Patent Application
20080081842
Hereinafter, preferred embodiments of a method of manufacturing an emulsion according to the present invention are described with reference to the attached drawings.
First, principles of the emulsification methods according to the present invention (a solubilization method and a phase inversion temperature emulsification method) are described. In the emulsification methods according to the present invention, a nonionic surfactant, an oil agent and water (hereafter, these are referred to as a material solution) are emulsified in a solubilized state or a phase inversion state, and then temperature of the solution is changed rapidly to a stabilization temperature, thereby forming an emulsion that has a fine particle size and high monodispersity.
As shown in
As shown in
As mentioned above, highly precise temperature controls are important in a step of emulsifying the material solution by heating to a solubilization temperature in the solubilization method or a phase inversion temperature in the phase inversion temperature emulsification method and mixing (an emulsification step), and after the emulsification step, in a step of rapidly shifting the emulsion to a stable two phase region (an emulsion stabilization step of rapidly cooling or rapidly heating an emulsion to a temperature at which the emulsion is stabilized). Herein, the temperature at which an emulsion is stabilized (stabilization temperature) denotes a temperature at which Ostwald ripening or coalescence of particles of the emulsion can be suppressed, and for example, is lower than the solubilization temperature or the phase inversion temperature by 20 to 40° C. or more.
The stability with time of an emulsion has deep relationships with monodispersity of the emulsion. An effect of a monodispersed emulsion on stabilization can be explained by Ostwald ripening based on Thompson-Freundlich formula.
That is, solubility of dispersed phase particles (emulsion particles) in the vicinity of an interface in a continuous phase depends on the curvature of the interface of the dispersed phase particles. Therefore, the smaller the sizes of the dispersed phase particles are, the larger its solubility in the continuous phase becomes. The larger the sizes of the dispersed phase particles are, the smaller its solubility in the continuous phase becomes.
In the case of polydispersed emulsions, concentration differences occur between surfaces of particles having different particle sizes. Therefore, materials of the dispersed phase tend to move to the continuous phase. As a result, small dispersed phase particles further become smaller, and large dispersed phase particles further become larger. Conversely, a monodispersed emulsion has a small concentration difference between surfaces of particles, and the move of materials described above becomes negligible, thereby being less prone to break and becoming stable (see Non-Patent Document: “New Techniques for Highly Stabilizing Emulsion”, p. 25 issued by TECHNICAL INFORMATION INSTITUTE CO., LTD.) Therefore, the higher monodispersity an emulsion has, the more excellent stability with time the emulsion exhibits.
Therefore, in the present invention, temperature controls in the emulsion stabilization step are conducted by using a micro device. In addition, mixing controls in the emulsification step are also preferably conducted by using a micro device.
Retention time during a shift from the emulsification step to the emulsion stabilization step is set to be as short as possible. The retention time is preferably equal to or less than 1 second, more preferably equal to or less than 0.1 second, and still more preferably equal to or less than 0.01 second.
The gradient of temperature change can be adjusted with the type of a heating medium, temperature, the equivalent diameter or the length of a microchannel, or the like. The gradient of temperature change is preferably adjusted to be equal to or greater than 100° C./second, and more preferably equal to or greater than 400° C./second.
A microchannel preferably has an equivalent diameter equal to or less than 1 mm, more preferably equal to or less than 500 μm, and still more preferably equal to or less than 100 m. For the purpose of conducting temperature control in a microchannel more precisely, an equivalent diameter of a microchannel is preferably determined so that temperature distribution between a radial center and a wall surface of a microchannel is equal to or less than ±1° C., and more preferably equal to or less than ±0.1° C.
An emulsion prepared according to the present invention preferably has a volume average particle size (Mv) equal to or less than 10 μm, more preferably equal to or less than 1 μm, and still more preferably equal to or less than 0.1 μm. The emulsion preferably has a particle size distribution (Mv/Mn) equal to or less than 1.4, and more preferably equal to or less than 1.3.
Next, various materials for implementing the emulsification methods are described.
