CN115624523B - Preparation method of ibuprofen suspension - Google Patents
Preparation method of ibuprofen suspension Download PDFInfo
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Abstract
The invention discloses a preparation method of ibuprofen suspension, which comprises the following steps: (1) Dry-mixing sucrose and xanthan gum with the formula amount of 7% to obtain a xanthan gum/sucrose dry-mixed material for standby; (2) Adding warm water into a liquid preparation tank, starting stirring, sequentially adding sodium benzoate, pregelatinized starch, sucrose with the formula amount of 93%, glycerol and citric acid, heating and boiling, preserving heat and stirring for 20-40 min, cooling to below 80 ℃, sieving with a 200-mesh sieve, and cooling to below 30 ℃ by cooling water; (3) Taking a xanthan gum/sucrose dry blend, slowly adding the mixture into a batching tank under stirring, and stirring until the mixture is dissolved; (4) Adding lemon yellow, allure red, strawberry essence and polysorbate 80 into a mixing tank, stirring for 10-20 min, and uniformly mixing; (5) Pretreating ibuprofen raw material, sieving with 150 mesh sieve, adding into a batching tank, mixing uniformly, adding water to 1000mL, stirring, and packaging to obtain the final product. The ibuprofen suspension prepared by the invention has stable quality and good drug absorption.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of ibuprofen suspension.
Background
Ibuprofen 2- (-4-isobutylphenyl) propionic acid is a good nonsteroidal antipyretic analgesic anti-inflammatory drug and is clinically used for treating fever and light to moderate pain. Ibuprofen is used as a water-insoluble drug, is hardly dissolved in water and is extremely easily dissolved in absolute ethyl alcohol, so that the in-vivo absorption and bioavailability of the drug are affected.
The medicine in the suspension is dispersed in a liquid dispersion medium in a solid particle state to form a dispersion system, the dispersion degree of medicine particles in the suspension is large, and a physical interface exists between the particles and the dispersion medium, so that the suspension particles have higher surface free energy, and the suspension is in an unstable state. Suspensions of hydrophobic drugs present greater stability problems than hydrophilic drugs.
The solubility of the medicine is related to the specific surface area of the material, the particle size of the medicine is reduced, the effective contact area of the medicine and the medium is increased, and the solubility and the dissolution rate of the medicine are improved. Therefore, the reduction of the particle size of the ibuprofen bulk drug by micronization technology is an effective way, and can effectively improve the dissolution and absorption of the drug. The mechanical crushing method has the defects of high energy consumption, low efficiency, wide product granularity distribution, easy destruction of the medicine structure and the like. Among them, the recrystallization method is an important and effective method for preparing micronized drugs, but the simple recrystallization method cannot obtain stable drug micropowder, so that a certain stabilizer needs to be added to ensure good micronization effect.
In addition, xanthan gum is used as a suspending agent commonly used in ibuprofen suspension, and because of extremely strong hydrophilicity, when the xanthan gum is directly added into water and is insufficiently stirred, water is absorbed by the outer layer to expand into a micelle, and water can be prevented from entering the inner layer, so that the action is influenced. In the prior art, the dry xanthan gum powder and dry powder auxiliary materials such as salt, sugar and the like are often dry mixed and then added for use, so that a certain dissolving effect of the xanthan gum can be ensured. However, the particle size and uniformity of dry powder auxiliary materials such as salt, sugar and the like can directly influence the dry mixing effect of the xanthan gum, and further influence the solubility of the xanthan gum in an aqueous solution, and finally influence the suspension effect.
In summary, how to design a preparation method of ibuprofen suspension, the particle size of ibuprofen powder can be reduced through micronization treatment of ibuprofen bulk drug, and the suspension effect of xanthan gum is promoted by controlling the dry-mixed state of the xanthan gum and other auxiliary materials, so that the problem to be solved urgently at present is solved.
Disclosure of Invention
The invention aims to solve the technical problems, and provides a preparation method of ibuprofen suspension, wherein the ibuprofen raw material medicine is subjected to micronization pretreatment by combining a recrystallization method with the addition of a stabilizer, so that the particle size of medicinal powder can be obviously reduced, and the stability and the availability of the medicine are improved; the sucrose is crushed and sieved by an antistatic screen, and then the crushed sucrose is mixed with the xanthan gum to prepare a dry mixture, so that the dissolving effect of the xanthan gum in water can be promoted.
The invention realizes the above purpose through the following technical scheme:
a method of preparing an ibuprofen suspension comprising the steps of:
(1) Dry-mixing sucrose and xanthan gum with the formula amount of 7% to obtain a xanthan gum/sucrose dry-mixed material for standby;
(2) Adding warm water into a liquid preparation tank, starting stirring, sequentially adding sodium benzoate, pregelatinized starch, sucrose with the formula amount of 93%, glycerol and citric acid, heating and boiling, preserving heat and stirring for 20-40 min, cooling to below 80 ℃, sieving with a 200-mesh sieve, and cooling to below 30 ℃ by cooling water;
(3) Taking a xanthan gum/sucrose dry blend, slowly adding the mixture into a batching tank under stirring, and stirring until the mixture is dissolved;
(4) Adding lemon yellow, allure red, strawberry essence and polysorbate 80 into a mixing tank, stirring for 10-20 min, and uniformly mixing;
(5) Pretreating ibuprofen raw material, adding the ibuprofen raw material into a batching tank, uniformly mixing, adding water to a constant volume of 1000mL, stirring, and encapsulating to obtain an ibuprofen suspension finished product.
The pretreatment method of the ibuprofen bulk drug comprises the following steps:
the method comprises the steps of taking ibuprofen raw material medicines, putting the ibuprofen raw material medicines into absolute ethyl alcohol to be completely dissolved to obtain an ibuprofen ethanol solution, slowly dripping the ibuprofen ethanol solution into an aqueous solution containing a stabilizer at the temperature of 1-6 ℃, starting stirring, centrifuging, filtering with a microporous filter membrane (0.3-5 mu m), washing, drying, crushing, and sieving with a 150-mesh sieve.
