Method for continuously preparing nano-emulsion by using temperature-controllable low-power ultrasonic tandem jacketed glass emulsifier

Abstract

The invention provides a method for continuously preparing nano-emulsion through a temperature-controllable low-power ultrasonic tandem jacketed glass emulsifier, and belongs to the technical field of nano-emulsions.The method comprises the following steps that 1, a water phase is prepared, specifically, a surfactant is added into deionized water, and the water phase is obtained; (2) preparing a pre-emulsion: adding the oil phase into the water phase to obtain an initial material, and then pre-emulsifying the initial material by adopting a high-speed homogenizer to form an initial emulsion; and (3) continuously preparing the nano-emulsion by using a temperature-controllable low-power ultrasonic tandem jacketed glass emulsifier to obtain the nano-emulsion. According to the method, the temperature is controllable, the transparent or semitransparent nano-emulsion which is small in particle size, has single dispersity and is stable for a long time can be continuously obtained under the conditions of low emulsifier input and mild emulsification, and the performance of the nano-emulsion is obviously better than that of nano-emulsions prepared by other high-energy emulsification methods.

Description

Technical Field

[0001] The invention belongs to the technical field of nanoemulsions, and in particular relates to a method for continuously preparing nanoemulsions using a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier. Background Art

[0002] Nanoemulsions usually have higher stability and bioavailability due to their small particle size and high specific surface area. This is of great significance for improving the efficacy of active ingredients, reducing side effects, and masking the odor of active ingredients. Soybean oil is widely used as the oil phase for preparing nanoemulsions due to its abundant resources, good biocompatibility and stability. Soybean oil nanoemulsions are widely used in the fields of cosmetic production, food processing, drug sustained release and absorption.

[0003] The preparation process of soybean oil nanoemulsion is mainly divided into low-energy emulsification method and high-energy emulsification method. Low-energy emulsification method is a method for preparing nanoemulsion at low energy consumption. The key lies in adding a large amount of various types of emulsifiers (surfactants and their adjuvants) during the emulsification process, and realizing the nano-sizing of the emulsion through specific process steps and conditions, while maintaining the stability and uniformity of the emulsion, so as to achieve the goal of preparing high-quality nanoemulsion at low energy consumption. This method has the advantages of energy saving and high efficiency, but it is limited by the type and dosage of emulsifiers. A large amount of emulsifier is often required to stabilize the droplets. High concentrations of emulsifiers may also cause side effects. Therefore, high-energy emulsification method has become more and more popular in recent years.

[0004] High-energy emulsification is a method for preparing nanoemulsions by using strong external forces (such as ultrasound, high-pressure homogenizer, etc.) to break up micron-sized droplets and quickly disperse them into nano-sized droplets. Generally speaking, this method uses a relatively small amount of emulsifier to efficiently and quickly prepare a large amount of nanoemulsions to meet the needs of large-scale production. The high-energy emulsification method can accurately control the particle size and distribution of the nanoemulsion by controlling operating parameters such as pressure, temperature, and time, thereby obtaining an ideal product, which is particularly important for application scenarios that require a specific particle size range. Almost any oil phase can be subjected to high-energy nanoemulsification, making it widely used in multiple fields such as drug delivery, cosmetics, and food. Therefore, as an advanced preparation technology, the high-energy emulsification method has the advantages of low emulsifier dosage, high efficiency and speed, controllable particle size, wide applicability, and enhanced functionality, stability, and bioavailability.

[0005] However, the high-energy emulsification method also has some disadvantages, such as high equipment cost, high energy consumption, and limitation of temperature-sensitive drugs. Specifically, the high-energy emulsification method relies on expensive equipment (such as ultrasonic crusher, high-pressure homogenizer, etc.), and a large amount of energy is consumed to break the emulsion droplets during the emulsification process. The high temperature that may be generated may affect the stability of certain temperature-sensitive active ingredients. In addition, due to the use of low-dose emulsifiers, the nanoemulsion prepared by the high-energy emulsification method has a large particle size and is unstable. Common high-pressure homogenization and microfluidization often require multiple homogenizations, the steps are cumbersome, and the homogenization effect still has a lot of room for improvement. The ultrasonic emulsification method often uses a probe-type ultrasonic instrument, and the ultrasonic sound field intensity is unevenly distributed, resulting in low energy utilization and a wide particle size distribution. At the same time, the direct contact of the probe causes metal particle contamination of the emulsion, which limits the industrial application and promotion of ultrasonic emulsification. The microfluidic emulsification method has the defects of easy blockage of the reactor, slow mixing, and poor operating freedom. Therefore, in order to obtain stable and high-quality nanoemulsions, it is necessary to carefully optimize the process parameters of the high-energy emulsification method, such as the selection and ratio of oil phase, water phase, emulsifier, and temperature and pressure during the emulsification process. It is also necessary to consider factors such as the purification of the nanoemulsion, the side effects of the emulsifier, energy efficiency, and the service life of the equipment. Summary of the invention

[0006] The object of the present invention is to provide a method for continuously preparing nanoemulsions by using a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier. The method can continuously obtain transparent or translucent nanoemulsions with small particle size and monodispersity and long-term stability under relatively low emulsifier input and mild emulsification conditions, and the performance is significantly better than that of nanoemulsions prepared by other high-energy emulsification methods.

