CN115624523A - Preparation method of ibuprofen suspension - Google Patents
Preparation method of ibuprofen suspension Download PDFInfo
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- CN115624523A CN115624523A CN202211323343.2A CN202211323343A CN115624523A CN 115624523 A CN115624523 A CN 115624523A CN 202211323343 A CN202211323343 A CN 202211323343A CN 115624523 A CN115624523 A CN 115624523A
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Abstract
The invention discloses a preparation method of ibuprofen suspension, which comprises the following steps: (1) Mixing sucrose and xanthan gum with the formula amount of 7% in a dry way to obtain a xanthan gum/sucrose dry mixture for later use; (2) Adding normal temperature water into the liquid preparation tank, starting stirring, sequentially adding sodium benzoate, pregelatinized starch, sucrose with the formula amount of 93%, glycerol and citric acid, heating to boil, keeping the temperature, 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 dry xanthan gum/sucrose mixture, slowly adding the dry xanthan gum/sucrose mixture into a mixing tank under stirring, and stirring until the dry xanthan gum/sucrose mixture is dissolved; (4) Adding lemon yellow, allura red, strawberry essence and polysorbate 80 into a mixing tank, stirring for 10-20 min, and mixing uniformly; (5) Pretreating ibuprofen raw materials, screening the ibuprofen raw materials by using a 150-mesh screen, adding the ibuprofen raw materials into a mixing tank, uniformly mixing, adding water to a constant volume of 1000mL, stirring, and encapsulating to obtain a finished product. The ibuprofen suspension prepared by the method 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 an ibuprofen suspension.
Background
Ibuprofen 2- (-4-isobutylphenyl) propionic acid is a good nonsteroidal antipyretic, analgesic and anti-inflammatory drug, and is clinically used for treating fever and light to moderate pain. Ibuprofen, as a poorly water-soluble drug, is almost insoluble in water and very soluble in anhydrous ethanol, thereby affecting the in vivo absorption and bioavailability of the drug.
The medicine in the suspension is dispersed in a liquid dispersion medium in a solid particle state to form a dispersion system, the medicine particles in the suspension have large dispersion degree, 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 agent is in an unstable state. Suspensions of hydrophobic drugs present greater stability problems than hydrophilic drugs.
The solubility of the drug is related to the specific surface area of the material, the particle size of the drug is reduced, the effective contact area of the drug and the medium is increased, and the solubility and the dissolution speed of the drug are improved. Therefore, the reduction of the particle size of the ibuprofen raw material drug by the micronization technology is an effective way, and the dissolution and absorption of the drug can be effectively improved. The mechanical crushing method has the defects of large energy consumption, low efficiency, wide particle size distribution of products, easy damage of medicine structures and the like. Among them, the recrystallization method is an important and effective method for preparing micronized drug, but the pure recrystallization method cannot obtain stable drug micropowder, so a certain stabilizer needs to be added to ensure good micronization effect.
In addition, xanthan gum is used as a commonly used suspending agent in ibuprofen suspension, and due to the strong hydrophilicity of xanthan gum, when the xanthan gum is directly added into water and is not stirred sufficiently, the outer layer absorbs water and swells into a micelle, so that water is prevented from entering the inner layer, and the exertion of the effect is influenced. In the prior art, dry xanthan gum powder and dry powder auxiliary materials such as salt, sugar and the like are often added for use after being dry-mixed, so that a certain dissolving effect of the xanthan gum can be ensured. However, the particle size and uniformity of dry powder excipients such as salt, sugar, etc. directly affect the dry mixing effect of xanthan gum, and further affect the solubility of xanthan gum in aqueous solution, and ultimately affect the suspending effect.
In conclusion, how to design a preparation method of an ibuprofen suspension can reduce the particle size of ibuprofen powder through micronization treatment of ibuprofen bulk drugs, and promote the suspending effect of xanthan gum by controlling the dry-mixing state of the xanthan gum and other auxiliary materials, which is a problem to be solved urgently at present.
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 and adding a stabilizer, so that the particle size of the medicinal powder can be remarkably reduced, and the stability and the utilization rate of the medicine are improved; the sucrose is also crushed and screened by an antistatic screen, and then is mixed with 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 purpose through the following technical scheme:
a method for preparing an ibuprofen suspension comprises the following steps:
(1) Mixing sucrose and xanthan gum with the formula amount of 7% in a dry way to obtain a xanthan gum/sucrose dry mixture for later use;
(2) Adding normal temperature water into the liquid preparation tank, starting stirring, sequentially adding sodium benzoate, pregelatinized starch, sucrose with the formula amount of 93%, glycerol and citric acid, heating to boil, stirring for 20-40 min under heat preservation, 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 mixture, slowly adding the mixture into a mixing tank under stirring, and stirring until the mixture is dissolved;
(4) Adding lemon yellow, allura red, strawberry essence and polysorbate 80 into a mixing tank, stirring for 10-20 min, and mixing uniformly;
(5) Pretreating the ibuprofen raw material medicine, then adding the ibuprofen raw material medicine into a mixing tank, uniformly mixing, adding water to a constant volume of 1000mL, stirring, and encapsulating to obtain an ibuprofen suspension finished product.