The preparation method of the stabilizer comprises the following steps:
s1, uniformly mixing 4-dodecylphenol with water and sodium carbonate, then dripping diglycidyl ether under the stirring condition of 100-110 ℃, and reacting for 1-3 h after dripping;
s2, uniformly mixing polyethylene glycol (PEG 1000, PEG2000, PEG4000 or PEG 6000), water and tertiary amine, slowly dripping the mixture into the product obtained in the step S1 under the stirring condition of 105-120 ℃, and reacting for 3-5 hours after dripping, thus obtaining the stabilizer.
Preferably, in the pretreatment step of the ibuprofen bulk drug, the mass ratio of the ibuprofen bulk drug to the absolute ethyl alcohol to the stabilizer to the water is 1: (22-30): (0.3-0.6): (200-400), the dropping speed of the aqueous solution containing the stabilizer is 2-5 ml/min, and the stirring speed is 800-1000 r/min.
Preferably, the molar ratio of the 4-dodecylphenol, the diglycidyl ether and the polyethylene glycol is 1: (1.2-1.4): (1.1-1.2), in the step S1, the mass ratio of 4-dodecylphenol, water and sodium carbonate is 1: (5-15): (0.2-0.3), in the step S2, the mass ratio of polyethylene glycol, water and tertiary amine is 1: (3-5): (0.1-0.2).
The invention also provides an antistatic screen in the preparation method of the ibuprofen suspension, wherein the sucrose with the formula amount of 7% is obtained by crushing (600-1000 r/min) sucrose raw materials and screening with an antistatic screen with the thickness of 0.075-0.12 mm, the antistatic screen is obtained by blending synthetic fibers (nylon 6) and antistatic agents and then shaping through melt spinning (the melting temperature is 240-250 ℃), and the addition amount of the antistatic agents is 0.5-2% of the total mass of the synthetic fibers.
Preferably, the preparation method of the antistatic agent comprises the following steps:
A. drying talcum powder, adding the talcum powder into ethanol solution of tetraethoxy divinyl disiloxane, stirring and reacting for 40-60 min at 80-90 ℃, and filtering and drying to obtain a product 1;
B. esterification reaction (reaction at 108-115 ℃ for 4-6 h) is carried out on ethoxyacetic acid and unsaturated fatty alcohol under the catalysis of concentrated sulfuric acid (the addition amount is 2-4% of the total mass of reactants), and polyaddition reaction (reaction at 65-75 ℃ for 2-3 h) is carried out on the obtained esterified product and the treated talcum powder under the condition of an initiator (tert-butyl hydroperoxide/sodium metabisulfite, azodiisoheptonitrile or diisopropyl peroxydicarbonate) and the addition amount is 0.3-0.5% of the total mass of reactants, so that a product 2 is obtained;
C. the ethanolamine and unsaturated fatty acid are subjected to esterification reaction (reaction for 3-5 h at 105-112 ℃) under the catalysis of concentrated sulfuric acid (the addition amount is 1-3% of the total mass of reactants), the obtained esterification product and the product 2 are subjected to polyaddition reaction (reaction for 3-4 h at 70-80 ℃) under the condition that the initiator (tert-butyl hydroperoxide/sodium metabisulfite, azodiisoheptanenitrile or diisopropyl peroxydicarbonate) is added, and the addition amount is 0.3-0.5% of the total mass of reactants, so that the antistatic agent finished product is obtained.
Preferably, the mol ratio of the tetraethoxy divinyl disiloxane, the unsaturated fatty alcohol, the unsaturated fatty acid and the unsaturated polyoxyethylene ether is 1: (0.9-1): (0.9-1): (0.8-1).
In the step A, the mass ratio of tetraethoxydivinyl disiloxane to ethanol is 1: (4-8), the mass of the tetraethoxydivinyl disiloxane is 1-5% of that of the talcum powder.
In the step B, the mol ratio of the ethoxyacetic acid to the unsaturated fatty alcohol is (1.1-1.2): 1, wherein the unsaturated fatty alcohol is 9-decaen-1-ol, 9-octadecen-1-ol or cis-11-hexadecen-1-ol.
In the step C, the mol ratio of the ethanolamine to the unsaturated fatty acid is (1.1-1.2): 1, wherein the unsaturated fatty acid is acrylic acid, octenoic acid or undecylenic acid.
The invention also provides a hydrophilic honeycomb filler in the preparation method of the ibuprofen suspension, which is characterized in that after the xanthan gum/sucrose dry blend is stirred and dissolved in the preparation process step (3) of the ibuprofen suspension, the hydrophilic honeycomb filler is added to continue stirring for 20-30 min (the stirring rate is 400-600 r/min); the hydrophilic honeycomb filler is prepared by spraying hydrophilic paint on the surface of the honeycomb filler. The honeycomb filler is made of PP, the specification is phi 10-50 mm, and the thickness of the honeycomb filler is 0.3-0.5 mm.
Preferably, the hydrophilic coating comprises the following preparation raw materials in parts by mass: 40-50 parts of water-based epoxy resin, 35-45 parts of room temperature curing water-based epoxy curing agent, 6-14 parts of hydrophilic polymer and 3-5 parts of inorganic filler (one or more of calcium carbonate, mica powder, barite and clay), wherein the hydrophilic polymer is obtained by adding and esterifying acetic acid and 1, 2-epoxy-9-sunflower alkene and then carrying out hydrosilylation with tri-tert-butyl silane.
Preferably, the preparation method of the hydrophilic polymer comprises the following steps:
adding acetic acid, an organic acid chromium salt catalyst (chromium acetate, the addition amount of which is 1-3 mol equivalent) and toluene (the addition amount of which is 1-3 times of the mass of acetic acid) into a reaction kettle, uniformly mixing, slowly adding 1, 2-epoxy-9-decene, stirring and reacting for 5-8 hours at 100-120 ℃, cooling, evaporating the solvent, distilling under reduced pressure to obtain a polyoxyethylene acetate type product, uniformly mixing the polyoxyethylene acetate type product with toluene (the addition amount of which is 1.5-4 times of the mass of the polyoxyethylene acetate type product) and a platinum catalyst (the addition amount of which is 5-30 ppm based on platinum), slowly adding tri-tert-butyl silane, stirring and reacting for 4-6 hours at 80-90 ℃, and evaporating the solvent to obtain a hydrophilic polymer, wherein the molar ratio of the acetic acid, the 1, 2-epoxy-9-decene and the tri-tert-butyl silane is 1: (5-20): (1-5).
