EP3408015B1 - Method for producing emulsions - Google Patents

Description

The invention relates to a method for producing emulsions.

In the following, emulsions are understood as meaning both colloidal emulsions and technical emulsions, the latter differing from colloidal emulsions in that they have considerably larger particle dimensions in the micrometer range.

A large number of branches of industry, for example the food industry, the pharmaceutical industry and the cosmetics industry, have a high demand for encapsulation, protection or targeted release of hydrophobic substances such as bioactive lipids, odorous substances, antioxidants and pharmaceuticals.

Emulsions are formed when two or more immiscible liquids are mixed together. One of these liquids is usually water soluble and the other is a lipophilic liquid that is immiscible with water. Depending on the mixing ratios and the surface modifier used, either water-in-oil emulsions or oil-in-water emulsions can be produced. A disadvantage of emulsions is their instability, which is based on physicochemical mechanisms such as gravity separation, flocculation, coalescence and Ostwald ripening. In oil-in-water emulsions, the most common reason for instability is the gravitational separation in the form of "creaming", which occurs due to the lower density of the oil particles.

There are several conventional methods of making emulsions. These processes are in particular mixing with high shear forces ("high shear mixing", rotor / stator systems), high pressure homogenization ("high pressure homogenization"), microfluidization ("microfluidization"), ultrasonic homogenization ("ultrasonic homogenization") or membrane emulsification ("membrane emulsification "). Most of these processes require a high energy input into the system in order to control the droplet size of the oil droplets formed. This energy input can take place in different ways, for example by heating, shear forces, or by increasing the pressure Pressure reduction. The stability of the emulsion increases as the droplet size decreases. Emulsions with an oil droplet size of more than 10 µm tend to change into two separate phases within a short time, while for an oil droplet size of less than 1 µm the stability of the emulsion increases with decreasing oil droplet size. However, with an oil droplet size of less than 1 µm, a four times larger energy input is necessary to reduce the oil droplet size by 50%, which limits the minimum oil droplet size that can be achieved. In addition, due to the energy input, there is a risk of the temperature rising to temperatures above 70 ° C, at which the emulsifiers can be destroyed.

In another technique, membrane emulsification, the limiting factors are the pore size of the membranes used and the pressure resulting from the viscosity of the oil phase.

With microfluidization, even under high pressure conditions, several passes are required to bring the oil droplet size below 1 µm. Because emulsification occurs in microchannels, blocking of these microchannels is one of the most common problems with this method.

In the DE 10 2009 008 478 A1 a method is described in which a solvent / anti-solvent precipitation takes place in the presence of surface-active molecules, a microjet reactor according to the EP 1 165 224 B1 is used. Such a microjet reactor has at least two opposing nozzles, each with an associated pump and feed line for spraying a liquid medium in each case into a reactor space enclosed by a reactor housing at a common collision point, a first opening being provided in the reactor housing through which a gas, a evaporating liquid, a cooling liquid or a cooling gas can be introduced to maintain the gas atmosphere inside the reactor, in particular at the point of collision of the liquid jets, or to cool the resulting products, and a further opening is provided for removing the resulting products and excess gas from the reactor housing is. A gas, an evaporating liquid or a cooling gas is therefore introduced into the reactor space via an opening in order to maintain a gas atmosphere in the interior of the reactor, in particular at the point of collision the liquid jets or to cool the resulting products and the resulting products and excess gas are removed through an opening from the reactor housing by overpressure on the gas inlet side or by negative pressure on the product and gas outlet side. If a solvent / non-solvent precipitation in such a microjet reactor, for example as in the EP 2 550 092 A1 is carried out, a dispersion of the precipitated particles is obtained. With such a reactor it is possible to generate particularly small particles. In this context, a solvent / non-solvent precipitation is understood to mean that a substance is dissolved in a solvent and collides as a liquid jet with a second liquid jet, the dissolved substance being precipitated again. A disadvantage of solvent / non-solvent precipitations is the fact that the dissolved and reprecipitated substance is in particulate form in the solvent-non-solvent mixture after the precipitation. The solvent content has the effect that, in many particles, an Ostwald ripening occurs in a time-dependent manner, which causes the particles to grow.

From the DE 10 2009 036 537 B3 a device for emulsifying at least two liquids is known, which comprises an emulsion reactor which has an outlet for removing the emulsion resulting from the mixing of the liquids and in which a plurality of nozzles are provided for injection at a substantially common collision point, each Nozzle is assigned a feed line and a pump, each of which pumps a liquid from an assigned tank through the feed line into the emulsion reactor.

the WO 99/28020 A1 describes a method of making heat sensitive emulsions or dispersions in which the components are pressurized, passed through a first high pressure mixing zone, then cooled in a heat exchanger and then passed through a second high pressure mixing zone.

the DE 26 04 610 A1 describes a process in which oil and water are sucked in from separate containers in the desired volume ratio and, as a mixture under high pressure in a pipe-nozzle system, is accelerated and decelerated several times at short intervals from a constant low base speed to about ten to twenty times the flow speed and then sprayed directly into the combustion chamber for burning. The pressure at the basic flow rate is 130 to 180 bar. the GB 331 928 A describes an apparatus for the production of emulsions or dispersions by spraying the components against one another. The pressure of the liquid jets is not specified here.