[0007] In order to achieve the above object, the present invention provides the following technical solutions:

[0008] A method for continuously preparing nanoemulsion by connecting a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier comprises the following steps:

[0009] (1) preparing an aqueous phase: adding a surfactant into deionized water to obtain an aqueous phase;

[0010] (2) preparing a pre-emulsion: adding the oil phase to the water phase to obtain an initial material, and then pre-emulsifying the initial material using a high-speed homogenizer to form an initial emulsion;

[0011] (3) preparing a nanoemulsion: the initial emulsion is emulsified by a temperature-controllable low-power ultrasonic series jacketed glass emulsifier to obtain a nanoemulsion;

[0012] The temperature-controllable low-power ultrasonic series jacketed glass emulsifier comprises an injection pump, an emulsion receiving bottle, and N ultrasonic jacketed glass emulsification units arranged in series between the injection pump and the emulsion receiving bottle, where N is greater than or equal to 2; the ultrasonic jacketed glass emulsification unit comprises an ultrasonic generator, a thermocouple thermometer, a circulating cooler, an ultrasonic transducer, and a glass jacketed beaker, wherein the ultrasonic transducer is connected to the glass jacketed beaker, the ultrasonic generator is connected to the ultrasonic transducer, and the circulating chiller and the thermocouple thermometer are respectively connected to the glass jacketed beaker.

[0013] Furthermore, the temperature-controllable low-power ultrasonic series jacketed glass emulsifier comprises a syringe pump, an emulsion receiving bottle, and two ultrasonic jacketed glass emulsification units arranged in series between the syringe pump and the emulsion receiving bottle.

[0014] The present invention connects two reactors in series, which is equivalent to dividing a high power into two low powers, so that an emulsion with a small particle size can be obtained. The first-stage emulsification can break the large oil droplets into small oil droplets, and the second-stage emulsification can further break the small oil droplets into smaller and more uniform emulsion droplets. Low power will also cause less loss to the reactor, thereby extending the life of the equipment. At the same time, the circulating chiller can make the reaction reach the optimal emulsification temperature at low power to obtain the optimal particle size, while the equipment in the prior art has no way to control the temperature and can only use higher power emulsification to obtain the optimal particle size.

[0015] The secondary ultrasonic emulsification currently available on the market requires the emulsion obtained by the primary ultrasonic emulsification to be injected into the glass emulsifier again through a syringe pump for secondary ultrasonic emulsification, which is not continuous enough compared to the tandem ultrasonic emulsification of the present invention. Therefore, continuous emulsification has the advantage of rapid mixing. During continuous emulsification, the temperature of the emulsion can remain almost unchanged during the process of the emulsion being transferred from the primary emulsification to the secondary emulsification. However, during intermittent emulsification, the temperature of the emulsion will drop after the primary emulsification when it leaves the reaction equipment, and it will take some time to heat up during the secondary emulsification, thereby affecting the temperature during emulsification. Therefore, continuous emulsification has good heat and mass transfer performance.

[0016] Furthermore, the glass jacketed beaker consists of an inner beaker and an outer jacket, the inner beaker is introduced with coolant through a circulating chiller, the outer jacket is connected to an injection pump to introduce the initial emulsion, and the coolant in the inner beaker heats or cools the initial emulsion in the outer jacket to control the temperature.

[0017] The present invention uses a syringe pump to transfer the initial emulsion into a glass jacket beaker through a connecting pipe, and an ultrasonic transducer converts the electrical signal generated by an ultrasonic generator into mechanical vibration, thereby generating cavitation in the glass jacket beaker, and continuously emulsifying is performed using the cavitation effect, and continuously emulsifying is performed at the bottom of the glass jacket beaker. The glass jacket beakers in the ultrasonic jacket glass emulsification unit are sequentially connected in series to form a continuous flow of the emulsion. In the continuous flow emulsification process, the inflow of the initial emulsion and the output of the nanoemulsion are both continuously performed. Compared with intermittent emulsification, it has the advantages of rapid mixing, good heat and mass transfer, easy amplification, and simple operation and maintenance.

[0018] Furthermore, the injection pump controls the flow rate of the initial emulsion to be 0.5 mL / min-2 mL / min.

[0019] Further, the temperature displayed by the thermocouple thermometer is 45°C-65°C.

[0020] Furthermore, the ultrasonic electric power of the ultrasonic generator is 57W-77W.

[0021] Temperature is very important for the preparation of nanoemulsions, which will affect the viscosity of the emulsion and thus the emulsification effect. However, it is difficult to control the temperature for ultrasonic emulsification to prepare nanoemulsions in the prior art. For example, the ultrasonic cleaning tank, which is common on the market, is heated to a set temperature and then stops heating, so it cannot be considered as temperature control. For example, if it keeps reacting, the cavitation effect will cause its temperature to rise continuously, and the temperature cannot be controlled at a certain expected given value. The position of the sensor used to monitor the temperature will affect the accuracy of the temperature reading. During the preparation of nanoemulsions in the ultrasonic cleaning tank, the heat transfer efficiency inside the emulsion may be inconsistent due to factors such as convection and diffusion. If the heating device is located on one side of the cleaning tank, it may cause uneven temperature distribution, and high-power ultrasound releases a large amount of heat. Due to the randomness and unevenness of the cavitation phenomenon, this heat release is not easy to accurately control. The device of the present invention can control the temperature of the emulsion through a circulating cooler during the entire emulsification process, and the thermocouple thermometer performs real-time display temperature control, which can ensure accurate temperature control during the ultrasonic emulsification process.