The invention has the beneficial effects that:
(1) According to the invention, the ibuprofen bulk drug is subjected to micronization treatment by a recrystallization process, so that the medicinal powder with small particle size and uniform distribution can be obtained, and the suspension effect of the ibuprofen suspension is promoted.
(2) In the invention, a stabilizer is added in the recrystallization process of ibuprofen to promote the dispersion and stability of crystal particles, the stabilizer is prepared by condensing diglycidyl ether with 4-dodecylphenol and polyethylene glycol respectively, and simultaneously, a lipophilic chain segment containing phenyl and a polyethylene glycol hydrophilic chain segment are introduced to promote the crystallization stability of ibuprofen.
(3) According to the invention, after the sucrose raw material is crushed and sieved by a sieve with 0.075-0.12 mm, the crushed sucrose raw material and xanthan gum are prepared into a dry blend, so that the dry blend effect of the xanthan gum can be promoted, and the solubility of the xanthan gum in water is promoted, so that the xanthan gum can be rapidly dissolved without high-speed shearing.
(4) Because the particle size of the sucrose to be screened is smaller, static electricity is easy to generate among sucrose particles to influence the screening effect, the invention adopts the antistatic screen to screen, the screen contains the antistatic agent, the antistatic agent is prepared by respectively grafting the hydrophilic chain segment containing ethoxy and the hydrophilic chain segment containing amino after the talcum powder is subjected to silanization treatment, and the antistatic effect is obvious.
(5) The dry-mixed effect of the xanthan gum is improved, and then the xanthan gum is quickly dissolved in water, so that the viscosity of a liquid medicine system is quickly increased to generate viscosity mutation, the system is unstable, and under the condition of micronization of the ibuprofen, the stability of the ibuprofen powder in the system is also reduced, so that the viscosity mutation effect needs to be eliminated, but the simple shearing effect is not obvious, and therefore, after the dry-mixed mixture of the xanthan gum and the sucrose is added, hydrophilic honeycomb filler is also added to stir, the viscosity mutation system is damaged, and the stability of the liquid medicine is ensured.
(6) The hydrophilic honeycomb filler is prepared by spraying hydrophilic paint on the surface of the honeycomb filler, wherein the hydrophilic paint contains hydrophilic polymers, which are obtained by adding acetic acid and 1, 2-epoxy-9-sunflower alkene for esterification and then adding tri-tert-butyl silane for hydrosilylation, and the obtained polymers contain polyoxyethylene hydrophilic main chains and epoxy group-containing long-chain hydrocarbon branched chains, so that the hydrophilic honeycomb filler can be compatible with hydrophilicity and compatibility in epoxy resin, and the hydrophilic effect of the hydrophilic honeycomb filler is promoted.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The ibuprofen suspension in this example comprises the following raw materials in mass: 20g of ibuprofen, 13g of pregelatinized starch, 2g of xanthan gum, 100g of glycerin, 300g of sucrose, 2g of citric acid, 2g of sodium benzoate, 0.5g of polysorbate 80, 0.02g of lemon yellow, 0.01g of allure red and 3g of strawberry essence, and the volume of purified water is fixed to 1000mL.
The preparation method of the ibuprofen suspension comprises the following steps:
(1) Dry-mixing sucrose and xanthan gum with the formula amount of 7% to obtain a xanthan gum/sucrose dry-mixed material for standby;
(2) Adding warm water into the liquid preparation tank, stirring, sequentially adding sodium benzoate, pregelatinized starch, sucrose with the formula amount of 93%, glycerol and citric acid, heating to boil, maintaining the temperature and stirring for 30min, cooling to below 80deg.C, sieving with 200 mesh sieve, and cooling to below 30deg.C with cooling water;
(3) Taking a xanthan gum/sucrose dry blend, slowly adding the mixture into a batching tank under stirring, and stirring until the mixture is dissolved;
(4) Adding lemon yellow, allure red, strawberry essence and polysorbate 80 into a mixing tank, stirring for 10min, and uniformly mixing;
(5) Mechanically crushing the ibuprofen raw material medicine (1000 r/min), sieving with a 150-mesh sieve, adding into a material mixing tank, uniformly mixing, adding water to a constant volume of 1000mL, stirring, and encapsulating to obtain a finished product.
Example 2
The present example provides a method for pretreatment of ibuprofen bulk drug, replacing mechanical pulverization in example 1, comprising the following steps:
the method comprises the steps of taking ibuprofen raw material medicines, placing the ibuprofen raw material medicines in absolute ethyl alcohol to be completely dissolved to obtain an ibuprofen ethanol solution, dripping the ibuprofen ethanol solution into an aqueous solution containing a stabilizer at the speed of 2ml/min at the temperature of 1 ℃, starting stirring (800 r/min), centrifuging, carrying out suction filtration by a microporous filter membrane (3 mu m), washing, drying, crushing, and sieving with a 150-mesh sieve. The mass ratio of the ibuprofen bulk drug to the absolute ethyl alcohol to the stabilizer to the water is 1:22:0.3:200.
the preparation method of the stabilizer comprises the following steps:
s1, according to the mass ratio of 1:5:0.2, uniformly mixing 4-dodecylphenol, water and sodium carbonate, then dripping diglycidyl ether under the stirring condition of 100 ℃, and reacting for 1h after dripping;
s2, according to the mass ratio of 1:3: and 0.1, uniformly mixing polyethylene glycol (PEG 1000), water and tertiary amine, then slowly dripping the mixture into the product obtained in the step S1 under the stirring condition of 105 ℃, and reacting for 3 hours after dripping is finished to obtain the stabilizer.
Wherein, the mol ratio of the 4-dodecylphenol, the diglycidyl ether and the polyethylene glycol is 1:1.2:1.1.
the remainder was the same as in example 1.
