosage forms, and the practical application is greatly limited.
Based on the situation, a new method for preparing the powder product is found, so that the defects of the product in application can be overcome, the dissolving time of the product in application is greatly reduced, and the application efficiency of the product is improved. The prepared powdery product can be mixed with one or more of auxiliary materials such as starch, hydroxymethyl cellulose bundle, magnesium stearate and the like according to a certain proportion and the main drug, and finally can be easily prepared into a series of products such as capsules, pills, tablets and the like, and the application prospect is wider.
Disclosure of Invention
The embodiment of the invention provides polyethylene glycol vitamin E succinate powder which is prepared by taking wax-like polyethylene glycol vitamin E succinate as a raw material, wherein the particle size of the powder is 10-100 meshes and accounts for more than 80%.
Specifically, the wax polyethylene glycol vitamin E succinate is obtained by melting, dissolving in a nonpolar solvent, vacuum-pumping and the like.
Preferably, the wax polyethylene glycol vitamin E succinate is obtained by melting, dissolving in a nonpolar solvent, carrying out primary vacuum drying, growing crystals at normal pressure, carrying out secondary vacuum drying and the like; the particle size of the powder is 60-100 meshes and accounts for more than 90%.
The invention provides a preparation method of polyethylene glycol vitamin E succinate powder, which comprises the following steps:
(1) melting: heating the raw material waxy polyethylene glycol vitamin E succinate to 30-60 ℃ to melt;
(2) dissolving with a nonpolar solvent: stirring the melted raw materials and the nonpolar solvent uniformly at the temperature of 30-60 ℃;
(3) vacuum pumping: vacuum-pumping at 10-30 deg.C and vacuum degree of-0.06 MPa-0.098 MPa, and drying to obtain polyethylene glycol vitamin E succinate powder.
Further, in the step (1), the melting time is 0.5-3.0 h; in the step (2), the stirring time is 0.5-3.0 h.
Wherein, in the step (2), the nonpolar solvent is selected from one or more of petroleum ether, n-hexane, cyclohexane, diethyl ether, isopropyl ether, n-butyl ether, pentane, heptane and the like, and is preferably petroleum ether; the weight ratio of the non-polar solvent to the polyethylene glycol vitamin E succinate is 0.3-3.0:1, preferably 1: 1. The nonpolar solvent added in this example is only partially miscible with the product, so addition of large amounts of solvent as in recrystallization is not required.
Preferably, step (3) comprises:
301, one vacuum suction: vacuum pumping is stopped when the material is turbid under the conditions of 10-30 ℃ and-0.06-0.098 Mpa of vacuum degree.
302, growing crystal at normal pressure: growing the crystal for 1-4h at the temperature of 20-30 ℃ and under the normal pressure; the grain growth is to obtain a product with more uniform granularity, and the product can be obtained without grain growth, but a wax-like product can be obtained, and a mixed system of the wax-like product and powder particles can be obtained, so that the particle size is uneven, and the application effect of the product is greatly reduced. The grain size of the product can be more than 90% in 60-100 meshes by grain growing.
303, secondary vacuum suction: vacuum-pumping at 10-30 deg.C and vacuum degree of-0.06 MPa-0.098 MPa, and drying to obtain polyethylene glycol vitamin E succinate powder.
Preferably, in 301: the vacuum degree is-0.07 Mpa to-0.08 Mpa; in 303: the vacuum degree is-0.095 Mpa-0.098 Mpa; in 301 and 303, the temperature of the vacuum suction is preferably 25 ℃.
Preferably, the method provided by the invention comprises the following steps:
(1) melting: heating the raw material waxy polyethylene glycol vitamin E succinate to 30-60 ℃ to melt for 0.5-3.0 h; more preferably: the temperature is 50 ℃ and the time is 2 h.
