CN113730352B - Dimethicone emulsion and preparation method thereof - Google Patents
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Abstract
The invention relates to a dimeticone emulsion and a preparation method thereof, wherein a high-pressure homogenization mode is adopted in the preparation process of the emulsion, the reaction conditions and the adding sequence of materials in the reaction process are strictly controlled, so that the dimeticone in the prepared emulsion is uniformly dispersed, can not be adhered to the inner wall surface of a tank, and can not generate the phenomenon of ointment or oil drops, the content of the dimeticone is high, D is high, and 90 the emulsion has the advantages of about 1 mu m particle size, large specific surface area, short defoaming time, good defoaming capability and stability, and the defoaming capability of the emulsion reaches 98 percent even at the high temperature of 60 ℃, so that the good stability is maintained. The dimeticone emulsion prepared by the method has low requirement on production equipment in the homogenizing process, and is suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a simethicone emulsion and a preparation method thereof.
Background
The simethicone is a dimethyl siloxane polymer, is a medical antifoaming agent commonly used in clinic, and can change the surface tension of bubbles to break the bubbles due to small surface tension, so that foams are eliminated.
Simethicone is insoluble in water, methanol, vegetable oils and paraffin, slightly soluble in ethanol, butanol and glycerol, and readily soluble in benzene, toluene, xylene, diethyl ether and chloroalkanes.
Emulsions belong to thermodynamically unstable heterogeneous systems.
The currently used dimeticone emulsion is prepared by mixing dimeticone and an emulsifier, emulsifying with a proper amount of water and adding other auxiliary materials. However, during the preparation of the dimeticone emulsion, the dimeticone is often adhered to the inner wall of the preparation tank body to cause low content, and meanwhile, the dimeticone is difficult to clean and difficult to clean after production, and the heat stability of the produced dimeticone emulsion is poor.
Chinese patent CN102048690A discloses a dimeticone emulsion and a preparation method thereof, which is characterized in that after a dimeticone silicon dioxide compound and a mixed emulsifier are mixed, a proper amount of water is added for homogenization, and the homogenized mixed solution is mixed with other auxiliary materials to obtain the dimeticone emulsion. In the preparation process, the requirement on the homogenizing condition is strict, the homogenizing rotating speed needs to reach 7000 r/min-10000 r/min, the condition can be realized in small-scale equipment in a laboratory, but the rotating speed is difficult to reach high in industrial production equipment, and the industrial large-scale production is difficult to carry out. In addition, during the preparation process of the dimeticone emulsion, the dimeticone is generally adhered to the inner wall of the tank body and is difficult to clean, so that the production efficiency is reduced, and the dimeticone content in the emulsion is low, oil drops are easy to appear under the condition of high temperature, and the thermal stability is poor.
Disclosure of Invention
The invention aims to provide a preparation method of a simethicone emulsion on the basis of the prior art.
Another object of the present invention is to provide a simethicone emulsion prepared by the above method.
The technical scheme of the invention is as follows:
a method for preparing dimeticone emulsion comprises the following steps:
(1) Uniformly mixing the dimeticone and the silicon dioxide, stirring and reacting for 10-60 hours at the temperature of 140-200 ℃, cooling to 10-30 ℃, adding a mixture of polysorbate 80 and sorbitan oleate, and stirring and mixing uniformly;
(2) Swelling the carboxymethyl cellulose in purified water at 50-80 ℃, uniformly stirring, adding the mixture into the mixed solution obtained in the step (1), and uniformly stirring and mixing;
(3) Uniformly mixing ethylparaben, dibutyl hydroxy toluene and absolute ethyl alcohol, adding into the mixed solution obtained in the step (2), and uniformly stirring and mixing;
(4) Homogenizing the mixed solution obtained in the step (3) under high pressure, wherein the homogenizing pressure is 200-1000 Bar, the homogenizing temperature is 50-80 ℃, the homogenizing frequency is 3-9 times, and cooling to 10-30 ℃ for later use after the high-pressure homogenization is finished;
(5) Dissolving saccharin sodium and essence in purified water, adding into the cooled mixed solution obtained in step (4), stirring, mixing, adding water to a constant volume, and continuously stirring to obtain simethicone emulsion;
wherein, every 300L of the simethicone emulsion contains the following components: 4-8 kg of dimethyl silicone oil, 0.1-0.3 kg of silicon dioxide, 1.2-1.5 kg of polysorbate, 1.2-1.5 kg of sorbitan oleate, 4-5 kg of carboxymethyl cellulose sodium, 0.2-0.4 kg of ethylparaben, 0.001-0.005 kg of dibutyl hydroxy toluene, 2-5 kg of absolute ethyl alcohol, 0.1-0.3 kg of saccharin sodium and 0.1-0.3 kg of essence.