The method for pretreating the ibuprofen bulk drug comprises the following steps:
the ibuprofen bulk drug is taken and placed in absolute ethyl alcohol to be completely dissolved to obtain an ibuprofen ethanol solution, the ibuprofen ethanol solution is slowly dripped into a water solution containing a stabilizer at the temperature of 1-6 ℃, stirring is started, centrifugation and microfiltration membrane (0.3-5 mu m) suction filtration are carried out after dripping, washing and drying are carried out, and the ibuprofen bulk drug is crushed and sieved by a 150-mesh sieve.
The preparation method of the stabilizer comprises the following steps:
s1, uniformly mixing 4-dodecylphenol, water and sodium carbonate, then dripping diglycidyl ether into the mixture under the stirring condition of 100-110 ℃, and reacting for 1-3 hours 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 condition of stirring at 105-120 ℃, and reacting for 3-5 hours after dripping to obtain the stabilizer.
Preferably, in the step of pretreating the ibuprofen raw material drug, the mass ratio of the ibuprofen raw material drug to absolute ethyl alcohol to the stabilizer to water is 1: (22-30): (0.3-0.6): (200-400), the acceleration of the aqueous solution drop 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 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 the 4-dodecylphenol to the water to the sodium carbonate is 1: (5-15): (0.2-0.3), in the step S2, the mass ratio of the polyethylene glycol to the water to the 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 7% of sucrose in formula amount is obtained by crushing (600-1000 r/min) sucrose raw material and sieving with 0.075-0.12 mm antistatic screen, the antistatic screen is obtained by blending synthetic fiber (nylon 6) and antistatic agent and then forming through melt spinning (the melting temperature is 240-250 ℃) and the addition amount of the antistatic agent is 0.5-2% of the total mass of the synthetic fiber.
Preferably, the preparation method of the antistatic agent comprises the following steps:
A. drying talcum powder, adding the dried talcum powder into an ethanol solution of tetraethoxy divinyl disiloxane, stirring and reacting at the temperature of 80-90 ℃ for 40-60 min, and filtering and drying to obtain a product 1;
B. performing esterification reaction (reaction at 108-115 ℃ for 4-6 h) 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), performing addition polymerization reaction (reaction at 65-75 ℃ for 2-3 h) on the obtained esterification product and treated talcum powder under the condition that an initiator (tert-butyl hydroperoxide/sodium metabisulfite, azodiisoheptanonitrile or diisopropyl peroxydicarbonate is 0.3-0.5% of the total mass of the reactants), and obtaining a product 2;
C. and (2) performing esterification reaction on ethanolamine and unsaturated fatty acid under the catalysis condition of concentrated sulfuric acid (the addition amount is 1-3% of the total mass of reactants) (reaction for 3-5 h at 105-112 ℃), and performing addition polymerization reaction on the obtained esterification product, a product 2 and unsaturated polyoxyethylene ether under the condition of an initiator (tert-butyl hydroperoxide/sodium metabisulfite, azodiisoheptonitrile or diisopropyl peroxydicarbonate, the addition amount is 0.3-0.5% of the total mass of the reactants) (reaction for 3-4 h at 70-80 ℃), so as to obtain the finished antistatic agent.
Preferably, the mole ratio of the tetraethoxydivinyl 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 tetraethoxy divinyl 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, the unsaturated fatty alcohol is 9-decaene-1-alcohol, 9-octadecene-1-alcohol or cis-11-hexadecene-1-alcohol.
In the step C, the molar ratio of the ethanolamine to the unsaturated fatty acid is (1.1-1.2): 1, 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, and the preparation method further comprises the step of adding the hydrophilic honeycomb filler to continue stirring for 20-30 min (the stirring speed is 400-600 r/min) after the xanthan gum/sucrose dry mixture is stirred and dissolved in the preparation process step (3) of the ibuprofen suspension; the hydrophilic honeycomb filler is prepared by spraying hydrophilic coating on the surface of the honeycomb filler. The material of the honeycomb filler is PP, the specification is phi 10-50 mm, and the sheet thickness 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 pottery clay), wherein the hydrophilic polymer is prepared by performing addition esterification on acetic acid and 1, 2-epoxy-9-decene and then performing hydrosilylation on the product and tri-tert-butylsilane.
Preferably, the preparation method of the hydrophilic polymer comprises the following steps:
adding acetic acid, an organic acid chromate catalyst (chromium acetate, the adding amount is 1-3% of molar equivalent), toluene (the adding amount is 1-3 times of the mass of acetic acid), uniformly mixing, slowly adding 1, 2-epoxy-9-decene, stirring and reacting at 100-120 ℃ for 5-8 h, cooling, evaporating a solvent, distilling under reduced pressure to obtain a polyoxyethylene acetate product, uniformly mixing the polyoxyethylene acetate product, toluene (the adding amount is 1.5-4 times of the mass of the polyoxyethylene acetate product) and a platinum catalyst (the adding amount is 5-30 ppm of platinum), slowly adding tri-tert-butylsilane, stirring and reacting at 80-90 ℃ for 4-6 h, 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-butylsilane is 1: (5-20): (1-5).