Example 3
On the basis of the embodiment 2, the embodiment also provides an antistatic screen in the preparation method of the ibuprofen suspension, wherein the sucrose with the formula amount of 7% is obtained by crushing (600 r/min) a sucrose raw material and screening with a 0.12mm antistatic screen, the antistatic screen is obtained by blending nylon 6 and an antistatic agent and then performing melt spinning (the melting temperature is 240 ℃) molding, and the addition amount of the antistatic agent is 0.5% of the total mass of the nylon 6.
The preparation method of the antistatic agent comprises the following steps:
A. after the talcum powder is dried, the talcum powder is added with the following components in percentage by mass: 4, stirring and reacting in ethanol solution of tetraethoxy divinyl disiloxane at 80 ℃ for 40min, and filtering and drying to obtain a product 1; the mass of the tetraethoxydivinyl disiloxane is 1% of that of the talcum powder;
B. the molar ratio was set to 1.1:1 ethoxyacetic acid and unsaturated fatty alcohol (9-decaen-1-ol) are subjected to esterification reaction for 4 hours under the catalysis condition of concentrated sulfuric acid (the addition amount is 2 percent of the total mass of reactants) and at the temperature of 108 ℃, and the obtained esterified product and the treated talcum powder are subjected to polyaddition reaction for 2 hours under the conditions of an initiator (tert-butyl hydroperoxide/sodium metabisulfite, the addition amount is 0.3 percent of the total mass of reactants) and at the temperature of 65 ℃ to obtain a product 2;
C. the molar ratio was set to 1.1:1 and unsaturated fatty acid (acrylic acid) are subjected to esterification reaction for 3 hours under the catalysis condition of concentrated sulfuric acid (the addition amount is 1% of the total mass of reactants) and at 105 ℃, and the obtained esterification product, the product 2 and unsaturated polyoxyethylene ether are subjected to polyaddition reaction for 3 hours under the conditions of an initiator (azodiisoheptanenitrile, the addition amount is 0.3% of the total mass of reactants) and at 70 ℃ to obtain an antistatic agent finished product.
Wherein, the mol ratio of the tetraethoxy divinyl disiloxane, the unsaturated fatty alcohol, the unsaturated fatty acid and the unsaturated polyoxyethylene ether is 1:0.9:0.9:0.8.
the remainder was the same as in example 2.
Example 4
On the basis of the embodiment 3, the embodiment provides a hydrophilic honeycomb filler in the preparation method of the ibuprofen suspension, and after the xanthan gum/sucrose dry blend is stirred and dissolved in the preparation process step (3) of the ibuprofen suspension, the hydrophilic honeycomb filler is added to continuously stir for 20min at the speed of 400 r/min; the hydrophilic honeycomb filler is prepared by spraying hydrophilic paint on the surface of the honeycomb filler. The honeycomb filler is made of PP, has the specification of phi 10mm and the thickness of 0.3mm
The hydrophilic coating comprises the following preparation raw materials in parts by mass: 40 parts of aqueous epoxy resin, 35 parts of room temperature curing aqueous epoxy curing agent, 6 parts of hydrophilic polymer and 3 parts of inorganic filler (calcium carbonate).
The preparation method of the hydrophilic polymer comprises the following steps:
adding acetic acid, chromium acetate catalyst (1% molar equivalent) and toluene (equal to acetic acid in mass) into a reaction kettle, uniformly mixing, slowly adding 1, 2-epoxy-9-sunflower alkene, stirring at 100 ℃ for reacting for 5 hours, cooling, evaporating solvent, distilling under reduced pressure to obtain a polyoxyethylene acetate type product, uniformly mixing the polyoxyethylene acetate type product with toluene (1.5 times of the polyoxyethylene acetate type product in mass) and a platinum catalyst (the addition amount of the platinum catalyst is 5ppm based on platinum), slowly adding tri-tert-butyl silane, stirring at 80 ℃ for reacting for 4 hours, and evaporating solvent to obtain a hydrophilic polymer, wherein the molar ratio of the acetic acid to the 1, 2-epoxy-9-sunflower alkene to the tri-tert-butyl silane is 1:5:1.
the remainder was the same as in example 3.
Example 5
The embodiment provides a preparation method of ibuprofen suspension, wherein the method for preprocessing ibuprofen bulk drug comprises the following steps:
the method comprises the steps of taking ibuprofen raw material medicines, putting the ibuprofen raw material medicines into absolute ethyl alcohol to be completely dissolved to obtain ibuprofen ethanol solution, dripping the ibuprofen ethanol solution into aqueous solution containing a stabilizer at the speed of 3.5ml/min at the temperature of 3 ℃, starting stirring (900 r/min), centrifuging, filtering with a microporous filter membrane, washing, drying, crushing, and sieving with a 150-mesh sieve. The mass ratio of the ibuprofen bulk drug to the absolute ethyl alcohol to the stabilizer to the water is 1:26:0.45:300.
the preparation method of the stabilizer comprises the following steps:
s1, according to the mass ratio of 1:10:0.25, uniformly mixing 4-dodecylphenol, water and sodium carbonate, then dripping diglycidyl ether under the condition of stirring at 105 ℃, and reacting for 2 hours after dripping;
s2, according to the mass ratio of 1:4: and 0.15, uniformly mixing polyethylene glycol (PEG 2000), water and tertiary amine, then slowly dripping the mixture into the product obtained in the step S1 under the stirring condition at 112 ℃, and reacting for 4 hours after dripping is finished to obtain the stabilizer.
Wherein, the mol ratio of the 4-dodecylphenol, the diglycidyl ether and the polyethylene glycol is 1:1.3:1.15.
the embodiment also provides an antistatic screen in the preparation method of the ibuprofen suspension, wherein the sucrose with the formula amount of 7% is obtained by crushing (800 r/min) a sucrose raw material and screening with a 0.10mm antistatic screen, the antistatic screen is obtained by blending nylon 6 and an antistatic agent and then forming through melt spinning (the melting temperature is 245 ℃), and the addition amount of the antistatic agent is 0.12% of the total mass of the nylon 6.