The nonionic surfactant is required to be hydrophilic for obtaining W/O emulsions. Examples of the nonionic surfactant may include: POE sorbitan fatty esters such as POE sorbitan monooleate, POE sorbitan monostearate, or POE sorbitan trioleate; POE sorbitol fatty esters such as POE sorbitol monooleate, POE sorbitol pentaoleate, or POE sorbitol monostearate; POE glycerol fatty esters such as POE glycerol monostearate, POE glycerol monoisostearate, or POE glycerol triisostearate; POE fatty esters such as POE monooleate, POE distearate, or POE dioleate; POE alkylethers such as POE oleyl ether, POE stearyl ether, POE behenyl ether, POE 2-octyldodecyl ether, POE 2-hexyldecyl ether, POE 2-heptylundecyl ether, POE 2-decyltetradecyl ether, POE 2-decylpentadecyl ether, or POE cholestanol ether; POE alkylphenyl ethers such as POE nonylphenyl ether; POE·POP block copolymers; POE·POP alkylethers such as POE·POP cetyl ether, POE·POP 2-decyltetradecyl ether, or POE·POP hydrogenated lanolin; POE castor oil or hardened castor oil derivatives such as a POE castor oil; POE beeswax/lanolin derivatives such as POE sorbitol beeswax; sugar esters such as sucrose monooleate, and polyglycerol monoalkyl esters and polyglycerol monoalkyl ethers. These hydrophilic nonionic surfactants may be used alone or in combination of two or more of them.
Examples of the oil may include: hydrocarbon such as liquid paraffin, squalene, squalane, paraffin or vaseline; ethers such as ethylene glycol dioctyl ether; monoesters such as cetyl octanoate, octyldodecyl myristate, isopropyl palmitate, butyl stearate, myristyl myristate, decyl oleate, or oleyl oleate; higher alcohols such as isostearyl alcohol, octyldodecanol, oleyl alcohol, or lanolin alcohol; higher fatty acids such as eicosanoic acid; diesters such as di-2-ethylhexyl sebacate, or di-2-ethylhexyl adipate; glyceryl monoethers such as glycerol monooleyl ether; acid amides such as lauroyl lauryl amine; and natural animal or vegetable oils. These oils may be used alone or in combination of two or more of them.
The oil agent is determined depending on types or usages of target products. Examples of the oil agent may include: liquid paraffin, paraffin wax, vaseline, squalene, squalane, lanolin, higher alcohols, higher alcohol-fatty ester, fatty ester, monoglyceride fatty acid, diglyceride, triglyceride, natural animal or vegetable oils, silicone oils and the like. These oil agents may be solid, semisolid, or liquid. These oil agents may be used alone or in combination of two or more of them as necessary.
Besides the nonionic surfactant, the oil agent and the water, various components can be added. Furthermore, if necessary, aromatics, colorants, other powders, preservatives, medicaments, viscosity bodying agents, ultraviolet absorbing agents, chelating agents, other oils, surfactants, active auxiliaries or the like may be added to products to which the method of manufacturing an emulsion according to the present invention is applied.
The “micro device” in the present invention denotes a generic name of devices for passing fluids through microchannels, and/or combining fluids in the microchannels, thereby conducting processes such as mixing, reactions, or heat exchange. In particular, a micro device whose principal purpose is mixing is called a micromixer, a micro device whose principal purpose is conducting a reaction is called a micro reactor, and a micro device whose principal purpose is heat exchange is called a micro heat exchanger. The microchannel or a stream passing through the microchannel has a diameter or an equivalent diameter (in the case that the section of the channel or the stream is not circular) equal to or less than 1 mm. In particular, the diameter or the equivalent diameter is typically equal to or less than 500 μm, and preferably equal to or less than 100 μm.
The term equivalent diameter in the present invention is also called equilibrium diameter, and used in the mechanical engineering field. When a piping (a channel in the present invention) with an arbitrary sectional form is represented by its equivalent circular pipe, the diameter of the equivalent circular pipe is referred to as an equivalent diameter and defined as deq=4 A/p where A represents the sectional area of the piping and P represents the wetted perimeter length (peripheral length) of the piping. When the formula is applied to a circular pipe, the equivalent diameter is equal to the diameter of the circular pipe. The equivalent diameter is used to estimate flow or heat transfer properties of a piping based on data of its equivalent circular pipe. The equivalent diameter represents spatial scale (representative length) of phenomenon.