[0022] The temperature, flow rate and electric power in the device of the present invention work together to produce a nanoemulsion with small and uniform particle size under specific conditions. This is mainly because although theoretically the lower the flow rate, the better the emulsification effect, too low a flow rate can easily cause the droplets to aggregate to form large droplets; within a certain range, theoretically the higher the power, the better the emulsification effect, but increasing the power after the optimal power of the present invention cannot reduce the particle size, but instead causes more energy consumption; at the same time, with a suitable temperature, a nanoemulsion with small and uniform particle size can be obtained.

[0023] Furthermore, the ultrasonic frequency of the ultrasonic generator is 20-1000kHz.

[0024] Furthermore, the ultrasonic frequency of the ultrasonic generator is 20-50kHz.

[0025] Generally speaking, it is difficult to obtain a nanoemulsion with an average droplet size less than 60nm and uniformly dispersed by utilizing a 20-50kHz ultrasound-assisted high-energy emulsification method. To obtain the above-mentioned transparent or translucent high-quality nanoemulsion, it is generally necessary to adopt a 300-850kHz high-frequency ultrasonic emulsifier. However, the temperature-controlled low-power ultrasonic series jacketed glass emulsifier of the present invention can obtain a nanoemulsion with an average droplet size less than 60nm and uniformly dispersed by adopting a 20-50kHz low-frequency ultrasound.

[0026] The ultrasonic jacketed glass emulsification unit 3 comprises an ultrasonic transducer and a jacketed glass beaker (25-2500 mL) for mixing reactants; the jacketed glass beaker is tightly coupled with the ultrasonic transducer, and the jacketed glass beaker is located on the radiation surface of the ultrasonic transducer.

[0027] The present invention uses an impedance analyzer to measure the natural frequency of the ultrasonic generator and adjusts the parameters of the ultrasonic generator accordingly. The adjustment is the center frequency of the ultrasonic generator's frequency tracking. For example, if the measured natural frequency is 21.1kHz, the ultrasonic generator will use 21.1kHz as the center frequency for frequency tracking.

[0028] The thermocouple thermometer 44 is used to monitor the emulsification temperature of the emulsion in real time.

[0029] The circulating cooler 5 is used to control the emulsification temperature (10-80°C) of the emulsification in real time during the emulsification process. Since temperature plays a vital role in the preparation of nanoemulsions, the temperature can be controlled in real time during the emulsification process. However, there are currently few reports on the temperature control method of ultrasonic-assisted emulsification. The present invention describes in detail the real-time control and online detection method of the emulsification temperature. When the temperature is controlled at the optimal temperature for emulsification, the smallest droplet size can be obtained.

[0030] The emulsion receiving bottle 7 is used to receive the nanoemulsion.

[0031] Furthermore, the oil phase is vegetable oil.

[0032] Furthermore, the vegetable oil includes but is not limited to olive oil, peanut oil, rapeseed oil, and soybean oil.

[0033] Furthermore, in step (2), the volume ratio of the oil phase to the water phase is 1:(1-20).

[0034] Furthermore, in the step (1), the mass fraction of the surfactant in the water phase is 1%-20%; and the HLB value of the surfactant in the step (1) is 8-18.

[0035] Furthermore, the average particle size of the droplets of the nanoemulsion is less than 60 nm, and the polydispersity index PDI is 0.05-0.20.

[0036] Further, the thermocouple thermometer is arranged at the outlet of the emulsion of the glass jacketed beaker.

[0037] The present invention arranges the thermocouple thermometer at the outlet of the emulsion of the glass jacket beaker, which facilitates inserting the temperature detection line of the thermocouple thermometer into the device to monitor the temperature. Meanwhile, the temperature monitoring at this position is more beneficial to the quality of the nanoemulsion.

[0038] Furthermore, in step (2), the volume ratio of the oil phase to the water phase is 1:(1-20).

[0039] Furthermore, in step (2), the volume ratio of the oil phase to the water phase is 1:(8-10).

[0040] Furthermore, in step (1), the mass fraction of the surfactant in the water phase is 1%-20%.

[0041] Furthermore, in step (1), the mass fraction of the surfactant in the water phase is 5%-8%.

[0042] Furthermore, the HLB value of the surfactant in step (1) is 8-18.

[0043] Furthermore, the HLB value of the surfactant in step (1) is 10-14.

[0044] Compared with the prior art, the advantages and beneficial effects of the present invention are:

[0045] 1. The method of the present invention can be used to continuously prepare nanoemulsions of oils such as soybean oil. Under low emulsifier input and mild conditions, the average particle size of the nanoemulsion droplets that can be obtained is less than 60nm, and the polydispersity index (PDI) is 0.05-0.20. In addition, the obtained nanoemulsion is transparent or translucent and has long-term stability at 4°C and 25°C. The side effects caused by high-dose emulsifiers are essentially reduced. At the same time, the device of the present invention can prepare emulsions with a particle size of 35-500nm by changing the conditions, which can meet the market demand for emulsions of various particle sizes and has a wide range of applications.