The dimeticone emulsion prepared by the method adopts a high-pressure homogenization mode in the preparation process of the emulsion, strictly controls the reaction conditions and the adding sequence of materials in the reaction process, ensures that the dimeticone in the prepared emulsion can not be adhered to the inner wall surface of a tank, does not generate ointment or oil drops, has high dimeticone content and good defoaming capability and stability, and ensures that the defoaming capability of the emulsion reaches 98 percent and the good stability is maintained even if the prepared emulsion is placed at the high temperature of 60 ℃ for 30 days.
In the experimental process, it is found that in the step (1), the simethicone and the silicon dioxide are uniformly mixed, and are stirred and reacted at the temperature of 140-200 ℃, the stirring and reacting time needs to be strictly controlled, and the stirring and reacting time is too short, so that the defoaming capability of the prepared simethicone emulsion is reduced under the condition of high temperature, for example, at the temperature of 60 ℃, and the reduction amplitude of the defoaming capability is gradually increased along with the increase of the time.
For the invention, the stirring time in the step (1) is controlled to be 10-60 hours, under the action of the coordination of other conditions, the prepared dimeticone emulsion has good defoaming capability and stability, and even if the dimeticone emulsion is placed at the high temperature of 60 ℃ for 30 days, the defoaming capability of the emulsion reaches 98%, no oil drop occurs, and the good stability is maintained. In a preferred embodiment, the reaction time is 10 to 24 hours with stirring.
For the present invention, in the step (1), the temperature of the stirring reaction is 140 to 200 ℃, and may be, but not limited to, 140 ℃, 150 ℃, 160 ℃, 170 ℃, 180 ℃ or 200 ℃, and for better effects, the temperature of the stirring reaction is 160 to 180 ℃.
In the step (2), the carboxymethyl cellulose is swelled in purified water at 50-80 ℃ to obtain a uniform viscous solution, and in the experimental process, the temperature of the purified water has a non-negligible influence on the property, content, defoaming capability and stability of the prepared emulsion. When the temperature of the purified water is too low, an oil layer or ointment appears on the surface of the prepared emulsion, the oil layer or ointment adheres to the inner wall surface of the tank and is difficult to clean, so that the content is low, and the defoaming capability and the stability are also particularly poor. When the temperature of the purified water is too high, emulsion particles are damaged in the preparation process of the emulsion, and the emulsion particles float upwards in a flocculent shape, so that the emulsion has poor properties, low content, poor defoaming capability and poor stability.
For the invention, the temperature of purified water is controlled to be 50-80 ℃ in the swelling process, but not limited to 50 ℃, 60 ℃, 65 ℃, 70 ℃ or 80 ℃, under the coordination of other conditions, the prepared dimeticone emulsion has good defoaming capability and stability, even if the dimeticone emulsion is placed at the high temperature of 60 ℃ for 30 days, the defoaming capability of the dimeticone emulsion reaches 98%, ointment and oil drops do not appear, and the stability is excellent. In a preferred embodiment, in the step (2), the temperature of the purified water at the time of swelling is 60 to 70 ℃.
For the invention, in the step (4), a high-pressure homogenizing mode is adopted in the homogenizing process, high-shear homogenizing is not needed, under the coordination of other conditions, the problems that simethicone is easy to adhere to the surface of the inner wall of a tank in the preparation process of the emulsion and is difficult to clean, and the content is low are solved, ointment or oil drops do not appear, the defoaming capability and the emulsion stability are good, even if the emulsion is placed for 30 days at the high temperature of 60 ℃, the defoaming capability and the stability are still good, the requirement on production equipment is low, and the method is suitable for large-scale industrial production.
In the homogenizing process, the homogenizing pressure is controlled to be 200-1000 Bar, but the homogenizing pressure can be but is not limited to 200Bar, 300Bar, 400Bar, 500Bar, 600Bar, 700Bar, 800Bar, 900Bar or 1000Bar, and in order to obtain better effect, the homogenizing pressure is 400-800 Bar.