The invention has the beneficial effects that:
(1) According to the invention, the ibuprofen raw material medicine is micronized through a recrystallization process, so that 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 process of recrystallization of ibuprofen, a stabilizing agent is added to promote dispersion and stabilization of crystallized particles, the stabilizing agent is obtained by respectively condensing diglycidyl ether with 4-dodecylphenol and polyethylene glycol, and a lipophilic chain segment containing phenyl and a hydrophilic chain segment of polyethylene glycol are introduced to promote crystallization stabilization of ibuprofen.
(3) According to the invention, the sucrose raw material is crushed and sieved by a 0.075-0.12 mm screen, and then is prepared into a dry mixture with xanthan gum, so that the dry mixing effect of the xanthan gum can be promoted, the solubility of the xanthan gum in water is promoted, and the xanthan gum can be rapidly dissolved without high-speed shearing.
(4) Because the particle size of the sucrose to be screened is smaller, and the sucrose particles are easy to generate static electricity 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 an ethyoxyl-containing oleophylic chain segment and an amino-containing hydrophilic chain segment after the talcum powder is subjected to silanization treatment, and the antistatic effect is obvious.
(5) After the dry mixing effect of the xanthan gum is improved, 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 the stability of ibuprofen powder in the system is also reduced under the condition of ibuprofen micronization, so that the viscosity mutation effect needs to be eliminated, but the simple shearing effect is not obvious, and therefore, after the xanthan gum/sucrose dry mixture is added, hydrophilic honeycomb filler is added for stirring, 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 coating on the surface of the honeycomb filler, wherein the hydrophilic coating contains hydrophilic polymers, and the hydrophilic polymers are obtained by performing addition esterification on acetic acid and 1, 2-epoxy-9-decene and then performing hydrosilylation on the acetic acid and the tri-tert-butylsilane, and the obtained polymers contain polyoxyethylene hydrophilic main chains and epoxy-containing long-chain hydrocarbon branched chains, can be compatible with hydrophilicity and compatibility in epoxy resin, and promote the hydrophilic effect of the hydrophilic honeycomb filler.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The ibuprofen suspension of the present example had the following raw material composition and mass: 20g of ibuprofen, 13g of pregelatinized starch, 2g of xanthan gum, 100g of glycerol, 300g of sucrose, 2g of citric acid, 2g of sodium benzoate, 80.5g of polysorbate, 0.02g of lemon yellow, 0.01g of allura red, 3g of strawberry essence, and the volume of purified water is up to 1000mL.
The preparation method of the ibuprofen suspension comprises the following steps:
(1) Mixing sucrose and xanthan gum with the formula amount of 7% in a dry way to obtain a xanthan gum/sucrose dry mixture for later use;
(2) Adding normal temperature water into the liquid preparation tank, starting stirring, sequentially adding sodium benzoate, pregelatinized starch, sucrose with the formula amount of 93%, glycerol and citric acid, heating to boil, stirring for 30min under heat preservation, cooling to below 80 deg.C, sieving with 200 mesh sieve, and cooling to below 30 deg.C with cooling water;
(3) Taking a xanthan gum/sucrose dry mixture, slowly adding the mixture into a mixing tank under stirring, and stirring until the mixture is dissolved;
(4) Adding lemon yellow, allura red, strawberry essence and polysorbate 80 into a mixing tank, stirring for 10min, and mixing;
(5) Mechanically pulverizing ibuprofen raw materials (1000 r/min), sieving with a 150-mesh sieve, adding into a mixing tank, mixing, adding water to a constant volume of 1000mL, stirring, and encapsulating to obtain the final product.
Example 2
This example provides a method for pre-treating ibuprofen bulk drug, which replaces the mechanical pulverization in example 1, and the pre-treatment includes the following steps:
the ibuprofen active pharmaceutical ingredients are taken and placed in absolute ethyl alcohol to be completely dissolved to obtain an ibuprofen ethanol solution, the ibuprofen ethanol solution is dropwise added into a water solution containing a stabilizer at the temperature of 1 ℃, stirring is started (800 r/min), centrifugation, microfiltration membrane (3 mu m) suction filtration, washing and drying are carried out after dropwise addition, and the ibuprofen active pharmaceutical ingredients are crushed and then sieved by a 150-mesh sieve. The mass ratio of the ibuprofen raw material 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, mixing the components in a mass ratio of 1:5:0.2 uniformly mixing the 4-dodecylphenol, water and sodium carbonate, then dripping diglycidyl ether under the stirring condition of 100 ℃, and reacting for 1 hour after dripping;
s2, mixing the components in a mass ratio of 1:3:0.1 evenly mixing polyethylene glycol (PEG 1000), water and tertiary amine, then slowly dripping into the product obtained in the step S1 under the condition of stirring at 105 ℃, and reacting for 3 hours after dripping to obtain the stabilizer.
Wherein the mol ratio of the 4-dodecylphenol to the diglycidyl ether to the polyethylene glycol is 1:1.2:1.1.
the rest was the same as in example 1.