[0046] 2. Compared with microfluidic emulsification and high-pressure homogenization emulsification technology, the present invention uses ultrasound-assisted emulsification technology to solve the blockage problem in microfluidic emulsification by unblocking cavitation bubbles and strengthening mass transfer, and improves the mixing efficiency by using microjets, shock waves and local high temperature and high pressure effects, and improves the degree of freedom of operation because of its adjustable power. Generally speaking, the prior art uses 20-50kHz ultrasound-assisted high-energy emulsification method to obtain a nanoemulsion with an average particle size of emulsion droplets less than 60nm and uniform dispersion. To obtain transparent or translucent high-quality nanoemulsion, it is generally necessary to use a 300-850kHz high-frequency ultrasonic emulsifier. However, the present invention uses 20-50kHz low-frequency ultrasound and a temperature-controlled low-power ultrasound series jacketed glass emulsifier to obtain a nanoemulsion with an average particle size of emulsion droplets less than 60nm and uniform dispersion.

[0047] 3. At the same time, the present invention adopts continuous flow technology to solve the problem of uneven ultrasonic sound field. In the continuous flow emulsification process, the inflow of the initial emulsion and the output of the nanoemulsion are both continuous. Compared with the intermittent emulsification in other methods, it has the advantages of rapid mixing, good heat and mass transfer, easy scale-up, simple operation and maintenance, etc. It effectively solves the problems of emulsion droplet size and dispersibility, as well as batch-to-batch differences.

[0048] 4. In the method of the present invention, temperature plays a vital role in the preparation process of nanoemulsion. It is necessary to realize real-time temperature control during the emulsification process. However, there are few reports on temperature control methods for ultrasonic-assisted emulsification. The present invention discloses real-time control and online detection methods for emulsification temperature. When the temperature is controlled at the optimal temperature for emulsification, the smallest droplet size can be obtained. By adjusting the primary or secondary ultrasonic power, the ultrasonic power or frequency combination can be flexibly changed to further improve energy efficiency and reduce energy consumption. The present invention adopts an online temperature control and monitoring method, which is more conducive to controlling the size and dispersibility of nanoemulsion droplets.

[0049] 5. The method of the present invention can reduce cavitation damage to the glass jacket mixer due to the low ultrasonic input power, and extend the service life of the jacket glass emulsifier. The ultrasonic series emulsifier is made of glass material, and the metal particle contamination of the nanoemulsion caused by ultrasonic cavitation of the conventional metal ultrasonic probe is completely eliminated. In order to extend the service life, the low-power, multi-emulsifier series technology is adopted to reduce the cavitation intensity of a single emulsifier, which can minimize the damage of cavitation to the emulsifier, and thus extend the service life of the emulsifier. Compared with mechanical stirring, high-pressure homogenization and other equipment, the present invention does not require large equipment and can be applied to laboratory sample processing and large-scale industrial applications. At the same time, the operating cost is low, the operation is simple, and the maintenance is convenient.

[0050] 6. The nanoemulsion prepared by the present invention has good storage stability. At 4°C and 25°C, the nanoemulsion continuously prepared by the temperature-controllable low-power ultrasonic series jacketed glass emulsifier of the present invention has very good stability. After long-term storage for 45 days at low and high temperatures, the average particle size of the emulsion droplets can still maintain good stability, which is of great significance for the practical application of the nanoemulsion. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 It is a schematic diagram of the structure of a temperature-controllable low-power ultrasonic series jacketed glass emulsifier.

[0052] Figure 2 The invention discloses a process flow for continuously preparing nanoemulsion by using a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier.

[0053] Figure 3 Example 1 Schematic diagram of the change of average particle size DS and polydispersity index PDI of nanoemulsion continuously prepared by a single ultrasonic jacketed glass emulsification unit with preparation time.

[0054] Figure 4 Example 8 Schematic diagram of the changes in the average particle size DS and polydispersity index PDI of the nanoemulsion prepared by the secondary cycle of a single ultrasonic jacketed glass emulsification unit with storage time.

[0055] Figure 5 Example 9: Schematic diagram of the change of average particle size DS and polydispersity index PDI of nanoemulsion with preparation time by continuous preparation of nanoemulsion using temperature-controllable low-power ultrasound in series with a jacketed glass emulsifier.

[0056] Figure 6 Example 9: Schematic diagram of the change of average particle size DS and polydispersity index PDI of nanoemulsion as a function of storage time for continuous preparation using a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier.

[0057] Figure 7 Schematic diagram comparing the emulsification conditions, average particle size of nanoemulsion droplets and their distribution of the tandem ultrasonic emulsification in Example 11 and the secondary ultrasonic emulsification in Example 8.

[0058] Figure 8 Comparative Example 1: Schematic diagram of the change of average particle size DS and polydispersity index PDI of nanoemulsion droplets with the number of cycles prepared by high-pressure homogenizer.

[0059] Fig. 9 Schematic diagram of the nanoemulsion prepared in Example 11.

[0060] Fig.10 Schematic diagram of the structure of a glass jacketed beaker.

[0061] Fig.11 Schematic diagram of the effect of different temperatures on particle size in Examples 1, 6, and 7.