Hereinafter, preferred device configurations for conducting the emulsification methods are described. It should be noted that the present embodiments disclose an example of forming a stable oil-in-water emulsion by emulsifying a material solution at a phase inversion temperature and rapidly cooling the solution.
The micromixer 12 is composed of a feed component 22, a combining component 24, and an ejection component 26 each having a cylindrical shape. In the case of forming the micromixer 12, these components are assembled by being integrally fastened to form a cylindrical single piece. This assembly is conducted, for example, by providing bores (or holes, not shown) passing through the cylinder in the peripheral portions of the components at the same spacing, and the components are integrally fastened to form a single piece via bolts/nuts.
A surface of the feed component 22 facing the combining component 24 has ring-shaped channels 28 and 30 formed concentrically. Each of the channels has a rectangle section. In the illustrated embodiment, bores 32 and 34 are formed to penetrate the feed component 22 in its thickness direction (or height direction) to reach the ring-shaped channels respectively.
The combining component 24 has bores 36 penetrating in the thickness direction. As for the bores 36, in the case of coupling the components to form the micromixer 12, the edge 40 of the bores 36, the edge being located on a surface of the combining component facing the feed component, opens to the ring-shaped channel 28. In the illustrated embodiment, four bores 36 are formed, and these bores are arranged at the same spacing in the peripheral direction of the ring-shaped channel 28.
The combining component 24 has bores 38 penetrating the component like the bores 36. As with the bores 36, the bores 38 is also formed to open to the ring-shaped channel 30. In the illustrated embodiment, the bores 38 are also arranged at the same spacing in the peripheral direction of the ring-shaped channel 30. The bores 36 and 38 are arranged alternately.
A surface 42 of the combining component 24 facing the ejection component 26 has microchannels 44 and 46. One end of the microchannel 44 or 46 is an opening of the bore 36 or 38, and the other end is the center 48 of the surface 42. Every microchannel extends from a bore toward the center 48 and merges into the center. The section of a microchannel may be, for example, a rectangle.
The ejection component 26 has a bore 50 (a mixing channel) penetrating the center of the component in its thickness direction. Therefore, one end of this bore opens to the center 48 of the combining component 24, and the other end opens to outside of the micromixer.
As is readily understood, the ring-shaped channels 28 and 30 correspond to feed channels of the micromixer of the present invention, fluids A and B fed at the ends of the bores 32 and 34 from outside of the micromixer flow to the ring-shaped channels 28 and 30 via the bores 32 and 34 respectively.
The ring-shaped channel 28 communicates with the bores 36. The fluid A flowing to the ring-shaped channel 28 enters the microchannel 44 via the bores 36. The ring-shaped channel 30 communicates with the bores 38. The fluid B flowing to the ring-shaped channel 30 enters the microchannel 46 via the bores 38. As is evident, the fluids A and B are separated into four in the combining region, flowing to the microchannels 44 and 46 respectively and then flowing toward the center 48.
As is readily understood, the bore 36 or 38 and the microchannel 44 or 46 correspond to a subchannel of a micromixer of the present invention. The center 48 of the combining component corresponds to a combining region. The central axis of the microchannel 44 and the central axis of the microchannel 46 intersect at the center 48. The combined fluids are ejected via the bore 50 outside of the micromixer as a stream LM. Therefore, the bore 50 corresponds to an ejection channel of the micromixer.