Example 3
On the basis of embodiment 2, this embodiment also provides an antistatic screen in the preparation method of the ibuprofen suspension, wherein the sucrose with a formula amount of 7% is obtained by pulverizing a sucrose raw material (600 r/min) and sieving the sucrose raw material by using a 0.12mm antistatic screen, the antistatic screen is obtained by blending nylon 6 and an antistatic agent and then molding the mixture through melt spinning (the melt temperature is 240 ℃), 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. drying the talcum powder, and adding the talcum powder into the mixture according to the mass ratio of 1:4, stirring and reacting at 80 ℃ for 40min in an ethanol solution of tetraethoxydivinyl disiloxane, and filtering and drying to obtain a product 1; the mass of the tetraethoxydivinyl disiloxane is 1 percent of that of the talcum powder;
B. mixing the components in a molar ratio of 1.1:1, performing esterification reaction on ethoxyacetic acid and unsaturated fatty alcohol (9-decene-1-alcohol) at 108 ℃ for 4 hours under the catalysis of concentrated sulfuric acid (the addition amount is 2 percent of the total mass of reactants), performing addition polymerization reaction on the obtained esterification product and treated talcum powder 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 the reactants) and 65 ℃ to obtain a product 2;
C. mixing the components in a molar ratio of 1.1: and (2) carrying out esterification reaction on the ethanolamine of 1 and unsaturated fatty acid (acrylic acid) for 3 hours at 105 ℃ under the catalysis condition of concentrated sulfuric acid (the addition amount is 1 percent of the total mass of reactants), and carrying out addition polymerization reaction on the obtained esterification product, the product 2 and unsaturated polyoxyethylene ether for 3 hours at 70 ℃ under the conditions of an initiator (azobisisoheptonitrile, the addition amount is 0.3 percent of the total mass of the reactants), thus obtaining the antistatic agent finished product.
Wherein the mole ratio of the tetraethoxydivinyl disiloxane to the unsaturated fatty alcohol to the unsaturated fatty acid to the unsaturated polyoxyethylene ether is 1:0.9:0.9:0.8.
the rest is the same as in example 2.
Example 4
On the basis of example 3, this example provides a hydrophilic honeycomb filler in the preparation method of ibuprofen suspension, and after the xanthan gum/sucrose dry mixture is stirred and dissolved in the preparation process step (3) of ibuprofen suspension, the method further includes adding the hydrophilic honeycomb filler and continuing stirring at the speed of 400r/min for 20min; the hydrophilic honeycomb filler is prepared by spraying hydrophilic coating on the surface of the honeycomb filler. The honeycomb filler is made of PP with specification of phi 10mm and sheet thickness of 0.3mm
The hydrophilic coating comprises the following preparation raw materials in parts by mass: 40 parts of water-based epoxy resin, 35 parts of room-temperature curing water-based epoxy curing agent, 6 parts of hydrophilic polymer and 3 parts of inorganic filler (calcium carbonate).
The preparation method of the hydrophilic macromolecule comprises the following steps:
adding acetic acid, a chromium acetate catalyst (1% of molar equivalent) and toluene (equal to the mass of acetic acid) into a reaction kettle, uniformly mixing, slowly adding 1, 2-epoxy-9-decene, stirring and reacting at 100 ℃ for 5 hours, cooling, evaporating a solvent, distilling under reduced pressure to obtain a polyoxyethylene acetate product, uniformly mixing the polyoxyethylene acetate product with toluene (1.5 times of the mass of the polyoxyethylene acetate product) and a platinum catalyst (the addition amount of which is 5ppm calculated by platinum), slowly adding tri-tert-butylsilane, stirring and reacting at 80 ℃ for 4 hours, and evaporating the solvent to obtain a hydrophilic polymer, wherein the molar ratio of acetic acid to 1, 2-epoxy-9-decene to tri-tert-butylsilane is 1:5:1.
the rest is the same as in example 3.
Example 5
The embodiment provides a preparation method of an ibuprofen suspension, wherein the method for pretreating an ibuprofen bulk drug comprises the following steps:
the ibuprofen raw material medicine is taken and placed in absolute ethyl alcohol to be completely dissolved to obtain an ibuprofen ethanol solution, the ibuprofen ethanol solution is dropwise added into an aqueous solution containing a stabilizer at the temperature of 3 ℃ at the speed of 3.5ml/min, stirring is started (900 r/min), centrifugation, microfiltration membrane suction filtration, washing and drying are carried out after dropwise addition, and the ibuprofen ethanol solution is crushed and sieved by a 150-mesh sieve. The mass ratio of the ibuprofen raw material 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, preparing a mixture of S1: 10:0.25 evenly mixing the 4-dodecylphenol, water and sodium carbonate, then dripping the diglycidyl ether into the mixture under the stirring condition at 105 ℃, and reacting for 2 hours after dripping;
s2, mixing the raw materials in a mass ratio of 1:4:0.15 evenly mixing polyethylene glycol (PEG 2000), water and tertiary amine, then slowly dripping into the product obtained in the step S1 under the condition of stirring at 112 ℃, and reacting for 4 hours after dripping to obtain the stabilizer.