Further, the homogenization temperature is 50 to 80 ℃, but not limited to 50 ℃, 60 ℃, 65 ℃, 70 ℃ or 80 ℃, and for better effect, the homogenization temperature is 60 to 70 ℃.
Further, the number of homogenization is 3 to 9, but not limited to 3, 4, 6, 7, 8 or 9, and in order to obtain a more preferable effect, the number of homogenization is 4 to 8.
In the invention, the auxiliary materials such as the dimeticone, the silicon dioxide, the carboxymethyl cellulose, the polysorbate 80, the sorbitan oleate and the like are homogenized under high pressure, and the pressure, the temperature and the times in the high-pressure homogenization process are controlled, so that the dimeticone is uniformly dispersed in the viscous carboxymethyl cellulose mixed solution, can not be adhered to the inner wall surface of a tank, and can not generate the phenomena of ointment and oil drops, and the dimeticone D in the prepared emulsion 90 The particle size is about 1 mu m, the specific surface area is large, the defoaming time is short, the content of dimeticone is high, the defoaming capability and the emulsion stability are good, the defoaming capability and the stability are still kept even if the emulsion is placed at the high temperature of 60 ℃ for 30 days, the requirement on production equipment is low, and the emulsion is suitable for large-scale industrial production.
In the experimental process, the problem that simethicone is adhered to the inner wall surface of a tank, the problem of difficult cleaning and low content exists in the prepared emulsion by adopting the homogenization condition disclosed in the prior art and the high-pressure homogenization condition of the invention without adding or partially adding a uniform solution swelled by carboxymethyl cellulose in the homogenization process, and if the condition is not controlled properly, the prepared emulsion even has ointment or oil drops, the defoaming capability is good, and the stability of the emulsion is poor.
By adopting the technical scheme of the invention, the advantages are as follows:
the invention provides a method for preparing dimeticone emulsion, which adopts a high-pressure homogenization mode in the preparation process of the emulsion and strictly controls the reaction conditions and the adding sequence of materials in the reaction process, so that the dimeticone in the prepared emulsion is uniformly dispersed, can not be adhered to the inner wall surface of a tank, and can not generate ointment or oil drops, the content of the dimeticone is high, D is D 90 The emulsion has the advantages of particle size of about 1 mu m, large specific surface area, short defoaming time, good defoaming capability and stability, and good stability, wherein the defoaming capability of the emulsion reaches 98% even if the emulsion is placed at a high temperature of 60 ℃ for 30 days.
The dimeticone emulsion prepared by the method of the invention does not need high shear homogenization in the homogenization process, has low requirements on production equipment, and is suitable for large-scale industrial production.
Detailed Description
The simethicone emulsion and the preparation method thereof of the present invention are further illustrated by the following examples, which are not intended to limit the present invention in any way.
Example 1
A simethicone emulsion comprises the following components, which are shown in Table 1 in detail:
table 1 formulation Components and specific amounts
| Dimethicone | 6kg |
| Silicon dioxide | 0.15kg |
| Polysorbate 80 | 1.35kg |
| Sorbitan oleate | 1.35kg |
| Sodium carboxymethylcellulose | 4.5kg |
| Hydroxyphenyl Ethyl ester | 0.3kg |
| Dibutylhydroxytoluene | 0.003kg |
| Anhydrous ethanol | 3kg |
| Saccharin sodium salt | 0.15kg |
| Essence | 0.15kg |
| Adding water to constant volume | 300L |
The preparation method comprises the following steps:
(1) Stirring and mixing the dimeticone and the silicon dioxide, stirring and reacting for 12 hours at the temperature of 170 ℃, cooling to 10-30 ℃, adding a mixture of polysorbate 80 and sorbitan oleate, and stirring and mixing uniformly;
(2) Swelling carboxymethyl cellulose in 200kg of purified water with the temperature of 65 ℃, uniformly stirring, adding the mixture into the mixed solution obtained in the step (1), and uniformly stirring and mixing;
(3) Dissolving ethylparaben and dibutyl hydroxy toluene in absolute ethyl alcohol, adding into the mixed solution obtained in the step (2), and stirring and mixing uniformly;
(4) Carrying out high-pressure homogenization on the mixed solution obtained in the step (3), wherein the homogenization pressure is 600Bar, the homogenization temperature is 65 ℃, the homogenization times are 6 times, and cooling to 10-30 ℃ for later use after the high-pressure homogenization is finished;
(5) And (5) dissolving saccharin sodium and essence in purified water, adding the purified water into the cooled mixed solution obtained in the step (4), stirring and mixing uniformly, adding water to a constant volume, and continuously stirring uniformly to obtain the simethicone emulsion.