An example of preferred specifications of the micromixer in
Sectional form, width, depth, and diameter of the ring-shaped channel 28: a rectangle section, 1.5 mm, 1.5 mm, and 25 mm Sectional form, width, depth, and diameter of the ring-shaped channel 30: a rectangle section, 1.5 mm, 1.5 mm, and 20 mm
Diameter, and length of the bore 32: 1.5 mm and 10 mm (circular section)
Diameter, and length of the bore 34: 1.5 mm and 10 mm (circular section)
Diameter, and length of the bore 36: 0.5 mm and 4 mm (circular section)
Diameter, and length of the bore 38: 0.5 mm and 4 mm (circular section)
Sectional form, width, depth, and length of the microchannel 44: a rectangle section, 100 μm, 60 μm, and 12.5 mm
Sectional form, width, depth, and length of the microchannel 46: a rectangle section, 100 μm, 60 μm, and 10 mm
Diameter, and length of the bore 50: 500 μm and 10 mm (circular section)
It should be noted that, in order to connect conduits for feeding the fluids A and B to the micromixer 12, and in order to connect a conduit for ejecting an emulsified solution LM from the micromixer 12, threaded portions are provided to the bores 32, 34 and 50.
The channel member 56 is formed on a corrugated partition plate crossing and dividing the channel 54. The channel member 56 has a plurality of U-shaped microchannels.
A cover member 58 is fixed on the top surface of the channel 54 to form a fine rectangle cylinder as a whole. In the cover member 58, a slit outlet 60 is perforated at a position where corresponds to the channel member 56. The outlet 60 is connected with a delivery opening (not shown) of a treated solution so as to deliver a mixed treated solution.
In the micromixer 12′ constituted as mentioned above, two fluids enter the U-shaped channels of the channel member 56 respectively from both sides of the channel 54 shown in
An example of such a micromixer to be used is an IMM micro reactor slit type (LIGA techniques) micromixer (type: SSIMM).
As mentioned above, a micromixer is preferably used as a device which mixes and emulsifies the material solution in the emulsification step in view of easy temperature control and high mixing properties. However, the device is not limited thereto. Another device which mixes and emulsifies the material solution such as a stirring tank can be used as long as the material solution can be mixed and emulsified under heat (at about a solubilization temperature or a phase inversion temperature).
The inner tube 72 preferably has an equivalent diameter equal to or less than 1 mm, and more preferably equal to or less than 500 μm. The length L of the inner tube 72 is determined so that the length is long enough to cool an emulsified material solution to a temperature at which the solution stabilizes.
A refrigerant inlet 74A to which a refrigerant flows and a refrigerant outlet 74B for ejecting the refrigerant passed through the outer tube 74 are connected to the outer tube 74. The temperature of the refrigerant entering the outer tube 74 is controlled with a control device or the like, thereby cooling a fluid in the inner tube 72 to a predetermined temperature. The temperature control of the micro heat exchanger 14 can be conducted by adjusting the temperature of the refrigerant with the temperature control part 20.
The temperature control system in the micro heat exchanger 14 is not limited to the above embodiment. The temperature may be controlled by placing the whole device into a temperature controlled vessel. Alternatively, it is also possible that a heater structure such as a metal resistance wire or polysilicon is prepared in a device and the heater structure is used for the heating while self-cooling is conducted for the cooling. As for sensing of temperature, in the case of using a metal resistance wire, another same metal resistance wire as in the heater is prepared and temperature is detected based on change of a value of resistance of the resistance wire. In the case of using polysilicon, temperature is detected by using a thermocouple. Alternatively, the heating and the cooling may be conducted from outside by contacting a Peltier device with the micro heat exchanger 14. The methods are selected depending on usages, a material of the body of a micro heat exchanger 14, or the like.
The micro heat exchanger is not restricted to the above embodiments. Another micro heat exchanger may be used as long as it has a microchannel with an equivalent diameter equal to or less than 1 mm and a function of controlling the temperature of a fluid passing through the microchannel. For example, an IMM micro heat exchanger (manufactured by ITEC Co., Ltd.), an external heating micro heat exchanger of Karlsruhe (EP1046867), or the like may also be preferably used.
The micromixer 12 and the micro heat exchanger 14 are preferably connected so that spacing between them is as small as possible. That is, the retention time from the outlet of the micromixer 12 to the inlet of the micro heat exchanger 14 is preferably designed to be equal to or less than 1 second, preferably equal to or less than 0.1 second, and more preferably equal to or less than 0.01 second.