[0062] In the figure, 1. injection pump, 2. ultrasonic generator, 3. ultrasonic transducer, 4. thermocouple thermometer, 5. circulating cooler, 6. glass jacketed beaker, 7. emulsion receiving bottle. DETAILED DESCRIPTION

[0063] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0064] See also Figure 1-2 The present invention provides a method for continuously preparing nanoemulsion by using a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier, comprising the following steps:

[0065] (1) Preparation of aqueous phase: Tween 80 and Span 80 were mixed as surfactants (Span 80 accounted for 28wt%, Tween 80 accounted for 72wt%, and HLB value was 12) and added to deionized water as aqueous phase, wherein the mass fraction of the surfactant in the aqueous phase was 6%. HLB value, i.e., hydrophilic-lipophilic balance value, is an indicator to measure the degree of balance between hydrophilic groups and lipophilic groups in surfactant molecules. Surfactants with high HLB values ​​mean that the hydrophilic groups in their molecules accounted for a large proportion, and therefore had stronger hydrophilicity. The present invention prepares an O / W type emulsion, while an oil-in-water emulsion is an emulsion system with water as the continuous phase and oil as the dispersed phase. In this system, oil droplets are wrapped by surfactant molecules and dispersed in water. In order to enable the oil droplets to be stably dispersed in water, the surfactant molecules need to have strong hydrophilicity so as to form a good interfacial film with the aqueous phase and reduce the interfacial tension between oil and water. The HLB value of the surfactant used in the present invention is 8-18, and the optimal condition HLB of 12 is selected for the experiment.

[0066] (2) Preparation of pre-emulsion: 1 volume part of oil phase (soybean oil) was added to 9 volume parts of the aqueous phase prepared above to obtain an initial material, and then the initial material was pre-emulsified at a speed of 7000 rpm for 1 min using a high-speed homogenizer to form an initial emulsion;

[0067] (3) Continuously preparing nanoemulsion using a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier: The temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier includes a syringe pump 1, an ultrasonic generator 2, an ultrasonic transducer 3, a thermocouple thermometer 4, a circulating chiller 5, a glass jacketed beaker 6 and an emulsion receiving bottle 7. Two glass jacketed beakers 6 are connected through a silicone tube; the syringe pump 1 is connected to one glass jacketed beaker 6 through a silicone tube with a syringe, and the other glass jacketed beaker 6 is connected to the emulsion receiving bottle 7 through silicone; the ultrasonic generator 2 is connected to the ultrasonic transducer 3 through a power cord, and the ultrasonic transducer 3 is connected to the glass jacketed beaker 6 respectively; the circulating chiller 5 is inserted into the coolant in the glass jacketed beaker 6 through a silicone tube and a glass tube; the thermocouple thermometer 4 is extended into the outlet of the jacketed glass beaker for temperature measurement. The circulating chiller 5 is set to a fixed temperature, and then the coolant is passed into the middle of the glass jacketed beaker 6 through a rubber tube and a glass tube to cool the surrounding nanoemulsion. The initial emulsion is sequentially introduced into two glass-jacketed beakers 6 from the syringe of the syringe pump 1 , and finally the nanoemulsion is received by the emulsion receiving bottle 7 .

[0068] The initial emulsion is continuously injected into the ultrasonic series jacketed glass emulsifier 3 through the injection pump 1 for emulsification treatment to obtain a nanoemulsion, wherein the ultrasonic power is adjusted by the ultrasonic generator 2, the emulsification temperature is controlled and monitored in real time by the circulating cooler 5, the internal cooler of the glass jacketed emulsifier and the thermocouple thermometer 4, the flow rate is controlled by the injection pump 1, and the residence time is determined by the flow rate.

[0069] Example 1 Continuous preparation of nanoemulsion using a single ultrasonic jacketed glass emulsification unit

[0070] The temperature-controllable low-power ultrasonic jacketed glass emulsifier comprises a syringe pump 1, an ultrasonic generator 2, an ultrasonic transducer 3, a thermocouple thermometer 4, a circulating cooler 5, a glass jacketed beaker 6 and an emulsion receiving bottle 7. The syringe pump 1 is connected to a single glass jacketed beaker 6 through a silicone tube with a syringe, and the glass jacketed beaker 6 is connected to the emulsion receiving bottle 7 through silicone; the ultrasonic generator 2 is connected to the ultrasonic transducer 3 through a power line, and the ultrasonic transducer 3 is connected to the glass jacketed beaker 6 respectively.

[0071] The initial emulsion is continuously injected into a single glass jacket beaker 6 through a syringe pump 1 for emulsification treatment to obtain a nanoemulsion, wherein the emulsification ultrasonic power is controlled by an ultrasonic generator 2 to 77W, the emulsification temperature is controlled by a circulating cooler 5 to 65°C, and the flow rate is controlled by a syringe pump 1 to 1.0mL / min. The obtained nanoemulsion has an average droplet size of 71nm and a PDI of 0.400.

[0072] The average particle size (DS) and PDI of the nanoemulsion prepared continuously in this example change with the preparation time. Figure 3After 30 min, the average particle size (DS) and PDI of the nanoemulsions hardly changed over time, indicating that a single ultrasonic jacketed glass emulsification unit can continuously and stably prepare nanoemulsions.

[0073] Example 2 Continuous preparation of nanoemulsion using a single ultrasonic jacketed glass emulsification unit

[0074] The difference between this embodiment and embodiment 1 is that the flow rate is controlled to 0.5 mL / min by the syringe pump 1. The nanoemulsion obtained in this embodiment has an average droplet size of 58 nm and a PDI of 0.310.