Example 2
The formula of the dimeticone emulsion in the embodiment is the same as that in the embodiment 1, and the specific preparation method is as follows:
(1) Stirring and mixing the dimeticone and the silicon dioxide, stirring and reacting for 24 hours at 160 ℃, cooling to 10-30 ℃, adding a mixture of polysorbate 80 and sorbitan oleate, and stirring and mixing uniformly;
(2) Swelling carboxymethyl cellulose in 200kg of purified water with the temperature of 70 ℃, uniformly stirring, adding the mixture into the mixed solution obtained in the step (1), and uniformly stirring and mixing;
(3) Dissolving ethylparaben and dibutyl hydroxy toluene in absolute ethyl alcohol, adding into the mixed solution obtained in the step (2), and stirring and mixing uniformly;
(4) Homogenizing the mixed solution obtained in the step (3) under high pressure, wherein the homogenizing pressure is 800Bar, the homogenizing temperature is 70 ℃, the homogenizing times are 4 times, and cooling to 10-30 ℃ for later use after the high-pressure homogenization is finished;
(5) And (3) dissolving saccharin sodium and essence in purified water, adding the mixture into the cooled mixed solution obtained in the step (4), uniformly stirring, adding water to a constant volume, and continuously uniformly stirring to obtain the simethicone emulsion.
Example 3
The formula of the dimeticone emulsion in the embodiment is the same as that in the embodiment 1, and the specific preparation method is as follows:
(1) Stirring and mixing the dimeticone and the silicon dioxide, stirring and reacting for 10 hours at the temperature of 170 ℃, cooling to 10-30 ℃, adding a mixture of polysorbate 80 and sorbitan oleate, and stirring and mixing uniformly;
(2) Swelling carboxymethyl cellulose in 200kg of purified water with the temperature of 60 ℃, uniformly stirring, adding the mixture into the mixed solution obtained in the step (1), and uniformly stirring and mixing;
(3) Dissolving ethylparaben and dibutyl hydroxy toluene in absolute ethyl alcohol, adding into the mixed solution obtained in the step (2), and stirring and mixing uniformly;
(4) Homogenizing the mixed solution obtained in the step (3) under high pressure, wherein the homogenizing pressure is 400Bar, the homogenizing temperature is 60 ℃, the homogenizing times are 8 times, and cooling to 10-30 ℃ for later use after the high-pressure homogenization is finished;
(5) And (3) dissolving saccharin sodium and essence in purified water, adding the mixture into the cooled mixed solution obtained in the step (4), uniformly stirring, adding water to a constant volume, and continuously uniformly stirring to obtain the simethicone emulsion.
The dimeticone emulsion prepared in the example is subjected to influence factor and stability investigation:
the samples in the examples were placed under light irradiation of 4500Lux at a high temperature of 60 ℃ for 30 days, and under accelerated conditions (40 ℃ &75% RH) for 6 months, and the properties of the samples, the content of dimethicone, the particle size of emulsion droplets, the Zera potential, the defoaming ability, and the emulsion stability were examined.
And (3) detection of defoaming capability: taking 50ml of a non-foam 1% Triton X-100 aqueous solution, carefully injecting the solution into two clean 250ml measuring cylinders, measuring 2.0ml of a test sample, placing the test sample into one measuring cylinder, sealing the two measuring cylinders, similarly and intensively shaking for 5 times, measuring the foam height after 1 minute, and calculating the defoaming capability to be not less than 80% by taking the foam amount of a non-emulsion sample as 100% and reducing the foam amount of the test sample.
Emulsion stability: after shaking the test sample up, 10ml of the sample is placed in a centrifuge tube and centrifuged at 4000 rpm for 15 minutes, and if no layering phenomenon is observed, the sample meets the regulations.
The influence factors and stability test results of the samples in example 1 are shown in Table 2, and the samples in example 2 and example 3 have similar experimental results.