(2) Dissolving with a nonpolar solvent: uniformly stirring the melted raw materials and a nonpolar solvent at the temperature of 30-60 ℃ for 0.5-3.0h, wherein the nonpolar solvent is selected from one or more of petroleum ether, n-hexane, cyclohexane, diethyl ether, isopropyl ether, n-butyl ether, pentane and heptane, and the weight ratio of the nonpolar solvent to polyethylene glycol vitamin E succinate is 0.3-3.0: 1; more preferably: the temperature is 50 ℃, the time is 1h, the nonpolar solvent is petroleum ether, and the weight ratio of the petroleum ether to the polyethylene glycol vitamin E succinate is 1: 1.
(3) Vacuum pumping: vacuum pumping is carried out at the temperature of 10-30 ℃ and the vacuum degree of-0.07 Mpa to-0.08 Mpa (the early stage of the vacuum degree is small, the crystal form of the material appears, the crystal slowly grows, the vacuum is prevented from being too high, the crystal is dried before appearing, and waxy products with large granularity are avoided) until the material is turbid; then growing the crystal for 1-4h at the temperature of 20-30 ℃ and under the normal pressure; and finally, vacuum-pumping at the temperature of 10-30 ℃ and the vacuum degree of-0.095 Mpa-0.098 Mpa (the later vacuum degree is high, most of crystals are formed, and the solvent is required to be pumped out in high vacuum), and obtaining the polyethylene glycol vitamin E succinate powder after the solvent is pumped out. More preferably: the vacuum pumping temperature is 25 ℃, the crystal growing temperature is 25 ℃, and the crystal growing time is 3 hours.
In addition, the invention also provides application of the polyethylene glycol vitamin E succinate powder obtained by the preparation method, which is used as a raw material of a capsule medicament (mainly used as a solubilizer, and also can be used as an active ingredient, such as vitamin E supplement), and can be also used in tablets and pills. The powder product can be better mixed with other raw materials, has more advantages than the wax product in the aspect of capsule filling, has better solubility than the wax product, and greatly improves the bioavailability of the product.
The polyethylene glycol vitamin E succinate powder product obtained by the invention has consistent and uniform powder particle size and excellent fluidity. The preparation method is economical and environment-friendly, has no raw material loss and is simple to operate. The powder obtained by the method is more convenient to use than wax-like polyethylene glycol vitamin E succinate, has wider application in the practical application process, particularly has excellent fluidity in the aspect of medicine solubilization, not only has more advantages than wax-like products in the aspect of capsule filling, but also has better dissolubility than wax-like products, and greatly improves the bioavailability of the product.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention are described in further detail below.
Example 1
In a 250ml three-necked flask, 50g of waxy polyethylene glycol vitamin E succinate was added, slowly warmed to 50 ℃ and stirred at 50 ℃ for 1h, 50g of petroleum ether (boiling range 60 ℃ to 90 ℃) was added and stirred at 50 ℃ for 2 h.
After stirring, the temperature of the material is reduced to 35 ℃, vacuum concentration is started at the moment, and the vacuum degree is controlled to be about-0.07 Mpa until the temperature is slowly reduced to 25 ℃ and maintained.
When the material in the flask becomes turbid, the vacuum is removed, and the crystal is grown for 3 hours under the condition of normal pressure and at the temperature of 25 ℃ by stirring. After the crystal growth is finished, the temperature is controlled to be 20-30 ℃, the vacuum degree is controlled to be-0.095-0.098 Mpa, until the nonpolar solvent is drained, and finally 49.7g of white powdery polyethylene glycol vitamin E succinate product can be obtained, and the yield is 99.4%. Wherein, the content of the powder is 1.7g below 60 meshes, 27.4g below 60-80 meshes, 18.5g above 80-100 meshes and 2.1g above 100 meshes; the product is mainly concentrated between 60 and 100 meshes and accounts for 92.4 percent.
Example 2
In a 250ml three-necked flask, 50g of waxy polyethylene glycol vitamin E succinate was added, slowly warmed to 50 ℃ and stirred at 40 ℃ for 2h, 100g of cyclohexane was added and stirred at 55 ℃ for 1 h.