Wherein the mol ratio of the 4-dodecylphenol to the diglycidyl ether to 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) sucrose raw materials and sieving through a 0.10mm antistatic screen, the antistatic screen is obtained by blending nylon 6 and an antistatic agent and then molding 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. drying the talcum powder, and adding the talcum powder into the mixture according to the mass ratio of 1:6, stirring and reacting at 85 ℃ for 50min in an ethanol solution of tetraethoxydivinyl disiloxane, and filtering and drying to obtain a product 1; the mass of the tetraethoxy divinyl disiloxane is 3 percent of that of the talcum powder;
B. mixing the components in a molar ratio of 1.15:1, performing esterification reaction (reaction at 110 ℃ for 5 hours) on ethoxyacetic acid and unsaturated fatty alcohol (9-octadecen-1-ol) under the catalysis of concentrated sulfuric acid (the addition amount is 3 percent of the total mass of reactants), performing addition polymerization reaction (reaction at 70 ℃ for 2.5 hours) on the obtained esterification product and treated talcum powder under the condition of an initiator (azobisisoheptonitrile, the addition amount is 0.4 percent of the total mass of the reactants), and obtaining a product 2;
C. mixing the components in a molar ratio of 1.15: the ethanolamine of 1 and unsaturated fatty acid (octenoic acid) are subjected to esterification reaction (reaction at 108 ℃ for 4 h) under the catalysis of concentrated sulfuric acid (the addition amount is 2 percent of the total mass of reactants), and the obtained esterification product, the product 2 and unsaturated polyoxyethylene ether are subjected to addition polymerization (reaction at 75 ℃ for 3.5 h) under the condition of an initiator (diisopropyl peroxydicarbonate, the addition amount is 0.4 percent of the total mass of reactants), so that the finished product of the antistatic agent is obtained.
Wherein the mole ratio of the tetraethoxydivinyl disiloxane to the unsaturated fatty alcohol to the unsaturated fatty acid to 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, and the preparation method further comprises the steps of adding the hydrophilic honeycomb filler and continuously stirring at the speed of 500r/min for 25min after stirring and dissolving the xanthan gum/sucrose dry mixture in the preparation process step (3) of the ibuprofen suspension; the hydrophilic honeycomb filler is prepared by spraying hydrophilic coating 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 water-based epoxy resin, 40 parts of room-temperature curing water-based epoxy curing agent, 10 parts of hydrophilic polymer and 4 parts of inorganic filler (argil).
The preparation method of the hydrophilic macromolecule comprises the following steps:
adding acetic acid, a chromium acetate catalyst (2% of molar equivalent) and toluene (the addition amount is 2 times of the mass of acetic acid) into a reaction kettle, uniformly mixing, slowly adding 1, 2-epoxy-9-decene, stirring and reacting at 110 ℃ for 6 hours, cooling, evaporating a solvent, carrying out reduced pressure distillation 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 a platinum catalyst (the addition amount is 20ppm based on platinum), slowly adding tri-tert-butylsilane, stirring and reacting at 85 ℃ for 5 hours, and evaporating the solvent to obtain the hydrophilic polymer, wherein the molar ratio of acetic acid to 1, 2-epoxy-9-decene to tri-tert-butylsilane is 1:12:3.
the rest was the same as in example 4.
Example 6
The embodiment provides a preparation method of an ibuprofen suspension, wherein the method for pretreating an ibuprofen bulk drug comprises the following steps:
the ibuprofen raw material medicine is taken and placed in absolute ethyl alcohol to be completely dissolved to obtain an ibuprofen ethanol solution, the ibuprofen ethanol solution is dropwise added into a water solution containing a stabilizer at the temperature of 6 ℃, stirring is started (1000 r/min), centrifugation, microfiltration membrane suction filtration, washing and drying are carried out after dropwise addition, and the ibuprofen ethanol solution is crushed and sieved by a 150-mesh sieve. The mass ratio of the ibuprofen raw material 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, mixing the components in a mass ratio of 1:15:0.3, uniformly mixing the 4-dodecylphenol, water and sodium carbonate, then dripping diglycidyl ether under the stirring condition of 110 ℃, and reacting for 3 hours after dripping;
s2, mixing the raw materials in a mass ratio of 1:5:0.2 evenly mixing polyethylene glycol (PEG 6000), water and tertiary amine, then slowly dripping into the product obtained in the step S1 under the condition of stirring at 120 ℃, and reacting for 5 hours after dripping to obtain the stabilizer.
Wherein the mol ratio of the 4-dodecylphenol to the diglycidyl ether to 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) sucrose raw materials and sieving with a 0.075mm antistatic screen, the antistatic screen is obtained by blending nylon 6 and an antistatic agent and then molding 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. drying the talcum powder, and adding the talcum powder into the mixture according to the mass ratio of 1:8, stirring and reacting at 90 ℃ for 60min in an ethanol solution of tetraethoxydivinyl disiloxane, and filtering and drying to obtain a product 1; the mass of the tetraethoxy divinyl disiloxane is 5 percent of that of the talcum powder;
B. mixing the components in a molar ratio of 1.2:1, performing esterification reaction (reaction at 115 ℃ for 6 hours) on ethoxyacetic acid and unsaturated fatty alcohol (cis-11-hexadecen-1-ol) under the catalysis of concentrated sulfuric acid (the addition amount is 4 percent of the total mass of reactants), performing addition polymerization reaction (reaction at 75 ℃ for 3 hours) on the obtained esterification product and treated talcum powder under the condition of an initiator (diisopropyl peroxydicarbonate, the addition amount is 0.5 percent of the total mass of the reactants), and obtaining a product 2;
C. mixing the components in a molar ratio of 1.2: the ethanolamine of 1 and unsaturated fatty acid (undecylenic acid) are subjected to esterification reaction (reaction at 112 ℃ for 5 h) under the catalysis of concentrated sulfuric acid (the addition amount is 3 percent of the total mass of reactants), the obtained esterification product, a product 2 and unsaturated polyoxyethylene ether are subjected to addition polymerization (reaction at 80 ℃ for 4 h) under the condition of an initiator (tert-butyl hydroperoxide/sodium metabisulfite, the addition amount is 0.5 percent of the total mass of reactants), and the finished product of the antistatic agent is obtained.