Table 2 example 1 sample influencing factors and stability investigation results
The experiments show that the dimeticone emulsion prepared by the invention has good stability, is placed for 30 days under the condition of influencing factors (illumination 4500Lux and high temperature 60 ℃) and is placed for 6 months under the condition of accelerated test (40 ℃ and 75 percent RH), and the content, the pH value, the particle size, the Zeta potential, the defoaming capability and the emulsion stability of the sample have no obvious difference compared with 0 day.
Comparative example 1
A simethicone emulsion comprises the following components, which are shown in Table 3:
TABLE 3 Components and specific amounts in the formulations
The preparation method comprises the following steps:
(1) Uniformly mixing the dimeticone and the silicon dioxide, placing the mixture in an oven at the temperature of 170 ℃ for 4 hours, taking out the mixture, and cooling the mixture to 10-30 ℃ to obtain a dimeticone silicon dioxide compound for later use;
(2) Dispersing sodium carboxymethylcellulose into 500mL of purified water to obtain a uniform solution for later use;
(3) Dissolving dibutyl hydroxy toluene with anhydrous ethanol to obtain uniform ethanol solution;
(4) Evenly mixing polysorbate 80 and sorbitan oleate to obtain a mixed emulsifier for later use;
(5) Dissolving saccharin sodium, essence and ethylparaben with 100mL of water to obtain a uniform solution for later use;
(6) Mixing the dimeticone silicon dioxide compound and the mixed emulsifier at 75 ℃, adding the mixture into 200mL of purified water at 75 ℃, homogenizing in a homogenizer for 3min at a homogenizing rotation speed of 10000r/min, and then stirring and cooling at a stirring rotation speed of 20r/min;
(7) And 6, adding the carboxymethyl cellulose sodium dispersion solution, the dibutyl hydroxy toluene ethanol solution, the saccharin sodium, the fresh milk essence and the ethylparaben solution when the temperature is reduced to 40 ℃, finally adding water to a constant volume of 1000mL, stirring and cooling to 10-30 ℃.
Comparative example 2
The formulation of the simethicone emulsion in this comparative example is the same as that in example 1, and the specific preparation method is as follows:
(1) Uniformly mixing the dimeticone and the silicon dioxide, placing the mixture in an oven at the temperature of 170 ℃ for 12 hours, taking out the mixture, and cooling the mixture to 10-30 ℃ for later use;
(2) Dispersing sodium carboxymethylcellulose in 150L of purified water to obtain a uniform solution for later use;
(3) Dissolving dibutyl hydroxy toluene with absolute ethyl alcohol to obtain a uniform ethanol solution for later use;
(4) Evenly mixing polysorbate 80 and sorbitan oleate to obtain a mixed emulsifier for later use;
(5) Dissolving saccharin sodium, essence, and ethylparaben with 30L water to obtain uniform solution;
(6) Mixing the dimeticone silicon dioxide compound and a mixed emulsifier at 65 ℃, adding 60L purified water at 65 ℃, homogenizing in a homogenizer for 10min at 3000r/min, then carrying out high-pressure homogenization at 600Bar at 65 ℃ for 6 times, then stirring, cooling, and stirring at 20r/min;
(7) And 6, adding a carboxymethyl cellulose sodium dispersion solution, a dibutyl hydroxy toluene ethanol solution, saccharin sodium, fresh milk essence and an ethylparaben solution when the temperature is reduced to 40 ℃, finally adding water to a constant volume of 300L, stirring and cooling to 10-30 ℃.
Comparative example 3
The formulation of the simethicone emulsion in this comparative example is the same as that in example 1, and the specific preparation method is as follows:
(1) Stirring and mixing the dimeticone and the silicon dioxide, stirring and reacting for 9 hours at the temperature of 170 ℃, cooling to 10-30 ℃, adding a mixture of polysorbate 80 and sorbitan oleate, and stirring and mixing uniformly;
(2) Swelling carboxymethyl cellulose in 200kg of purified water with the temperature of 65 ℃, uniformly stirring, adding the mixture into the mixed solution obtained in the step (1), and uniformly stirring and mixing;
(3) Dissolving ethylparaben and dibutyl hydroxy toluene in absolute ethyl alcohol, adding into the mixed solution obtained in the step (2), and stirring and mixing uniformly;
(4) Homogenizing the mixed solution obtained in the step (3) under high pressure, wherein the homogenizing pressure is 600Bar, the homogenizing temperature is 65 ℃, the homogenizing times are 6 times, and cooling to 10-30 ℃ for later use after the high-pressure homogenization is finished;
(5) And (5) dissolving saccharin sodium and essence in purified water, adding the purified water into the cooled mixed solution obtained in the step (4), stirring and mixing uniformly, adding water to a constant volume, and continuously stirring uniformly to obtain the simethicone emulsion.