After stirring, the temperature of the material was reduced to 35 deg.C, at which time the vacuum was turned on and controlled at about-0.08 MPa until the temperature was slowly reduced to 25 deg.C and maintained.
When the material in the flask becomes turbid, the vacuum is removed, and the crystal is grown for 2h under the condition of normal pressure and at the temperature of 25 ℃ by stirring. After the crystal growth is finished, the temperature is controlled to be 20-30 ℃, the vacuum degree is controlled to be-0.095-0.098 Mpa, until the nonpolar solvent is drained, and finally, 50.0g of white powdery polyethylene glycol vitamin E succinate product can be obtained, and the yield is 100%. Wherein, the content of the powder is 1.3g below 60 meshes, 31.1g below 60-80 meshes, 15.0g above 80-100 meshes and 2.6g above 100 meshes; the product is mainly concentrated between 60 and 100 meshes and accounts for 92.2 percent.
Example 3
In a 1000ml three-necked flask, 350g of waxy polyethylene glycol vitamin E succinate was added, slowly warmed to 50 ℃ and stirred at 50 ℃ for 1h, 350g of petroleum ether (boiling range 60 ℃ to 90 ℃) was added and stirred at 50 ℃ for 1 h.
After stirring, the temperature of the material was reduced to 35 deg.C, at which time the vacuum was turned on and controlled at about-0.08 MPa until the temperature was slowly reduced to 25 deg.C and maintained.
When the material in the flask becomes turbid, the vacuum is removed, and the crystal is grown for 3 hours under the condition of normal pressure and at the temperature of 25 ℃ by stirring. After the crystal growth is finished, the temperature is controlled to be 20-30 ℃, the vacuum degree is controlled to be-0.095-0.098 Mpa, until the nonpolar solvent is drained, and finally, 350.0g of white powdery polyethylene glycol vitamin E succinate product can be obtained, and the yield is 100%. Wherein, the content of the powder is 7.7g below 60 meshes, 131.8g between 60 and 80 meshes, 199.2g between 80 and 100 meshes and 11.3g above 100 meshes; the product is mainly concentrated between 60 meshes and 100 meshes and accounts for 94.6 percent.
As can be seen from the products of examples 1-3, the process yields are essentially 100% with no loss of product; meanwhile, the obtained product has uniform particles, and the product with 60-100 meshes accounts for more than 90 percent.
Comparative example 1
In a 1000ml three-necked flask, 350g of waxy polyethylene glycol vitamin E succinate was added, slowly warmed to 50 ℃ and stirred at 50 ℃ for 1h, 350g of petroleum ether (boiling range 60 ℃ to 90 ℃) was added and stirred at 50 ℃ for 1 h. After stirring, the temperature of the materials is reduced to 20-30 ℃, the vacuum degree is-0.095-0.098 Mpa, until the non-polar solvent is dried, 350.0g of polyethylene glycol vitamin E succinate product can be obtained, and the yield is 100%. Wherein 44.5g below 10 meshes, 121.4g between 10 and 60 meshes, 145.7g between 60 and 80 meshes, 32.1g between 80 and 100 meshes and 6.3g above 100 meshes; the product is mainly concentrated between 10 meshes and 100 meshes and accounts for 84.5 percent; the 60-100 meshes account for 50.8 percent, the product distribution range is obviously enlarged, and the granularity is not uniform.
Comparative example 2
100g of waxy raw material was taken and put into a crusher and crushed for 0.5min, and the product was found to be still waxy and to form a mass of paste. Indicating that the requirements cannot be met by simple physical crushing.
Comparative example 3
50g of wax-like raw material is put into 50g of petroleum ether to be stirred and dissolved, and the mixture is evaporated to dryness to obtain a wax-like product, but a powdery product cannot be obtained.