The preparation method of the antistatic agent comprises the following steps:
A. after the talcum powder is dried, the talcum powder is added with the following components in percentage by mass: 6, stirring and reacting in ethanol solution of tetraethoxy divinyl disiloxane at 85 ℃ for 50min, and filtering and drying to obtain a product 1; the mass of the tetraethoxydivinyl disiloxane is 3% of that of the talcum powder;
B. the molar ratio was set to 1.15:1 and unsaturated fatty alcohol (9-octadecen-1-ol) are subjected to esterification reaction (reaction for 5h at 110 ℃ C.) under the catalysis of concentrated sulfuric acid (the addition amount is 3% of the total mass of reactants), and the obtained esterified product and the treated talcum powder are subjected to polyaddition reaction (reaction for 2.5h at 70 ℃ C.) under the condition of an initiator (azodiisoheptanenitrile, the addition amount is 0.4% of the total mass of reactants) to obtain a product 2;
C. the molar ratio was set to 1.15:1 and unsaturated fatty acid (octenoic acid) are subjected to esterification reaction (reaction for 4 hours at 108 ℃) under the catalysis of concentrated sulfuric acid (the addition amount is 2% of the total mass of reactants), and the obtained esterification product, the product 2 and unsaturated polyoxyethylene ether are subjected to polyaddition reaction (reaction for 3.5 hours at 75 ℃) under the condition of an initiator (diisopropyl peroxydicarbonate, the addition amount is 0.4% of the total mass of reactants), so as to obtain the antistatic agent finished product.
Wherein, the mol ratio of the tetraethoxy divinyl disiloxane, the unsaturated fatty alcohol, the unsaturated fatty acid and the unsaturated polyoxyethylene ether is 1:0.95:0.95:0.9.
the embodiment also provides a hydrophilic honeycomb filler in the preparation method of the ibuprofen suspension, which is characterized in that after the xanthan gum/sucrose dry blend is stirred and dissolved in the preparation process step (3) of the ibuprofen suspension, the hydrophilic honeycomb filler is added to continue stirring for 25min at the speed of 500 r/min; the hydrophilic honeycomb filler is prepared by spraying hydrophilic paint on the surface of the honeycomb filler. The specification of the honeycomb filler is phi 30mm, and the thickness of the sheet is 0.4mm.
The hydrophilic coating comprises the following preparation raw materials in parts by mass: 45 parts of aqueous epoxy resin, 40 parts of room temperature curing aqueous epoxy curing agent, 10 parts of hydrophilic polymer and 4 parts of inorganic filler (clay).
The preparation method of the hydrophilic polymer comprises the following steps:
adding acetic acid, chromium acetate catalyst (2 mol equivalent) and toluene (the addition amount is 2 times of the mass of the acetic acid) into a reaction kettle, uniformly mixing, slowly adding 1, 2-epoxy-9-sunflower alkene, stirring at 110 ℃ for reaction for 6 hours, cooling, evaporating solvent, distilling under reduced pressure to obtain a polyoxyethylene acetate type product, uniformly mixing the polyoxyethylene acetate type product with toluene (the addition amount is 2.5 times of the mass of the polyoxyethylene acetate type product) and platinum catalyst (the addition amount is 20ppm based on platinum), slowly adding tri-tert-butyl silane, stirring at 85 ℃ for reaction for 5 hours, and evaporating solvent to obtain a hydrophilic polymer, wherein the molar ratio of the acetic acid, the 1, 2-epoxy-9-sunflower alkene and the tri-tert-butyl silane is 1:12:3.
the remainder was the same as in example 4.
Example 6
The embodiment provides a preparation method of ibuprofen suspension, wherein the method for preprocessing ibuprofen bulk drug comprises the following steps:
the method comprises the steps of taking ibuprofen raw material medicines, putting the ibuprofen raw material medicines into absolute ethyl alcohol to be completely dissolved to obtain ibuprofen ethanol solution, dripping the ibuprofen ethanol solution into an aqueous solution containing a stabilizer at a speed of 5ml/min at a temperature of 6 ℃, starting stirring (1000 r/min), centrifuging, carrying out suction filtration by a microporous filter membrane, washing, drying, crushing, and sieving with a 150-mesh sieve. The mass ratio of the ibuprofen bulk drug to the absolute ethyl alcohol to the stabilizer to the water is 1:30:0.6:400.
the preparation method of the stabilizer comprises the following steps:
s1, according to the mass ratio of 1:15:0.3, uniformly mixing 4-dodecylphenol, water and sodium carbonate, then dripping diglycidyl ether under the stirring condition of 110 ℃, and reacting for 3 hours after dripping;
s2, according to the mass ratio of 1:5: and 0.2, uniformly mixing polyethylene glycol (PEG 6000), water and tertiary amine, then slowly dripping the mixture into the product obtained in the step S1 under the stirring condition of 120 ℃, and reacting for 5 hours after dripping is finished, thus obtaining the stabilizer.
Wherein, the mol ratio of the 4-dodecylphenol, the diglycidyl ether and the polyethylene glycol is 1:1.4:1.2.
the embodiment also provides an antistatic screen in the preparation method of the ibuprofen suspension, wherein the sucrose with the formula amount of 7% is obtained by crushing (1000 r/min) a sucrose raw material and screening with an antistatic screen with the thickness of 0.075mm, the antistatic screen is obtained by blending nylon 6 and an antistatic agent and then forming through melt spinning (the melting temperature is 250 ℃), and the addition amount of the antistatic agent is 2% of the total mass of the nylon 6.