Comparative example 4
The formulation of the simethicone emulsion in this comparative example is the same as that in example 1, and the specific preparation method is as follows:
(1) Stirring and mixing the dimeticone and the silicon dioxide, stirring and reacting for 12 hours at the temperature of 170 ℃, cooling to 10-30 ℃, adding a mixture of polysorbate 80 and sorbitan oleate, and stirring and mixing uniformly;
(2) Swelling carboxymethyl cellulose in 200kg of purified water with the temperature of 40 ℃, uniformly stirring, adding the mixture into the mixed solution obtained in the step (1), and uniformly stirring and mixing;
(3) Dissolving ethylparaben and dibutyl hydroxy toluene in absolute ethyl alcohol, adding into the mixed solution obtained in the step (2), and stirring and mixing uniformly;
(4) Carrying out high-pressure homogenization on the mixed solution obtained in the step (3), wherein the homogenization pressure is 600Bar, the homogenization temperature is 40 ℃, the homogenization frequency is 6 times, and cooling to 10-30 ℃ for later use after the high-pressure homogenization is finished;
(5) And (3) dissolving saccharin sodium and essence in purified water, adding the mixture into the cooled mixed solution obtained in the step (4), uniformly stirring, adding water to a constant volume, and continuously uniformly stirring to obtain the simethicone emulsion.
Comparative example 5
The formulation of the simethicone emulsion in this comparative example is the same as that in example 1, and the specific preparation method is as follows:
(1) Stirring and mixing the dimeticone and the silicon dioxide, stirring and reacting for 12 hours at the temperature of 170 ℃, cooling to 10-30 ℃, adding a mixture of polysorbate 80 and sorbitan oleate, and stirring and mixing uniformly;
(2) Swelling carboxymethyl cellulose in 200kg of purified water with the temperature of 85 ℃, uniformly stirring, adding the mixture into the mixed solution obtained in the step (1), and uniformly stirring and mixing;
(3) Dissolving ethylparaben and dibutyl hydroxy toluene in absolute ethyl alcohol, adding into the mixed solution obtained in the step (2), and stirring and mixing uniformly;
(4) Homogenizing the mixed solution obtained in the step (3) under high pressure, wherein the homogenizing pressure is 600Bar, the homogenizing temperature is 85 ℃, the homogenizing times are 6 times, and cooling to 10-30 ℃ for later use after the high-pressure homogenization is finished;
(5) And (3) dissolving saccharin sodium and essence in purified water, adding the mixture into the cooled mixed solution obtained in the step (4), uniformly stirring, adding water to a constant volume, and continuously uniformly stirring to obtain the simethicone emulsion.
Comparative example 6
The formulation of the simethicone emulsion in this comparative example is the same as that in example 1, and the specific preparation method is as follows:
(1) Stirring and mixing the dimeticone and the silicon dioxide, stirring and reacting for 12 hours at the temperature of 170 ℃, cooling to 10-30 ℃, adding a mixture of polysorbate 80 and sorbitan oleate, and stirring and mixing uniformly;
(2) Swelling carboxymethyl cellulose in 200kg of purified water at 65 ℃, uniformly stirring, adding the uniform viscous solution accounting for 80% of the total mass into the mixed solution obtained in the step (1), and uniformly stirring and mixing;
(3) Dissolving ethylparaben and dibutyl hydroxy toluene in absolute ethyl alcohol, adding into the mixed solution obtained in the step (2), and stirring and mixing uniformly;
(4) Homogenizing the mixed solution obtained in the step (3) under high pressure, wherein the homogenizing pressure is 600Bar, the homogenizing temperature is 65 ℃, the homogenizing times are 6 times, and cooling to 10-30 ℃ for later use after the high-pressure homogenization is finished;
(5) And (3) dissolving saccharin sodium and essence in purified water, adding the mixture into the cooled mixed solution obtained in the step (4), continuously adding the solution swelled by the residual carboxymethyl cellulose in the step (2), uniformly stirring, adding water to a constant volume, and continuously uniformly stirring to obtain the simethicone emulsion.