[0075] Example 3 Continuous preparation of nanoemulsion using a single ultrasonic jacketed glass emulsification unit

[0076] The difference between this embodiment and embodiment 1 is that the flow rate is controlled to 2.0 mL / min by the syringe pump 1. The nanoemulsion obtained in this embodiment has an average droplet size of 105 nm and a PDI of 0.400.

[0077] Based on the analysis of Examples 1 to 3, the lower the flow rate, the longer the emulsification residence time, resulting in a smaller average particle size of the obtained emulsion droplets and a more uniform particle size distribution.

[0078] Example 4 Continuous preparation of nanoemulsion using a single ultrasonic jacketed glass emulsification unit

[0079] The difference between this embodiment and embodiment 1 is that the emulsification ultrasonic power is controlled by the ultrasonic generator 2 to be 57 W. The nanoemulsion obtained in this embodiment has an average droplet diameter of 104 nm and a PDI of 0.391.

[0080] Example 5 Continuous preparation of nanoemulsion using a single ultrasonic jacketed glass emulsification unit

[0081] The difference between this embodiment and embodiment 1 is that the emulsification ultrasonic power is controlled by the ultrasonic generator 2 to be 67 W. The nanoemulsion obtained in this embodiment has an average droplet size of 76 nm and a PDI of 0.350.

[0082] Based on the analysis of Example 1, Example 4 and Example 5, when the ultrasonic power increases, the average particle size of the emulsion droplets and the PDI gradually decrease. When the ultrasonic power is 77W, the average particle size of the emulsion droplets and the PDI decrease very little.

[0083] Example 6 Continuous preparation of nanoemulsion using a single ultrasonic jacketed glass emulsification unit

[0084] The difference between this embodiment and embodiment 1 is that the emulsification temperature is controlled by a circulating cooler to be 55° C. The nanoemulsion obtained in this embodiment has an average droplet diameter of 71 nm and a PDI of 0.334.

[0085] Example 7 Continuous preparation of nanoemulsion using a single ultrasonic jacketed glass emulsification unit

[0086] The difference between this embodiment and embodiment 1 is that the emulsification temperature is controlled to 45° C. by the circulating cooler 5. The nanoemulsion obtained in this embodiment has an average droplet diameter of 153 nm and a PDI of 0.462.

[0087] It can be seen from Example 1 and Example 6-7 that, under the same other conditions, Example 6 increases the temperature to 55°C, the average particle size of the emulsion droplets is 71nm, and the PDI is a nanoemulsion of 0.334; Example 1 increases the temperature to 65°C, and the average particle size of the emulsion droplets is 71nm, and the PDI is 0.400. Comprehensive analysis of Example 1, Example 6 and Example 7 shows that when the emulsification temperature is increased from 45°C to 55°C, the average particle size of the emulsion droplets is reduced exponentially. However, when the emulsification temperature continues to increase from 55°C to 65°C, the average particle size of the emulsion droplets no longer decreases. It can be seen that the emulsification temperature has a significant effect on the quality of the nanoemulsion. Compared with 45°C, under 55°C conditions, the water-oil interface is greatly increased after ultrasonic emulsification, so the emulsification effect will be better. Further increasing the temperature to 65°C, the ultrasonic emulsification water-oil interface has increased to the limit, so the droplet particle size no longer improves significantly.

[0088] Example 8: Preparation of Nanoemulsion Using a Single Ultrasonic Jacketed Glass Emulsification Unit for Multiple Cycles

[0089] The difference between this embodiment and embodiment 1 is that the initial emulsion is continuously injected into the glass jacket beaker 6 through the syringe pump 1 for continuous emulsification treatment to obtain the primary nanoemulsion. The obtained primary nanoemulsion is then subjected to the same continuous emulsification steps as above, and the cycle is repeated twice to obtain the secondary nanoemulsion, and the cycle is repeated three times to obtain the tertiary nanoemulsion. The emulsification ultrasonic power is controlled by the ultrasonic generator 2 to 77W, the emulsification temperature is controlled by the circulating cooler 5 to 65°C, and the flow rate is controlled by the syringe pump 1 to 2.0mL / min.

[0090] The average particle size of the primary nanoemulsion droplets in this embodiment is 103 nm, and the PDI is a nanoemulsion of 0.314. The average particle size of the secondary nanoemulsion droplets is 60 nm, and the PDI is a nanoemulsion of 0.166. The average particle size of the tertiary nanoemulsion droplets is 58 nm, and the PDI is a nanoemulsion of 0.146.

[0091] It can be seen that the use of a single ultrasonic jacketed glass emulsification unit 3 for two cycles to prepare nanoemulsions can significantly reduce the average particle size of the emulsion droplets and improve the particle size distribution. However, the use of a single ultrasonic jacketed glass emulsification unit 3 for three cycles to prepare nanoemulsions does not significantly improve the above indicators. Because the emulsification effect mainly depends on the size of the water-oil interface, and emulsification also mainly occurs at the water-oil interface, the water-oil interface is greatly increased after the second ultrasound, so the emulsification effect will be better. However, after the second ultrasound, the water-oil interface has increased to the limit, so the particle size no longer improves significantly after the third ultrasound.