In manufacturing micro devices such as a micromixer or a micro heat exchanger, in particular manufacturing of each component, semiconductor processing techniques, particularly an etching process such as photolithography etching, precision machinery processing techniques such as ultrafine electrical discharge machining, stereo lithography method, mirror finish processing techniques, or diffusion bonding techniques may be used. In addition, machining techniques using a general lathe or a drilling machine may be used. Those skilled in the art can manufacture the micro devices and components easily.
Materials used for micro devices are not particularly restricted. Materials which can be subjected to the processing techniques and are not influenced by fluids to be combined may be used. Examples of the materials may include: metallic materials such as iron, aluminum, stainless steel, titanium or various alloys; resin materials such as fluororesins or acrylic resins; and glass such as silicon or quartz.
The temperature control part 20 is a device for controlling the temperature of a thermostatic chamber 18 accommodating the body of the micromixer 12 or the micromixer 12. As for the micromixer 12, the micromixer 12 and a feed/ejection piping system (piping made of SUS) communicating with the micromixer 12 are placed in the thermostatic chamber 18. The temperature in the thermostatic chamber 18 is controlled by the temperature control part 20 to be at about a phase inversion temperature (equal to or less than ±0.1° C.). It should be noted that a method of controlling temperature of the micromixer 12 is not restricted to the above embodiments. The body of the micromixer 12 may have a temperature control mechanism.
The temperature control part 21 is a device for controlling the temperature of a refrigerant to be supplied to the micro heat exchanger 14. The micro heat exchanger 14 is controlled to be equal to or less than a stabilization temperature by controlling the temperature of a refrigerant to be supplied to the micro heat exchanger 14 with the temperature control part 21.
As a device that sends liquid, a device having precise flow rate and less prone to cause pulsing motion is preferable. For example, a plunger pump, a syringe pump or the like may be preferably used. The range of flow rate varies depending on a mixing and emulsification device to be used. A preferred flow rate is equal to or greater than a flow rate that applies shearing stress required for emulsification in the range of a guaranteed flow rate and pressure.
Next, operations in manufacturing equipment 10 are described with reference to
First, a solution A containing a nonionic surfactant and an oil agent, and a solution B mainly containing water are fed to a micromixer 12. The inside temperature of the micromixer 12 is heated to a phase inversion temperature by a thermostatic chamber 18. The solutions A and B are mixed via microchannels 44 and 46 to be emulsified. At this time, the solutions are emulsified at about a phase inversion temperature, thereby providing an emulsion that has a fine particle size and excellent monodispersity (an emulsification step).
Then a solution outflowing from the micromixer 12 enters a micro heat exchanger 14 in a period equal to or less than a second. The solution is subjected to heat exchange with a refrigerant to be controlled to have a temperature equal to or less than a stabilization temperature, whereby the solution is rapidly cooled to a temperature equal to or less than a stabilization temperature (an emulsion stabilization step).
In this way, because temperature distribution is small and temperature control is easily conducted in microchannels, an emulsion can be stabilized without proceeding of Ostwald ripening or coalescence of emulsion particles. Therefore, an emulsion that has a fine particle size and high monodispersity can be obtained.
According to the embodiments described above, an emulsion that has a fine particle size and high monodispersity can be obtained with less energy in comparison with an emulsification method by applying a general mechanical shearing stress.
Embodiments of a method of manufacturing an emulsion according to the present invention have been described so far. However, the present invention is not restricted to the above embodiments, and further various embodiments may be adopted.
For example, the present invention is also applicable to the case of forming a stable water-in-oil emulsion by rapidly heating an emulsion emulsified at about a phase inversion temperature. The present invention is also applicable to an emulsification step being conducted at a solubilization temperature.
The present invention is applicable to a method of manufacturing an emulsion that is widely used in industrial usages such as foods, make up materials, or pharmaceuticals.
Hereinafter, an example to which the method of manufacturing an emulsion according to the present invention is applicable is described. However, the present invention is not restricted thereto.
Experiments of manufacturing oil-in-water emulsions by the phase inversion temperature emulsification method by using two types of oil agents, pure water and a nonionic surfactant were conducted. Then comparison was conducted as to average particle sizes (Mv: based on volume) and particle size distributions (Mv/Mn) of oil droplets of emulsions obtained when an emulsification method and a cooling method after emulsification were changed.