The experimental results of the high temperature influencing factors of the emulsions prepared in examples and comparative examples are shown in tables 4 to 6, and the results of the cleaning conditions of the production equipment are shown in table 7.
TABLE 4 influence factor of high temperature 40 ℃ on Dimethicone emulsion samples from examples and comparative examples 0 day test results
TABLE 5 influence factor test results of high temperature 40 ℃ for Dimethicone emulsion samples in examples and comparative examples
TABLE 6 influence factor test results of high temperature 60 deg.C of Dimethicone emulsion samples in examples and comparative examples
TABLE 7 results of cleaning conditions of Dimethicone emulsion sample production facility in examples and comparative examples
Note: the cleaning method comprises the following steps: the cleaning agent is 0.5 percent of potassium hydroxide, 0.5 percent of sodium hydroxide, 2 percent of ethanol and 97 percent of purified water; the cleaning temperature is 60 ℃; the cleaning mode is that the cleaning agent is used for cleaning for 1 time, and the purified water is used for washing once. The higher the amount of drug remaining, the more difficult to clean.
As can be seen from tables 4 to 7: in the preparation process of the samples in the embodiments 1 to 3 of the invention, no oil layer is attached to the inner wall of the tank, and the drug residue is less than 3.08 mu g/cm 2 The cleaning is easy; the influence factors of high temperature of 40 ℃ and 60 ℃ have no obvious difference under 10 days, 30 days and 0 days, and compared with the samples in the comparative example, the high-temperature-resistant emulsion has better thermal stability, properties, defoaming capability, content and emulsion stability.
The sample (lot: 1L) in comparative example 1 is the emulsion prepared in example 1 of patent CN102048690A, and compared with the sample (lot: 300L) in example 1 of the present invention, oil layer is adhered to the inner wall of the tank during the preparation process, and the residual amount of the drug is 130.76 μ g/cm 2 It is difficult to clean; the influence factors of 0 day and 40 ℃ high temperature are not greatly different from those of 10 days and 30 days, but under the influence factor of 60 ℃ high temperature, the sample in the comparative example 1 has poor properties, oil drops appear, the content and the defoaming capability are obviously reduced, and the stability of the emulsion is poor.
Comparative example 2 sample (batch: 300L) is a sample prepared with reference to example 1 in patent CN102048690A in conjunction with actual production equipment. In actual production equipment, the rotating speed of a production type high-shear homogenizer cannot reach 7000 r/min-10000 r/min, high shear is firstly selected at 3000r/min for 10min in the homogenizing process, then high-pressure homogenization is carried out, and in the preparation process, high-pressure homogenization is carried outThe inner wall of the tank is adhered with an oil layer, and the drug residue is 90.85 mug/cm 2 It is difficult to clean. The influence factor results show that the comparative example 2 and the comparative example 1 have no great difference in thermal stability and defoaming capability under the influence factor of high temperature of 40 ℃; however, the thermal stability is worse under the influence of the high temperature of 60 ℃.
One obvious difference between comparative example 1 and comparative example 2 and the examples of the present application is that: comparative examples 1 and 2 in homogenizing, a dimethicone-silica mixture was mixed with a mixed emulsifier and then added to water to homogenize; in the embodiment, the dimeticone-silicon dioxide mixture and the mixed emulsifier are mixed and then added into the carboxymethyl cellulose sodium solution for high-pressure homogenization. For this difference, a comparative example 6 (batch: 300L) was provided, in which a dimethicone-silica mixture, a mixed emulsifier, and a solution swollen with 80% carboxymethylcellulose sodium were subjected to high-pressure homogenization, and there was no great difference in thermal stability and defoaming ability under the influence of a high temperature of 40 ℃; the defoaming capability can be reduced under the influence of the high temperature of 60 ℃, and the content is reduced along with the prolonging of the time, so that the poor defoaming capability is shown.
Comparative example 3 the sample (batch: 300L) is different from example 1 in that in comparative example 3, simethicone and silicon dioxide are stirred and mixed for 9 hours at 170 ℃ in the preparation process of the emulsion, and the short stirring reaction time directly influences the defoaming capability of the sample at high temperature of 60 ℃, so that the defoaming capability is obviously reduced.