[0092] Figure 4 The stability test results of nanoemulsion prepared by double cycle using a single ultrasonic jacketed glass emulsification unit are shown. Figure 5 It can be seen that the nanoemulsion prepared by the secondary cycle of a single ultrasonic jacketed glass emulsification unit 3 at 4°C and 25°C has very good stability.

[0093] Example 9: Continuous preparation of nanoemulsion using a temperature-controlled low-power ultrasonic series jacketed glass emulsifier

[0094] A method for continuously preparing nanoemulsion by connecting a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier comprises the following steps:

[0095] (1) Preparation of aqueous phase: Tween 80 and Span 80 were mixed as surfactants (Span 80 accounted for 28 wt %, Tween 80 accounted for 72 wt %, HLB value was 12) and added into deionized water as aqueous phase, wherein the mass fraction of surfactant in aqueous phase was 6%.

[0096] (2) Preparation of pre-emulsion: 1 volume part of oil phase (soybean oil) was added to 9 volume parts of the aqueous phase prepared above to obtain an initial material, and then the initial material was pre-emulsified at a speed of 7000 rpm for 1 min using a high-speed homogenizer to form an initial emulsion;

[0097] (3) Continuously preparing nanoemulsion using a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier: The temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier includes a syringe pump 1, an ultrasonic generator 2, an ultrasonic transducer 3, a thermocouple thermometer 4, a circulating chiller 5, a glass jacketed beaker 6 and an emulsion receiving bottle 7. Two glass jacketed beakers 6 are connected through a silicone tube; the syringe pump 1 is connected to one glass jacketed beaker 6 through a silicone tube with a syringe, and the other glass jacketed beaker 6 is connected to the emulsion receiving bottle 7 through silicone; the ultrasonic generator 2 is connected to the ultrasonic transducer 3 through a power cord, and the ultrasonic transducer 3 is connected to the glass jacketed beaker 6 respectively; the circulating chiller 5 is inserted into the coolant in the glass jacketed beaker 6 through a silicone tube and a glass tube; the thermocouple thermometer 4 is extended into the outlet of the jacketed glass beaker for temperature measurement. The circulating chiller 5 is set to a fixed temperature, and then the coolant is passed into the middle of the glass jacketed beaker 6 through a rubber tube and a glass tube to cool the surrounding nanoemulsion. The initial emulsion is sequentially introduced into two glass-jacketed beakers 6 from the syringe of the syringe pump 1 , and finally the nanoemulsion is received by the emulsion receiving bottle 7 .

[0098] The initial emulsion is continuously injected into a low-power ultrasonic series jacketed glass emulsifier through a syringe pump 1 for sequentially and continuously primary emulsification and secondary emulsification treatment to obtain a nanoemulsion, wherein the primary emulsification / secondary emulsification ultrasonic power is controlled by an ultrasonic generator 2 to be 67W, the primary emulsification / secondary emulsification temperature is controlled by a circulating cooler 5 to be 65°C, and the flow rate is controlled by a syringe pump 1 to be 2.0mL / min. The ultrasonic frequency of the ultrasonic generator is 20kHz.

[0099] The average particle size of the emulsion droplets obtained in this example is 58 nm, and the PDI is 0.170. The average particle size and PDI of the nanoemulsion prepared by the temperature-controlled low-power ultrasonic series jacketed glass emulsifier change with time. Figure 5 After 40 min, the average droplet size and PDI had almost no change with the preparation time, indicating that the ultrasonic series jacketed glass emulsifier can continuously and stably prepare nanoemulsions. Figure 6 The stability test results of the sample at 60 minutes of continuous preparation of nanoemulsion using a temperature-controlled low-power ultrasonic series-jacketed glass emulsifier are shown.

[0100] Depend on Figure 6 It can be seen that at 4°C and 25°C, the nanoemulsions continuously prepared using a temperature-controllable low-power ultrasound in series with a jacketed glass emulsifier have very good stability.

[0101] Example 10 Continuous preparation of nanoemulsion using a temperature-controlled low-power ultrasonic series jacketed glass emulsifier

[0102] The difference between this embodiment and embodiment 9 is that the primary emulsification / secondary emulsification temperature is controlled to 45° C. by the circulating cooler 5. The average particle size of the emulsion droplets obtained in this embodiment is 84 nm, and the PDI is 0.247.

[0103] Example 11 Continuous preparation of nanoemulsion using a temperature-controlled low-power ultrasonic series jacketed glass emulsifier

[0104] The difference between this embodiment and embodiment 9 is that the primary emulsification / secondary emulsification temperature is controlled by the circulating cooler 5 to be 55°C.

[0105] Comprehensive analysis of Example 9-Example 11 shows that, under the same other conditions, when the emulsification temperature is increased from 45°C to 55°C, the average particle size of the emulsion drops from 84nm to 54nm, and the PDI also drops from 0.247 to 0.180. When the emulsification temperature continues to increase from 55°C to 65°C, the average particle size of the emulsion drops changes to 58nm, and the PDI continues to drop to 0.170. It can be seen that the emulsification temperature has a significant effect on the quality of the nanoemulsion, because the emulsification effect mainly depends on the size of the water-oil interface, and emulsification also mainly occurs at the water-oil interface. Compared with 45°C, under 55°C conditions, the water-oil interface is greatly increased after ultrasonic emulsification, so the emulsification effect will be better. Further increasing the temperature to 65°C, the ultrasonic emulsification water-oil interface has increased to the limit, so the droplet particle size no longer significantly improves.