As can be seen from comparative examples 2 and 3, the use of conventional comminution and conventional evaporation to dryness (recrystallization also gives only waxy product) does not give a pulverulent product. As can be seen from comparative example 1, the grain size of the product obtained through the grain growing process is more uniform.
Application example 1
Putting 95g of water into a 250ml flask, stirring, heating to 60-65 ℃, adding 5g of waxy polyethylene glycol vitamin E succinate product into the flask, keeping the temperature for timing, completely dissolving the final product into the water to form a uniform liquid state, and taking 53 min.
Putting 95g of water into a 250ml flask, starting stirring, heating to 60-65 ℃, adding 5g of powdered polyethylene glycol vitamin E succinate product into the flask, keeping the temperature for timing, completely dissolving the final product into the water to form a uniform liquid, and taking 17 min.
The shorter dissolution time spent by the powder product than the wax product in both comparative experiments indicates that it has better solubility.
Application example 2
100g of waxy polyethylene glycol vitamin E succinate product is mixed with 100g of magnesium stearate (no main medicine is added), and the product is waxy and cannot be uniformly mixed, so that an encapsulating product cannot be prepared finally.
100g of powdery polyethylene glycol vitamin E succinate product is mixed with 100g of magnesium stearate (no main medicine is added), and the two are both powder, so that the two are well mixed, and the fluidity is excellent, and the capsule product can be easily prepared.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (4)
1. A method of making a polyethylene glycol vitamin E succinate powder, the method comprising:
(1) melting: heating the raw material waxy polyethylene glycol vitamin E succinate to 30-60 ℃ to melt;
(2) dissolving with a nonpolar solvent: stirring the melted raw materials and the nonpolar solvent uniformly at the temperature of 30-60 ℃;
(3) vacuum pumping: vacuum pumping is stopped when the material is turbid under the conditions of 10-30 ℃ and vacuum degree of-0.07 Mpa to-0.08 Mpa; then growing the crystal for 1-4h at the temperature of 20-30 ℃ and under the normal pressure; finally, vacuum pumping is carried out at the temperature of 10-30 ℃ and the vacuum degree of-0.095 Mpa-0.098 Mpa, and the polyethylene glycol vitamin E succinate powder is obtained after the solvent is pumped out.
2. The production method according to claim 1, wherein in the step (1), the melting time is 0.5 to 3.0 hours; in the step (2), the stirring time is 0.5-3.0 h.
3. The preparation method according to claim 1, wherein in the step (2), the nonpolar solvent is selected from one or more of petroleum ether, n-hexane, cyclohexane, diethyl ether, isopropyl ether, n-butyl ether, pentane and heptane, and the weight ratio of the nonpolar solvent to the polyethylene glycol vitamin E succinate is 0.3-3.0: 1.
4. The method of manufacturing according to claim 1, comprising:
(1) melting: heating the raw material waxy polyethylene glycol vitamin E succinate to 30-60 ℃ to melt for 0.5-3.0 h;
(2) dissolving with a nonpolar solvent: uniformly stirring the melted raw materials and a nonpolar solvent at the temperature of 30-60 ℃ for 0.5-3.0h, wherein the nonpolar solvent is selected from one or more of petroleum ether, n-hexane, cyclohexane, diethyl ether, isopropyl ether, n-butyl ether, pentane and heptane, and the weight ratio of the nonpolar solvent to the polyethylene glycol vitamin E succinate is 0.3-3.0: 1;
(3) vacuum pumping: vacuum pumping is stopped when the material is turbid under the conditions of 10-30 ℃ and vacuum degree of-0.07 Mpa to-0.08 Mpa; then growing the crystal for 1-4h at the temperature of 20-30 ℃ and under the normal pressure; finally, vacuum pumping is carried out at the temperature of 10-30 ℃ and the vacuum degree of-0.095 Mpa-0.098 Mpa, and the polyethylene glycol vitamin E succinate powder is obtained after the solvent is pumped out.
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