This experiment adopts the reverse phase suspension polymerization method, using hydroxypropyl methylcellulose (HPMC) as the raw material, sodium hydroxide solution as the water phase, cyclohexane as the oil phase, and divinyl sulfone (DVS) as the cross-linking Mixture of Tween-20 and Span-60 as a dispersant, stirring at a speed of 400-900r/min to prepare hydrogel microspheres.
Key words: hydroxypropyl methylcellulose; hydrogel; microspheres; dispersant
1.Overview
1.1 Definition of hydrogel
Hydrogel (Hydrogel) is a kind of high molecular polymer that contains a large amount of water in the network structure and is insoluble in water. A part of hydrophobic groups and hydrophilic residues are introduced into the water-soluble polymer with a network crosslinked structure, and the hydrophilic The residues bind to water molecules, linking the water molecules inside the network, while the hydrophobic residues swell with water to form cross-linked polymers. Jellies and contact lenses in daily life are all hydrogel products. According to the size and shape of hydrogel, it can be divided into macroscopic gel and microscopic gel (microsphere), and the former can be divided into columnar, porous sponge, fibrous, membranous, spherical, etc. The currently prepared microspheres and nanoscale microspheres have good softness, elasticity, liquid storage capacity and biocompatibility, and are used in the research of entrapped drugs.
1.2 Significance of topic selection
In recent years, in order to meet the requirements of environmental protection, polymer hydrogel materials have gradually attracted widespread attention because of their good hydrophilic properties and biocompatibility. Hydrogel microspheres were prepared from hydroxypropyl methylcellulose as raw material in this experiment. Hydroxypropyl methylcellulose is a non-ionic cellulose ether, white powder, odorless and tasteless, and has irreplaceable characteristics of other synthetic polymer materials, so it has high research value in the polymer field.
1.3 Development status at home and abroad
Hydrogel is a pharmaceutical dosage form that has attracted much attention in the international medical community in recent years and has developed rapidly. Since Wichterle and Lim published their pioneering work on HEMA cross-linked hydrogels in 1960, the research and exploration of hydrogels has continued to deepen. In the mid-1970s, Tanaka discovered pH-sensitive hydrogels when measuring the swelling ratio of aged acrylamide gels, marking a new step in the study of hydrogels. my country is in the stage of hydrogel development. Due to the extensive preparation process of traditional Chinese medicine and complex components, it is difficult to extract a single pure product when multiple components work together, and the dosage is large, so the development of Chinese medicine hydrogel may be relatively slow.
1.4 Experimental materials and principles
1.4.1 Hydroxypropyl methylcellulose
Hydroxypropyl methyl cellulose (HPMC), a derivative of methyl cellulose, is an important mixed ether, which belongs to non-ionic water-soluble polymers, and is odorless, tasteless and non-toxic.
Industrial HPMC is in the form of white powder or white loose fiber, and its aqueous solution has surface activity, high transparency and stable performance. Because HPMC has the property of thermal gelation, the product aqueous solution is heated to form a gel and precipitates, and then dissolves after cooling, and the gelation temperature of different specifications of the product is different. The properties of different specifications of HPMC are also different. The solubility changes with the viscosity and is not affected by the pH value. The lower the viscosity, the greater the solubility. As the content of methoxyl group decreases, the gel point of HPMC increases, the water solubility decreases, and the surface activity decreases. In the biomedical industry, it is mainly used as a rate-controlling polymer material for coating materials, film materials, and sustained-release preparations. It can also be used as a stabilizer, suspending agent, tablet adhesive, and viscosity enhancer.
1.4.2 Principle
Using the reverse phase suspension polymerization method, using Tween-20, Span-60 compound dispersant and Tween-20 as separate dispersants, determine the HLB value (surfactant is an amphiphile with hydrophilic group and lipophilic group Molecule, the amount of the size and force balance between the hydrophilic group and the lipophilic group in the surfactant molecule is defined as the approximate range of the hydrophilic-lipophilic balance value of the surfactant. Cyclohexane is used as the oil phase. Cyclohexane can better disperse the monomer solution and dissipate the heat generated in the experiment continuously. The dosage is 1-5 times that of the monomer aqueous solution. With a concentration of 99% divinyl sulfone as the cross-linking agent, and the amount of the cross-linking agent is controlled at about 10% of the dry cellulose mass, so that multiple linear molecules are bonded to each other and cross-linked into a network structure. A substance that covalently bonds or facilitates or ionic bond formation between polymer molecular chains.
Stirring is very important to this experiment, and the speed is generally controlled at the third or fourth gear. Because the size of the rotational speed directly affects the size of the microspheres. When the rotation speed is greater than 980r/min, there will be serious wall sticking phenomenon, which will greatly reduce the product yield; The cross-linking agent tends to produce bulk gels, and spherical products cannot be obtained.