The preparation method of the antistatic agent comprises the following steps:
A. after the talcum powder is dried, the talcum powder is added with the following components in percentage by mass: 8, stirring and reacting in ethanol solution of tetraethoxy divinyl disiloxane at 90 ℃ for 60min, and filtering and drying to obtain a product 1; the mass of the tetraethoxydivinyl disiloxane is 5% of that of the talcum powder;
B. the molar ratio was set to 1.2:1 ethoxyacetic acid and unsaturated fatty alcohol (cis-11-hexadecen-1-ol) are subjected to esterification reaction (reaction at 115 ℃ for 6 hours) under the catalysis of concentrated sulfuric acid (the addition amount is 4% of the total mass of reactants), and the obtained esterified product and the treated talcum powder are subjected to polyaddition reaction (reaction at 75 ℃ for 3 hours) under the condition of an initiator (diisopropyl peroxydicarbonate, the addition amount of which is 0.5% of the total mass of reactants) to obtain a product 2;
C. the molar ratio was set to 1.2: and (3) carrying out esterification reaction (reaction at 112 ℃ for 5 hours) on the ethanolamine and unsaturated fatty acid (undecylenic acid) under the catalysis of concentrated sulfuric acid (the addition amount is 3% of the total mass of reactants), and carrying out polyaddition reaction (reaction at 80 ℃ for 4 hours) on the obtained esterified product, the product 2 and unsaturated polyoxyethylene ether under the condition of an initiator (tert-butyl hydroperoxide/sodium metabisulfite, wherein the addition amount is 0.5% of the total mass of reactants), thereby obtaining the antistatic agent finished product.
Wherein, the mol ratio of the tetraethoxy divinyl disiloxane, the unsaturated fatty alcohol, the unsaturated fatty acid and the unsaturated polyoxyethylene ether is 1:1:1:1.
the embodiment also provides a hydrophilic honeycomb filler in the preparation method of the ibuprofen suspension, which is characterized in that after the xanthan gum/sucrose dry blend is stirred and dissolved in the preparation process step (3) of the ibuprofen suspension, the hydrophilic honeycomb filler is added to continue stirring for 30min at the speed of 600 r/min; the hydrophilic honeycomb filler is prepared by spraying hydrophilic paint on the surface of the honeycomb filler. The specification of the honeycomb filler is phi 50mm, and the thickness of the sheet is 0.5mm.
The hydrophilic coating comprises the following preparation raw materials in parts by mass: 50 parts of aqueous epoxy resin, 45 parts of room temperature curing aqueous epoxy curing agent, 14 parts of hydrophilic polymer and 5 parts of inorganic filler (comprising calcium carbonate and clay in equal mass ratio).
The preparation method of the hydrophilic polymer comprises the following steps:
adding acetic acid, chromium acetate catalyst (the addition amount is 3 mol equivalent) and toluene (the addition amount is 3 times of the mass of acetic acid) into a reaction kettle, uniformly mixing, slowly adding 1, 2-epoxy-9-decene, stirring at 120 ℃ for reaction for 8 hours, cooling, evaporating solvent, distilling under reduced pressure to obtain a polyoxyethylene acetate type product, uniformly mixing the polyoxyethylene acetate type product with toluene (the addition amount is 4 times of the mass of the polyoxyethylene acetate type product) and platinum catalyst (the addition amount is 30 ppm) and slowly adding tri-tert-butyl silane, stirring at 90 ℃ for reaction for 6 hours, and evaporating solvent to obtain a hydrophilic polymer, wherein the molar ratio of the acetic acid, the 1, 2-epoxy-9-decene and the tri-tert-butyl silane is 1:20:5.
the remainder was the same as in example 4.
Comparative example 1
The difference between this comparative example and example 4 is that in the pretreatment method of ibuprofen bulk drug, the stabilizer is polyethylene glycol.
Comparative example 2
The difference between the comparative example and the example 4 is that in the pretreatment method of the ibuprofen raw material, the mass ratio of the ibuprofen raw material to the absolute ethyl alcohol to the stabilizer to the water is 1:22:0.2:200.
comparative example 3
The difference between the comparative example and the example 4 is that in the pretreatment method of the ibuprofen raw material, the mass ratio of the ibuprofen raw material to the absolute ethyl alcohol to the stabilizer to the water is 1:22:0.7:200.
comparative example 4
The comparative example differs from example 5 in that the formulation of 7% sucrose was obtained from the sucrose starting material by crushing and sieving with a 0.10mm conventional nylon 6 sieve.
Comparative example 5
The comparative example is different from example 5 in that the antistatic agent was added in an amount of 0.3% of the total mass of nylon 6 in the antistatic mesh.
Comparative example 6
The comparative example is different from example 5 in that the antistatic agent was added in an amount of 2.2% of the total mass of nylon 6 in the antistatic mesh.
Comparative example 7
The difference between this comparative example and example 5 is that the antistatic agent was prepared without talc and the talc treated in step B was changed to tetraethoxydivinyl disiloxane.
Comparative example 8
This comparative example differs from example 6 in that the hydrophilic honeycomb filler was replaced with an untreated ordinary PP honeycomb filler.
Comparative example 9
The comparative example differs from example 6 in that the hydrophilic coating does not contain a hydrophilic polymer.
Comparative example 10
The present comparative example is different from example 6 in that the hydrophilic coating material does not contain an inorganic filler.
1. Basic Properties of ibuprofen suspensions prepared according to the present invention
The ibuprofen suspensions prepared in examples 1-6 of the present invention are orange suspensions, sweet tasting and having the fragrance of a flavoring agent. The pH value is 3.5-4.5, and the relative density is 1.090-1.200.
Sedimentation volume ratio: 0123-kou according to the four general rules of the 2020 edition of Chinese pharmacopoeiaThe sedimentation volume ratio was measured as required for the suspension formulations to be taken, and the objective object was ibuprofen suspensions prepared in examples 1 to 6 of the present invention and comparative examples 1 to 10. The specific method comprises the following steps: 50ml of the sample was measured with a plug cylinder, sealed, and shaken vigorously for 1 minute, and the starting height H of the suspension was recorded 0 Standing for 3 hours, recording the final height H of the suspension, and calculating according to the following formula: sedimentation volume ratio = H/H 0 。
TABLE 1
From the results, each ibuprofen suspension prepared by the invention meets the pharmacopoeia requirements. The ibuprofen suspensions prepared in examples 4, 5 and 6 of the invention are better, and the sedimentation volume ratio is 0.98.