The average particle sizes (Mv: based on volume) and particle size distributions (Mv/Mn) were measured with a flow particle image analyzer (SYSMEX CORPORATION: FPIA-2100). It should be noted that Mv/Mn (volume average particle size/number average particle size) is an indicator of monodispersity. The closer to 1 Mv/Mn is, the more excellent the monodispersity is.
Stirrer: magnetic stirrer
Micromixer: a single mixer manufactured by IMM (material: Ag, channel width: 40 μm)
Thermostatic chamber with stirrer (kept at 25° C.)
Double tube A made of SUS
(outer diameter of external tube: 21.7 mm, inner diameter of external tube: 18.4 mm, outer diameter of internal tube: 10 mm, inner diameter of internal tube: 8 mm, length: 100 mm)
Double tube B made of SUS
(outer diameter of external tube: 21.7 mm, inner diameter of external tube: 18.4 mm, outer diameter of internal tube: 1.58 mm, inner diameter of internal tube: 0.5 mm, length: 100 mm)
The double tubes A and B made of SUS were cooled by flowing cooling water at 5° C. along with the tubes at a flow rate of 5.6 L/minute.
Syringe pump manufactured by HARVARD, syringe for 50 mL
Emulsification step: conducted by immersing a micromixer or a beaker and a feed/ejection piping system (piping made of SUS) communicating therewith in a thermostatic chamber controlled to be at a predetermined temperature (equal to or less than ±0.1° C.)
Emulsion stabilization step: conducted by controlling the temperature of a refrigerant (cold water) fed to a micro heat exchanger
The solutions A and B were mixed in the thermostatic chamber kept at 63° C. and then cooled to 25° C.
In Example 1, the solutions A and B heated to 63° C. were fed to the micromixer at flow rates of 5 mL/minute and 5 mL/minute respectively to emulsify the solutions. After that, the emulsion was fed to the double tube B made of SUS at a flow rate of 10 mL/minute to cool the emulsion. The retention time in the double tube B was 0.1 seconds. It should be noted that cooling water at 5° C. was flowed along with the double tube B made of SUS at a flow rate of 5.6 L/minute.
Comparative Example 1 was conducted as with Example 1 except that the emulsion obtained by emulsifying the solutions A and B in a micromixer was cooled in the double tube A made of SUS.
Comparative Example 2 was conducted as with Example 1 except that the emulsion obtained by emulsifying the solutions A and B in a micromixer was cooled in a beaker in the thermostatic chamber set at 25° C. with stirring the solutions.
In Comparative Example 3, the solution A was added by a syringe pump at a flow rate of 10 mL/minute for 4 minutes via an SUS tube with an inner diameter of 2 mm to 40 mL of the solution B heated to 63° C. with being stirred with a stirrer (rotational frequency: 400 rpm), and the solutions were stirred for 30 minutes to conduct emulsification. After that, the emulsion was cooled in room temperature from 63° C. to 25° C. gradually.
As for Example 1 and Comparative Examples 1 to 3, average volume particle sizes (Mv) and particle size distributions were measured. The results are shown in Table 2.
As shown in Table 2, Example 1 in which the emulsion was cooled in a microchannel (Double tube B made of SUS) provided an emulsion that had a small average volume particle size and high monodispersity. On the other hand, Comparative Examples 1 to 3 provided an emulsion that had a larger average volume particle size and lower monodispersity than those of Example 1.
In particular, Comparative Example 1 in which the emulsion was cooled in a millichannel (Double tube A made of SUS) having temperature distribution provided an emulsion that had a larger average volume particle size and lower monodispersity than those of Example 1. Comparing Comparative Examples 2 and 3, conducting the emulsification step with a micromixer provided a smaller average volume particle size and higher monodispersity than with a standard stirring mixer.
In summary, by conducting a step of cooling an emulsion in a microchannel, an emulsion that has a fine particle size and high monodispersity can be obtained. Furthermore, it has been established that use of a micromixer for the emulsification step of preparing an emulsion can decrease average volume particle sizes and can increase monodispersity.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2006-269525 | Sep 2006 | JP | national |