Wherein the mole ratio of the tetraethoxydivinyl disiloxane to the unsaturated fatty alcohol to the unsaturated fatty acid to 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, and the preparation method further comprises the steps of adding the hydrophilic honeycomb filler and continuously stirring at the speed of 600r/min for 30min after stirring and dissolving the xanthan gum/sucrose dry mixture in the preparation process step (3) of the ibuprofen suspension; the hydrophilic honeycomb filler is prepared by spraying hydrophilic coating 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 water-based epoxy resin, 45 parts of room-temperature curing water-based epoxy curing agent, 14 parts of hydrophilic polymer and 5 parts of inorganic filler (comprising calcium carbonate and argil in equal mass ratio).
The preparation method of the hydrophilic macromolecule comprises the following steps:
adding acetic acid, a chromium acetate catalyst (the adding amount is 3% of molar equivalent) and methylbenzene (the adding amount is 3 times of the mass of the acetic acid) into a reaction kettle, uniformly mixing, slowly adding 1, 2-epoxy-9-decene, stirring and reacting at 120 ℃ for 8 hours, cooling, evaporating a solvent, carrying out reduced pressure distillation to obtain a polyoxyethylene acetate type product, uniformly mixing the polyoxyethylene acetate type product with methylbenzene (the adding amount is 4 times of the mass of the polyoxyethylene acetate type product) and a platinum catalyst (the adding amount is 30ppm calculated by platinum), slowly adding tri-tert-butylsilane, stirring and reacting at 90 ℃ for 6 hours, and evaporating the solvent to obtain the hydrophilic polymer, wherein the molar ratio of the acetic acid to the 1, 2-epoxy-9-decene to the tri-tert-butylsilane is 1:20:5.
the rest is the same as in example 4.
Comparative example 1
The comparative example differs from example 4 in that in the method of ibuprofen drug pretreatment, the stabilizing agent is polyethylene glycol.
Comparative example 2
The difference between the comparative example and the example 4 is that in the method for pretreating the ibuprofen bulk drug, the mass ratio of the ibuprofen bulk drug to the absolute ethyl alcohol to the stabilizer to the water is 1:22:0.2:200.
comparative example 3
The difference between the comparative example and the example 4 is that in the method for pretreating the ibuprofen bulk drug, the mass ratio of the ibuprofen bulk drug to the absolute ethyl alcohol to the stabilizer to water is 1:22:0.7:200.
comparative example 4
The comparative example differs from example 5 in that the formulation amount of 7% sucrose was obtained by crushing sucrose raw material and sieving with a 0.10mm conventional nylon 6 mesh.
Comparative example 5
This comparative example is different from example 5 in that the antistatic agent was added in an amount of 0.3% by mass based on the total mass of nylon 6 in the antistatic screen.
Comparative example 6
This comparative example is different from example 5 in that the antistatic agent was added in an amount of 2.2% by mass based on the total mass of nylon 6 in the antistatic screen.
Comparative example 7
This comparative example differs from example 5 in that no talc was included in the raw materials for the preparation of the antistatic agent and the treated talc 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
This comparative example is different from example 6 in that the hydrophilic coating does not contain a hydrophilic polymer.
Comparative example 10
This comparative example is different from example 6 in that the hydrophilic coating does not contain an inorganic filler.
1. Basic properties of ibuprofen suspension prepared by the invention
The ibuprofen suspension prepared in the embodiments 1 to 6 of the present invention is orange suspension, sweet in taste, and fragrant with a flavoring agent. The pH value is 3.5-4.5, and the relative density is 1.090-1.200.
Sedimentation volume ratio: the sedimentation volume ratio is determined by referring to the requirement of 0123-oral suspension of the general rule of four parts of China pharmacopoeia 2020 edition, and the target object is ibuprofen suspension prepared in examples 1-6 and comparative examples 1-10 of the invention. The specific method comprises the following steps: measuring the sample 50ml with a measuring cylinder with a plug, sealing, shaking for 1 min, and recording the initial height H of the suspension 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
According to the results, the ibuprofen suspension prepared by the method meets the pharmacopoeia requirements in all aspects. The ibuprofen suspensions prepared in the embodiments 4, 5 and 6 of the invention are excellent, and the sedimentation volume ratio is 0.98.
Compared with the example 1, the ibuprofen obtained in the example 2 is subjected to recrystallization pretreatment, so that micronized ibuprofen is obtained, and the sedimentation volume ratio of the suspension is improved. On the basis of the embodiment 2, the sucrose raw material is sieved and then is dry-mixed with the xanthan gum, so that the suspending effect of the xanthan gum is improved, but the dry-mixed effect of the xanthan gum is improved and then is rapidly dissolved in water, so that the viscosity of a liquid medicine system is rapidly increased to generate viscosity mutation, the system is unstable, and under the condition of micronization of ibuprofen, the stability of ibuprofen powder in the system is also reduced, so that the sedimentation volume ratio of the final suspension is not obviously improved. On the basis of example 3, after the xanthan gum/sucrose dry mixture is added, hydrophilic honeycomb filler is added for stirring, so that the viscosity mutation system is reduced, the sedimentation volume ratio of the suspension is obviously improved, and a good suspension effect is shown.