2. Experimental instruments and methods
2.1 Experimental Instruments
Electronic balance, multifunctional electric stirrer, polarizing microscope, Malvern particle size analyzer.
To prepare cellulose hydrogel microspheres, the main chemicals used are cyclohexane, Tween-20, Span-60, hydroxypropyl methylcellulose, divinyl sulfone, sodium hydroxide, distilled water, all of which Monomers and additives are used directly without treatment.
2.2 Preparation steps of cellulose hydrogel microspheres
2.2.1 Using Tween 20 as dispersant
Dissolution of hydroxypropylmethylcellulose. Accurately weigh 2g of sodium hydroxide and prepare a 2% sodium hydroxide solution with a 100ml volumetric flask. Take 80ml of the prepared sodium hydroxide solution and heat it in a water bath to about 50°C, weigh 0.2g of cellulose and add it to the alkaline solution, stir it with a glass rod, place it in cold water for an ice bath, and use it as the water phase after the solution is clarified. Use a graduated cylinder to measure 120ml of cyclohexane (oil phase) into a three-necked flask, draw 5ml of Tween-20 into the oil phase with a syringe, and stir at 700r/min for one hour. Take half of the prepared aqueous phase and add it to a three-necked flask and stir for three hours. The concentration of divinyl sulfone is 99%, diluted to 1% with distilled water. Use a pipette to take 0.5ml of DVS into a 50ml volumetric flask to prepare 1% DVS, 1ml of DVS is equivalent to 0.01g. Use a pipette to take 1ml into the three-neck flask. Stir at room temperature for 22 hours.
2.2.2 Using span60 and Tween-20 as dispersants
The other half of the water phase that has just been prepared. Weigh 0.01gspan60 and add it to the test tube, heat it in a 65-degree water bath until it melts, then drop a few drops of cyclohexane into the water bath with a rubber dropper, and heat it until the solution turns milky white. Add it to a three-neck flask, then add 120ml of cyclohexane, rinse the test tube with cyclohexane several times, heat for 5min, cool down to room temperature, and add 0.5ml of Tween-20. After stirring for three hours, 1ml of diluted DVS was added. Stir at room temperature for 22 hours.
2.2.3 Experimental results
The stirred sample was dipped in a glass rod and dissolved in 50ml of absolute ethanol, and the particle size was measured under a Malvern particle sizer. Using Tween-20 as a dispersant microemulsion is thicker, and the measured particle size of 87.1% is 455.2d.nm, and the particle size of 12.9% is 5026d.nm. The microemulsion of Tween-20 and Span-60 mixed dispersant is similar to that of milk, with 81.7% particle size of 5421d.nm and 18.3% particle size of 180.1d.nm.
3. Discussion of experimental results
For the emulsifier for preparing inverse microemulsion, it is often better to use the compound of hydrophilic surfactant and lipophilic surfactant. This is because the solubility of a single surfactant in the system is low. After the two are compounded, Each other’s hydrophilic groups and lipophilic groups cooperate with each other to have a solubilizing effect. The HLB value is also a commonly used index when selecting emulsifiers. By adjusting the HLB value, the ratio of the two-component compound emulsifier can be optimized, and more uniform microspheres can be prepared. In this experiment, weakly lipophilic Span-60 (HLB=4.7) and hydrophilic Tween-20 (HLB=16.7) were used as the dispersant, and Span-20 was used alone as the dispersant. From the experimental results, it can be seen that the compound The effect is better than a single dispersant. The microemulsion of the compound dispersant is relatively uniform and has a milk-like consistency; the microemulsion using a single dispersant has too high viscosity and white particles. The small peak appears under the compound dispersant of Tween-20 and Span-60. The possible reason is that the interfacial tension of the compound system of Span-60 and Tween-20 is high, and the dispersant itself is broken up under high-intensity stirring to form The fine particles will affect the experimental results. The disadvantage of the dispersant Tween-20 is that it has a large number of polyoxyethylene chains (n=20 or so), which makes the steric hindrance between the surfactant molecules larger and it is difficult to be dense at the interface. Judging from the combination of particle size diagrams, the white particles inside may be undispersed cellulose. Therefore, the results of this experiment suggest that the effect of using a compound dispersant is better, and the experiment can further reduce the amount of Tween-20 to make the prepared microspheres more uniform.
In addition, some errors in the experimental operation process should be minimized, such as the preparation of sodium hydroxide in the dissolution process of HPMC, the dilution of DVS, etc., should be standardized as much as possible to reduce experimental errors. The most important thing is the amount of dispersant, the speed and intensity of stirring, and the amount of cross-linking agent. Only when properly controlled can hydrogel microspheres with good dispersion and uniform particle size be prepared.