Compared with example 1, the ibuprofen in example 2 is subjected to recrystallization pretreatment, so that micronized ibuprofen is obtained, and the sedimentation volume ratio of the suspension is improved. Based on the embodiment 2, the sucrose raw material is screened and then dry-mixed with xanthan gum in the embodiment 3, so that the suspension effect of the xanthan gum is improved, but the xanthan gum is quickly dissolved in water after the dry-mixed effect is improved, so that the viscosity of a liquid medicine system is quickly increased to generate viscosity mutation, the system is unstable, and the stability of ibuprofen powder in the system is also reduced under the condition of micronization of the ibuprofen, so that the sedimentation volume ratio of the final suspension is not obviously improved. On the basis of the embodiment 3, after the xanthan gum/sucrose dry blend is added, a hydrophilic honeycomb filler is also added for stirring, so that the viscosity mutation system is lightened, the sedimentation volume ratio of the suspension is obviously improved, and a good suspension effect is shown.
Wherein, comparative examples 1 to 3 respectively changed the type and amount of the stabilizer in the recrystallization process, comparative examples 4 to 7 respectively changed the screen type of sucrose screening and the preparation method of the antistatic agent, and comparative examples 8 to 10 respectively changed the preparation raw materials of the hydrophilic honeycomb filler, and as a result, the sedimentation volume ratio of the ibuprofen suspension was reduced to different extents.
2. Particle size distribution of ibuprofen micropowder obtained by pretreatment
The ibuprofen crude drug of the present invention, the ibuprofen powder obtained by pulverizing example 1, the ibuprofen powders obtained by pretreatment of examples 4 to 6 and comparative examples 1 to 3 were subjected to particle size measurement by using an image particle distributor (BT-1600), and 50% of the obtained ibuprofen powder was subjected to the particle size D50 results are shown in Table 2.
TABLE 2
As can be seen from Table 2, compared with the ibuprofen bulk drug and example 1, the micronized ibuprofen obtained by carrying out recrystallization pretreatment on the ibuprofen in examples 4-6 of the invention has smaller particle size distribution which is not more than 10.5 mu m, and can obviously improve the stability of the suspension.
Comparative examples 1,2 and 3 changed the type and amount of stabilizer used in the recrystallization process, respectively, as compared with example 4, and as a result, the particle size of ibuprofen was increased, and the stability of suspension was lowered.
2. The volume resistivity of the antistatic screen of the invention and the water-solubility of xanthan gum
1. Determination of volume resistivity of antistatic Screen: the resistivities of the antistatic sieves obtained in examples 4 to 6 and comparative examples 4 to 7 of the present invention were measured using a PC68 type digital high resistance meter. The results are shown in Table 3.
2. Water-soluble properties of xanthan gum: the liquid medicine obtained after adding the dry-mixed mixture of the xanthan gum and the sucrose in the step (3) of the ibuprofen suspension preparation process of the examples 1, 3-6 and the comparative examples 4-10 is stirred at 600r/min, and the dissolution condition of the xanthan gum and the viscosity change values of the liquid medicine within 5min, 30min, 2h and 24h are recorded. The results are shown in Table 4.
TABLE 3 Table 3
As can be seen from Table 3, compared with the common nylon 6 screen of comparative example 4, the volume resistivity of the antistatic screens obtained in examples 4 to 6 of the present invention was reduced by 5 orders of magnitude, showing a good antistatic effect.
Comparative examples 5, 6 and 7 each changed the preparation raw materials of the antistatic agent, and as a result, the volume resistivity of the mesh was increased and the antistatic effect was reduced.
TABLE 4 Table 4
As can be seen from Table 4, compared with example 1, the dissolution rate of xanthan gum in the liquid medicine is obviously accelerated by sieving sucrose and then preparing xanthan gum/sucrose dry blend with xanthan gum in examples 3 to 6 of the invention.
In example 3, the dissolution rate was increased, but the viscosity was increased by 28cP within 5min, and a significant mutation was generated. In the embodiments 4 to 6, the xanthan gum/sucrose dry blend is added into the liquid preparation tank, and meanwhile, the hydrophilic honeycomb filler is added for stirring, so that the viscosity mutation is destroyed, and the viscosity value of the liquid medicine is stably increased.
Comparative examples 4 to 7 changed the screen type of sucrose screening and the preparation method of the antistatic agent, respectively, compared with example 5, so that screening of sucrose raw material was affected, and finally, the dissolution rate of xanthan gum was slowed down.
Compared with the example 6, the comparative examples 8 to 10 respectively change the preparation raw materials of the hydrophilic honeycomb filler, so that the dry mixture of the xanthan gum and the sucrose generates a certain degree of mutation after being added, and the stability of the liquid medicine is affected.
The invention has the beneficial effects that: according to the preparation method of the ibuprofen suspension, disclosed by the invention, the ibuprofen bulk drug is subjected to micronization pretreatment by combining a recrystallization method with the addition of the stabilizer, so that the particle size of medicinal powder can be obviously reduced, and the stability and the availability of the drug can be improved; the sucrose is crushed and sieved by an antistatic screen, and then the crushed sucrose is mixed with the xanthan gum to prepare a dry mixture, so that the dissolving effect of the xanthan gum in water can be promoted.
Finally, it should be noted that the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited to the above-mentioned embodiment, but may be modified or some of the technical features thereof may be replaced by other technical solutions described in the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. A pretreatment method of ibuprofen bulk drug is characterized in that: the method comprises the following steps:
placing the ibuprofen raw material medicine into absolute ethyl alcohol to be completely dissolved to obtain an ibuprofen ethanol solution, slowly dripping the ibuprofen ethanol solution into an aqueous solution containing a stabilizing agent at the temperature of 1-6 ℃, starting stirring, centrifuging, filtering with a microporous filter membrane, washing, drying, crushing, and sieving with a 150-mesh sieve to obtain the ibuprofen ethanol solution;
the preparation method of the stabilizer comprises the following steps:
s1, uniformly mixing 4-dodecylphenol with water and sodium carbonate, then dripping diglycidyl ether under the stirring condition of 100-110 ℃, and reacting for 1-3 h after dripping;
s2, uniformly mixing polyethylene glycol, water and tertiary amine, then slowly dripping the mixture into the product obtained in the step S1 under the stirring condition of 105-120 ℃, and reacting for 3-5 h after dripping is finished to obtain the stabilizer;
in the pretreatment step of the ibuprofen bulk drug, the mass ratio of the ibuprofen bulk drug to the absolute ethyl alcohol to the stabilizer to the water is 1: (22-30): (0.3-0.6): (200-400), the dropping speed of the ibuprofen ethanol solution is 2-5 ml/min, and the stirring speed is 800-1000 r/min;
the molar ratio of the 4-dodecylphenol to the diglycidyl ether to the polyethylene glycol is 1: (1.2-1.4): (1.1-1.2), in the step S1, the mass ratio of 4-dodecylphenol, water and sodium carbonate is 1: (5-15): (0.2-0.3), in the step S2, the mass ratio of polyethylene glycol, water and tertiary amine is 1: (3-5): (0.1-0.2).