Wherein, the types and the dosage of the stabilizing agent in the recrystallization process are respectively changed in the comparative examples 1 to 3, the type of a screen mesh for screening the cane sugar and the preparation method of the antistatic agent are respectively changed in the comparative examples 4 to 7, and the preparation raw materials of the hydrophilic honeycomb filler are respectively changed in the comparative examples 8 to 10, so that the sedimentation volume ratio of the ibuprofen suspension is reduced to different degrees.
2. The particle size distribution of the ibuprofen micropowder obtained by the pretreatment of the invention
The ibuprofen bulk drug, the ibuprofen powder obtained by crushing in example 1, the ibuprofen powder obtained by pre-treating in examples 4 to 6 and comparative examples 1 to 3 were subjected to particle size measurement by using an image particle distribution instrument (BT-1600), and the results of the obtained 50% passing particle size D50 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 performing recrystallization pretreatment on ibuprofen in examples 4 to 6 of the present invention has a smaller particle size distribution of not more than 10.5 μm, and can significantly improve the stability of the suspension.
Compared with example 4, comparative examples 1,2 and 3 respectively change the type and the dosage of the stabilizer in the recrystallization process, so that the particle size of ibuprofen is increased, and the stability of suspension is reduced.
2. Volume resistivity of the antistatic screen of the invention and water solubility properties of xanthan gum
1. Determination of the volume resistivity of the antistatic screen: the resistivity of the antistatic screens obtained in examples 4 to 6 of the present invention and comparative examples 4 to 7 was measured using a PC68 type digital high resistance meter. The results are shown in Table 3.
2. Water-soluble properties of xanthan gum: adding xanthan gum/sucrose dry mixture into the ibuprofen suspension preparation process step (3) of the examples 1, 3-6 and the comparative examples 4-10 of the invention under the stirring speed of 600r/min to obtain liquid medicine, and recording the dissolution condition of the xanthan gum and the viscosity change values of the liquid medicine within 5min, 30min, 2h and 24 h. The results are shown in Table 4.
TABLE 3
As can be seen from table 3, the volume resistivity of the antistatic screens obtained in examples 4 to 6 of the present invention was reduced by 5 orders of magnitude, and a good antistatic effect was exhibited, as compared to the common nylon 6 screen of comparative example 4.
Comparative examples 5, 6 and 7 changed the raw materials for the preparation of antistatic agents, respectively, and as a result, the volume resistivity of the screen was increased and the antistatic effect was reduced.
TABLE 4
As can be seen from table 4, compared with example 1, in examples 3 to 6 of the present invention, the xanthan gum/sucrose dry blend prepared by sieving sucrose metal and mixing with xanthan gum significantly increases the dissolution rate of xanthan gum in the drug solution.
In example 3, although the dissolution rate was increased, the viscosity increased by 28cP within 5min, resulting in a sharp transition. In the embodiments 4 to 6 of the invention, the xanthan gum/sucrose dry mixture is added into the liquid preparation tank, and the hydrophilic honeycomb filler is added and stirred together, so that the viscosity mutation is destroyed, and the viscosity value of the liquid medicine is stably increased.
Compared with example 5, comparative examples 4 to 7 respectively change the screen type of sucrose sieving and the preparation method of the antistatic agent, so that the sieving of the sucrose raw material is influenced, and finally, the dissolution rate of xanthan gum is reduced.
Compared with example 6, comparative examples 8 to 10 respectively change the preparation raw materials of the hydrophilic honeycomb filler, so that the xanthan/sucrose dry mixture generates a certain degree of mutation after being added, and the stability of the liquid medicine is influenced.
The invention has the beneficial effects that: according to the preparation method of the ibuprofen suspension, the ibuprofen raw material medicine is subjected to micronization pretreatment by combining a recrystallization method and adding a stabilizer, so that the particle size of the medicine powder can be remarkably reduced, and the stability and the utilization rate of the medicine can be improved; the sucrose is crushed and sieved by an antistatic screen, and then is mixed with 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 above-mentioned embodiments are only preferred embodiments of the present invention, and not intended to limit the present invention, and although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications and equivalents can be made in the technical solutions described in the foregoing embodiments, or some technical features thereof can be replaced. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A pretreatment method of ibuprofen bulk drug is characterized in that: the method comprises the following steps:
placing 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, 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, water and sodium carbonate, then dripping diglycidyl ether into the mixture under the stirring condition of 100-110 ℃, and reacting for 1-3 hours after dripping;
s2, uniformly mixing polyethylene glycol, water and tertiary amine, slowly dripping into the product obtained in the step S1 under the stirring condition of 105-120 ℃, and reacting for 3-5 hours after dripping to obtain the stabilizer.
2. The pretreatment method of ibuprofen bulk drug according to claim 1, characterized in that: in the step of pretreating the ibuprofen raw material drug, the mass ratio of the ibuprofen raw material drug to absolute ethyl alcohol to stabilizer to water is 1: (22-30): (0.3-0.6): (200-400), the acceleration of the aqueous solution drop containing the stabilizer is 2-5 ml/min, and the stirring speed is 800-1000 r/min.