Comparative example 4 (batch: 300L) differs from example 1 in that the temperature of purified water swelling sodium carboxymethylcellulose in comparative example 4 is low, and the homogenization temperature is also low during high-pressure homogenization, resulting in ointment adhesion to the inner wall of the tank during preparation of the emulsion, and a residual drug content of 430.61. Mu.g/cm 2 Difficult to clean; under the influence factor of 0 day, ointment appears on the surface layer, and has poor properties, low content, poor defoaming capability and poor stability; under the influence factors of high temperature of 40 ℃ and 60 ℃ for 10 days and 30 days, the performance of the emulsion is obviously reduced, and particularly poor properties, defoaming capability, content and emulsion stability are shown.
Comparative example 5 sample (batch): 300L) is different from example 1 in that the temperature of the purified water swelling sodium carboxymethylcellulose in comparative example 5 is higher, and the homogenization temperature is also higher during the high-pressure homogenization, so that the emulsion particles are destroyed during the preparation of the emulsion, and flocculent floating is formed, and the residual amount of the drug is 76.32. Mu.g/cm 2 It is difficult to clean; under the influence factor of 0 day, the surface layer has flocculent floating, poor properties, reduced content, poor defoaming capability and poor stability; under the influence factors of high temperature of 40 ℃ and 60 ℃ for 10 days and 30 days, the performance of the emulsion is obviously reduced, and particularly poor properties, defoaming capability, content and emulsion stability are shown.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it should be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (4)
1. The preparation method of the simethicone emulsion is characterized by comprising the following steps:
(1) Uniformly mixing simethicone and silicon dioxide, stirring and reacting for 10 to 24 hours at the temperature of 160 to 170 ℃, cooling to 10 to 30 ℃, adding a mixture of polysorbate 80 and sorbitan oleate, and stirring and uniformly mixing;
(2) Swelling sodium carboxymethylcellulose in purified water at 60-70 ℃, uniformly stirring, adding into the mixed solution obtained in the step (1), and uniformly stirring and mixing;
(3) Uniformly mixing ethylparaben, dibutyl hydroxy toluene and absolute ethyl alcohol, adding into the mixed solution obtained in the step (2), and uniformly stirring and mixing;
(4) Carrying out high-pressure homogenization on the mixed solution obtained in the step (3), wherein the homogenization pressure is 400-800Bar, the homogenization temperature is 60-70 ℃, the homogenization frequency is 4-8 times, and cooling to 10-30 ℃ for later use after the high-pressure homogenization is finished;
(5) Dissolving saccharin sodium and essence in purified water, adding into the cooled mixed solution obtained in step (4), stirring, mixing, adding water to a constant volume, and continuously stirring to obtain simethicone emulsion;
wherein, every 300L of the dimeticone emulsion contains the following components: 4 to 8kg of simethicone, 0.1 to 0.3kg of silicon dioxide, 80.2 to 1.5kg of polysorbate, 1.2 to 1.5kg of sorbitan oleate, 4 to 5kg of sodium carboxymethylcellulose, 0.2 to 0.4kg of ethylparaben, 0.001 to 0.005kg of dibutylhydroxytoluene, 2 to 5kg of absolute ethyl alcohol, 0.1 to 0.3kg of saccharin sodium and 0.1 to 0.3kg of essence.
2. The method of claim 1, wherein the simethicone emulsion comprises the following components in 300L: 5 to 7kg of simethicone, 0.13 to 0.17kg of silicon dioxide, 80.3 to 1.4kg of polysorbate, 1.3 to 1.4kg of sorbitan oleate, 4.3 to 4.7kg of sodium carboxymethylcellulose, 0.25 to 0.35kg of ethylparaben, 0.002 to 0.004kg of dibutyl hydroxy toluene, 2.5 to 3.5kg of absolute ethyl alcohol, 0.13 to 0.17kg of saccharin sodium and 0.13 to 0.17kg of essence.
3. The method of claim 1, wherein the simethicone emulsion comprises the following components in an amount of 300L: 6kg of dimeticone, 0.15kg of silicon dioxide, 1.35kg of polysorbate 80, 1.35kg of sorbitan oleate, 4.5kg of sodium carboxymethylcellulose, 0.3kg of ethylparaben, 0.003kg of butylated hydroxytoluene, 3kg of absolute ethyl alcohol, 0.15kg of saccharin sodium and 0.15kg of essence.
4. A simethicone emulsion prepared by the method of any one of claims 1-3.
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