2. A method for preparing ibuprofen suspension from ibuprofen bulk drug obtained by the pretreatment method according to claim 1, which is characterized in that: the method comprises the following steps:
(1) Dry-mixing sucrose and xanthan gum with the formula amount of 7% to obtain a xanthan gum/sucrose dry-mixed mixture for standby, wherein the sucrose with the formula amount of 7% is obtained by crushing sucrose raw materials and sieving with an antistatic screen of 0.075-0.12 mm;
(2) Adding warm water into a liquid preparation tank, starting stirring, sequentially adding sodium benzoate, pregelatinized starch, sucrose with the formula amount of 93%, glycerol and citric acid, heating and boiling, preserving heat and stirring for 20-40 min, cooling to below 80 ℃, sieving with a 200-mesh sieve, and cooling to below 30 ℃ by cooling water;
(3) Taking a xanthan gum/sucrose dry blend, slowly adding the mixture into a batching tank under stirring, stirring until the mixture is dissolved, adding hydrophilic honeycomb filler, and continuously stirring for 20-30 min;
(4) Adding lemon yellow, allure red, strawberry essence and polysorbate 80 into a mixing tank, stirring for 10-20 min, and uniformly mixing;
(5) Pretreating ibuprofen raw material, adding the ibuprofen raw material into a batching tank, uniformly mixing, adding water to a constant volume of 1000mL, stirring, and encapsulating to obtain an ibuprofen suspension finished product.
3. A process for the preparation of an ibuprofen suspension according to claim 2, characterized in that: the antistatic screen is obtained by blending synthetic fibers and antistatic agents and then carrying out melt spinning molding, wherein the addition amount of the antistatic agents is 0.5-2% of the total mass of the synthetic fibers;
the preparation method of the antistatic agent comprises the following steps:
A. drying talcum powder, adding the talcum powder into ethanol solution of tetraethoxy divinyl disiloxane, stirring and reacting for 40-60 min at 80-90 ℃, and filtering and drying to obtain treated talcum powder;
B. esterification reaction is carried out on ethoxyacetic acid and unsaturated fatty alcohol under the catalysis of concentrated sulfuric acid, the obtained esterification product and the treated talcum powder are subjected to polyaddition reaction under the condition of an initiator, and a product 2 is obtained, wherein the addition amount of the concentrated sulfuric acid is 2-4% of the total mass of reactants;
C. esterifying ethanolamine and unsaturated fatty acid under the catalysis of concentrated sulfuric acid, and performing polyaddition reaction on the obtained esterified product, the product 2 and unsaturated polyoxyethylene ether under the condition of an initiator to obtain an antistatic agent finished product;
the mol ratio of the tetraethoxy divinyl disiloxane to the unsaturated fatty alcohol to the unsaturated fatty acid to the unsaturated polyoxyethylene ether is 1: (0.9-1): (0.9-1): (0.8-1); in the step A, the mass ratio of tetraethoxydivinyl disiloxane to ethanol is 1: (4-8), the mass of the tetraethoxydivinyl disiloxane is 1-5% of that of talcum powder; in the step B, the mol ratio of the ethoxyacetic acid to the unsaturated fatty alcohol is (1.1-1.2): 1, wherein the unsaturated fatty alcohol is 9-decaen-1-ol, 9-octadecen-1-ol or cis-11-hexadecen-1-ol; in the step C, the mol ratio of the ethanolamine to the unsaturated fatty acid is (1.1-1.2): 1, wherein the unsaturated fatty acid is acrylic acid, octenoic acid or undecylenic acid.
4. A process for the preparation of an ibuprofen suspension according to claim 2 or 3, characterized in that: the hydrophilic honeycomb filler is prepared by spraying hydrophilic paint on the surface of the honeycomb filler;
the hydrophilic coating comprises the following preparation raw materials in parts by mass: 40-50 parts of aqueous epoxy resin, 35-45 parts of aqueous epoxy curing agent, 6-14 parts of hydrophilic polymer and 3-5 parts of inorganic filler, wherein the hydrophilic polymer is obtained by adding and esterifying acetic acid and 1, 2-epoxy-9-sunflower alkene and then adding the esterified hydrophilic polymer and tri-tert-butyl silane in a hydrosilylation manner;
the preparation method of the hydrophilic polymer comprises the following steps:
adding acetic acid, an organic acid chromium salt catalyst and toluene into a reaction kettle, uniformly mixing, slowly adding 1, 2-epoxy-9-sunflower alkene, stirring at 100-120 ℃ for reacting for 5-8 hours, cooling, evaporating the solvent, distilling under reduced pressure to obtain a polyoxyethylene acetate type product, uniformly mixing the polyoxyethylene acetate type product with toluene and a platinum catalyst, slowly adding tri-tert-butyl silane, stirring at 80-90 ℃ for reacting for 4-6 hours, and evaporating the solvent to obtain a hydrophilic polymer, wherein the molar ratio of the acetic acid to the 1, 2-epoxy-9-sunflower alkene to the tri-tert-butyl silane is 1: (5-20): (1-5).
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| CN114209650A (en) * | 2021-12-24 | 2022-03-22 | 海南鑫开源医药科技有限公司 | Process for improving content uniformity of ibuprofen suspension |
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| CN112516083A (en) * | 2020-12-15 | 2021-03-19 | 太阳升(亳州)生物医药科技有限公司 | Ibuprofen suspension and preparation method thereof |
| CN113368042A (en) * | 2021-05-31 | 2021-09-10 | 华润三九（南昌）药业有限公司 | Preparation method of ibuprofen suspension |
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