3. The pretreatment method of ibuprofen bulk drug according to claim 1, characterized in that: 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 the 4-dodecylphenol to the water to the sodium carbonate is 1: (5-15): (0.2-0.3), in the step S2, the mass ratio of the polyethylene glycol to the water to the tertiary amine is 1: (3-5): (0.1-0.2).
4. A method for preparing ibuprofen suspension by adopting the ibuprofen bulk drug obtained by the pretreatment method in claim 1 is characterized by comprising the following steps: the method comprises the following steps:
(1) Mixing sucrose and xanthan gum with the formula amount of 7% in a dry way to obtain a xanthan gum/sucrose dry mixture for later use;
(2) Adding normal temperature water into the liquid preparation tank, starting stirring, sequentially adding sodium benzoate, pregelatinized starch, sucrose with the formula amount of 93%, glycerol and citric acid, heating to boil, keeping the temperature, 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 dry xanthan gum/sucrose mixture, slowly adding the dry xanthan gum/sucrose mixture into a mixing tank under stirring, and stirring until the dry xanthan gum/sucrose mixture is dissolved;
(4) Adding lemon yellow, allura red, strawberry essence and polysorbate 80 into a mixing tank, stirring for 10-20 min, and mixing uniformly;
(5) Pretreating the ibuprofen raw material medicine, then adding the ibuprofen raw material medicine into a mixing tank, uniformly mixing, adding water to a constant volume of 1000mL, stirring, and encapsulating to obtain an ibuprofen suspension finished product.
5. An antistatic screen in a process for the preparation of an ibuprofen suspension according to claim 4, characterized in that: the cane sugar with the formula amount of 7% is obtained by crushing a cane sugar raw material and sieving the crushed cane sugar through an antistatic screen with the size of 0.075-0.12 mm, the antistatic screen is obtained by blending synthetic fibers and an antistatic agent and then carrying out melt spinning forming, and the addition amount of the antistatic agent is 0.5-2% of the total mass of the synthetic fibers.
6. The antistatic screen of claim 5, wherein: the preparation method of the antistatic agent comprises the following steps:
A. drying talcum powder, adding the dried talcum powder into an ethanol solution of tetraethoxy divinyl disiloxane, stirring and reacting at the temperature of 80-90 ℃ for 40-60 min, and filtering and drying to obtain a product 1;
B. carrying out esterification reaction 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 carrying out addition polymerization reaction on the obtained esterification product and treated talcum powder under the condition of an initiator to obtain a product 2;
C. and (3) carrying out esterification reaction on ethanolamine and unsaturated fatty acid under the catalysis of concentrated sulfuric acid, and carrying out addition polymerization reaction on the obtained esterification product, the product 2 and unsaturated polyoxyethylene ether under the condition of an initiator to obtain the finished product of the antistatic agent.
7. The antistatic screen of claim 6, wherein: the molar ratio of the tetraethoxydivinyl 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 tetraethoxy divinyl disiloxane to ethanol is 1: (4-8), wherein the mass of the tetraethoxy divinyl 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, the unsaturated fatty alcohol is 9-decaene-1-alcohol, 9-octadecen-1-ol or cis-11-hexadecen-1-ol; in the step C, the molar ratio of the ethanolamine to the unsaturated fatty acid is (1.1-1.2): 1, the unsaturated fatty acid is acrylic acid, octenoic acid or undecylenic acid.
8. A hydrophilic honeycomb filler in a process for the preparation of an ibuprofen suspension according to any of claims 5 to 7, characterized in that: stirring and dissolving a xanthan gum/sucrose dry mixture in the preparation process step (3) of the ibuprofen suspension, and then adding a hydrophilic honeycomb filler and continuously stirring for 20-30 min; the hydrophilic honeycomb filler is prepared by spraying hydrophilic coating on the surface of the honeycomb filler.
9. The hydrophilic honeycomb filler according to claim 8, wherein: 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 water-based epoxy curing agent, 6-14 parts of hydrophilic polymer and 3-5 parts of inorganic filler, wherein the hydrophilic polymer is obtained by performing hydrosilylation on acetic acid and 1, 2-epoxy-9-decene after addition esterification and then performing hydrosilylation on the acetic acid and the tri-tert-butylsilane.
10. The hydrophilic honeycomb filler according to claim 9, characterized in that: the preparation method of the hydrophilic macromolecule comprises the following steps:
adding acetic acid, an organic acid chromate catalyst and methylbenzene into a reaction kettle, uniformly mixing, slowly adding 1, 2-epoxy-9-decene, stirring and reacting at 100-120 ℃ for 5-8 h, cooling, evaporating a solvent, carrying out reduced pressure distillation to obtain a polyoxyethylene acetate type product, uniformly mixing the polyoxyethylene acetate type product with the methylbenzene and a platinum catalyst, slowly adding tri-tert-butylsilane, stirring and reacting at 80-90 ℃ for 4-6 h, and then evaporating the solvent to obtain a hydrophilic polymer, wherein the molar ratio of the acetic acid to the 1, 2-epoxy-9-decene to the tri-tert-butylsilane is 1: (5-20): (1-5).
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| 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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