[0106] In addition, if Figure 7 As shown, the temperature-controlled low-power ultrasonic series jacketed glass emulsifier continuously prepares nanoemulsions at lower temperature and lower power (67W, 55°C), and the droplet size obtained by emulsification is smaller than that of the secondary high-power and high-temperature ultrasonic treatment (77W, 65°C). In this way, the use of ultrasonic series jacketed glass emulsifiers can not only obtain better nanoemulsions, but also reduce energy consumption and extend the service life of the emulsifier. The excellent performance of ultrasonic series jacketed glass emulsifiers in preparing nanoemulsions mainly comes from the continuous process, while the secondary ultrasonic emulsification is not continuous enough compared to the serial ultrasonic emulsification. The emulsion obtained by the first ultrasonic emulsification needs to be injected into the glass emulsifier again through the injection pump 1 for the second ultrasonic emulsification, and the time consumed by the serial ultrasonic emulsification is less than that consumed by multiple ultrasonic emulsifications, and the operation is more convenient. Therefore, in general, ultrasonic series jacketed glass emulsification performs better than the secondary ultrasonic emulsification in all aspects.

[0107] Comparative Example 1: Preparation of Nanoemulsion Using High-Pressure Homogenizer

[0108] The same formula and method as in Example 1 were used to prepare the initial emulsion, and the initial emulsion was subjected to 1, 3, 5, 8, 10, and 15 cycles respectively at a pressure of 80 MPa, a temperature of 65° C., and an electric power of 600 W. The results are as follows: Figure 8 shown.

[0109] Depend on Figure 8 It can be seen that under the same temperature conditions, the electric power used by the high-pressure homogenizer is about 5 times that of the ultrasonic series reactor. In comparison, the high-pressure homogenizer consumes a lot of energy for emulsification. And the average particle size of the emulsion droplets only drops to about 100nm after 15 cycles, while the ultrasonic series jacketed glass emulsifier can continuously prepare a well-dispersed nanoemulsion with an average particle size of about 54nm.

[0110] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for continuously preparing nanoemulsions by connecting a temperature-controlled low-power ultrasonic series jacketed glass emulsifier, characterized in that: The following steps are involved: (1) preparing an aqueous phase: adding a surfactant into deionized water to obtain an aqueous phase; (2) preparing a pre-emulsion: adding the oil phase to the water phase to obtain an initial material, and then pre-emulsifying the initial material using a high-speed homogenizer to form an initial emulsion; (3) preparing a nanoemulsion: the initial emulsion is emulsified by a temperature-controllable low-power ultrasonic series jacketed glass emulsifier to obtain a nanoemulsion; The temperature-controllable low-power ultrasonic series jacketed glass emulsifier comprises an injection pump, an emulsion receiving bottle, and N ultrasonic jacketed glass emulsification units arranged in series between the injection pump and the emulsion receiving bottle, where N is greater than or equal to 2; the ultrasonic jacketed glass emulsification unit comprises an ultrasonic generator, a thermocouple thermometer, a circulating cooler, an ultrasonic transducer, and a glass jacketed beaker, wherein the ultrasonic transducer is connected to the glass jacketed beaker, the ultrasonic generator is connected to the ultrasonic transducer, and the circulating chiller and the thermocouple thermometer are respectively connected to the glass jacketed beaker.

2. The method for continuously preparing nanoemulsion by a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier according to claim 1, characterized in that: The glass jacket beaker consists of an inner beaker and an outer jacket. Coolant is introduced into the inner beaker through a circulating chiller, and the outer jacket is connected to an injection pump to introduce initial emulsion. The coolant in the inner beaker heats or cools the initial emulsion in the outer jacket to control the temperature.

3. The method for continuously preparing nanoemulsion by a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier according to claim 2, characterized in that: The ultrasonic frequency of the ultrasonic generator is 20-1000kHz.

4. The method for continuously preparing nanoemulsion by a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier according to claim 1, characterized in that: The injection pump controls the flow rate of the initial emulsion to be 0.5 mL / min-2 mL / min.

5. The method for continuously preparing nanoemulsion by a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier according to claim 1, characterized in that: The temperature displayed by the thermocouple thermometer is 45℃-65℃.

6. The method for continuously preparing nanoemulsion by using a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier according to claim 1, characterized in that: The ultrasonic power of the ultrasonic generator is 57W-77W.

7. The method for continuously preparing nanoemulsion by a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier according to claim 1, characterized in that: The oil phase is vegetable oil.

8. The method for continuously preparing nanoemulsion by a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier according to claim 1, characterized in that: The volume ratio of the oil phase to the water phase in the step (2) is 1:(1-20).

9. The method for continuously preparing nanoemulsion by a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier according to claim 1, characterized in that: The mass fraction of the surfactant in the aqueous phase in the step (1) is 1%-20%; the HLB value of the surfactant in the step (1) is 8-18.

10. The method for continuously preparing nanoemulsion by a temperature-controllable low-power ultrasonic series-connected jacketed glass emulsifier according to claim 3, characterized in that: The ultrasonic frequency of the ultrasonic generator is 20-50 kHz.

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