The object of the invention is therefore to create a new process for the production of emulsions which also enables the production of asymmetrical emulsions.

This object is achieved according to the invention in that in a first step at least one pre-emulsion is generated from at least two immiscible liquids and then in a second step at least two liquid streams of the at least one pre-emulsion are pumped through separate nozzles with a defined diameter in a microjet reactor, whereby the pressure of the liquid jets is between 5 and 500 bar in order to achieve the flow velocity of the liquid flows of more than 10 m / s and that the liquid flows meet at a collision point in a room, the room being filled or acted upon with gas and the gas pressure in the space is 0.05 to 30 bar, preferably 0.2 to 10 bar and particularly preferably 0.5 to 5 bar.

Gas, in particular inert gas or inert gas mixtures, but also reactive gas, can be fed into the space through a gas inlet.

Since in the case of a large number of emulsions, namely the asymmetrical emulsions in which the oil and water phases are not present in a ratio of 1: 1, it has been found to be advantageous in the context of the invention to first prepare a pre-emulsion from the oil and the water phase . This can be done, for example, via normal stirring processes, ultrasound treatment, Ultraturrax, a dissolver disk, etc. This pre-emulsion is then introduced in the form of two liquid flows into a device in which both liquid flows meet at a collision point in a room, for example a microjet reactor.

Such a microjet reactor is from EP 1 165 224 B1 famous.

Due to the method of collision of the jets under increased pressure used in the microjet reactor, the droplet size of the emulsion depends on the system and operating parameters, in particular the nozzle size in the microjet reactor and the pump pressure of the conveying pumps for the two liquid flows. In contrast to the usual use of microjet reactors, in the method according to the invention, the collision energy in the microjet reactor does not cause any precipitation reactions, but rather emulsions are formed.

Due to the collision of the liquid streams with high flow velocities, at which a plate-shaped collision plate forms at the collision point, a homogeneous emulsion with an oil droplet size of less than 1 µm is achieved due to the kinetic energy, which is also very stable. No additional energy input, such as shear forces, is required for this. It can be carried out in the aqueous phase at temperatures between 0.degree. C. and 100.degree. C., preferably at temperatures between room temperature and 70.degree. C., particularly preferably at temperatures between room temperature and 50.degree. The pressure of the liquid jets is between 5 and 5,000 bar, preferably between 10 and 1,000 bar and particularly preferably between 20 and 500 bar.

Since the collision occurs in the space, there is no risk of blocking, as is the case with microchannels. About the diameter of the nozzles that

The flow rate of the liquid streams and the temperature, the oil droplet size in the emulsion can be influenced. The resulting emulsion is discharged from the room through the outlet. There is thus a continuously operating process. In order to obtain the smallest possible oil droplet sizes, it is possible to feed an already obtained emulsion again under the same conditions through both inlets into the room, which can be repeated several times if necessary.

There is also the possibility of connecting the outlet of the space with the gas inlet of a second space in which further liquid flows are introduced into the emulsion formed, for example in order to change the surface properties of the emulsion. If two liquid flows collide, they preferably enclose an angle of 180 °, with three liquid flows the angle is preferably 120 °, etc. With three liquid flows, two liquids are immiscible with one another, etc.

According to the invention, it is preferred that the diameter of the nozzles is identical or different and is 10 to 5,000 μm, preferably 50 to 3,000 μm and particularly preferably 100 to 2,000 μm. It is possible to work with nozzles of different diameters, for example on one side of a nozzle with a diameter of 100 µm and on the other side of a nozzle with a diameter of 300 µm. Of course, the diameters of the nozzles can also be the same on both sides.

According to the invention it is provided that the flow velocities of the liquid streams after the nozzle are identical or different and are more than 20 m / s, preferably more than 50 m / s and particularly preferably more than 100 m / s.

Here, too, one of the liquid flows can have a higher flow velocity than the other liquid flow, for example on the one hand 50 m / s and on the other hand 100 m / s. Here, too, it is possible for the flow velocities of the two liquid streams to be the same.

The flow speed of the liquid streams after the nozzle can reach 500 m / s or 1,000 m / s.

The distance between the nozzles is preferably less than 5 cm, preferably less than 3 cm and particularly preferably less than 1 cm.

It is preferred that the gas pressure in the space is 0.2 to 10 bar and preferably 0.5 to 5 bar.

The droplet size can also be influenced via the gas pressure.

It can be useful to heat or cool the gas before it enters the room in order to influence the temperature in the room.

Furthermore, it is within the scope of the invention that a solvent is introduced into the space through a further inlet.

For example, propylene glycol can be introduced into the room as a further solvent through the further inlet.

One embodiment of the invention consists in the fact that during the collision there is a pressure of less than 100 bar, preferably less than 50 bar and particularly preferably less than 20 bar in the space.

It is also possible to pass the liquid flows and / or the emulsion formed through a heat exchanger in order to control the temperature of the liquid flows before the collision or that of the emulsion after the collision.

It is also within the scope of the invention that the emulsion produced is encapsulated in a further step.

It is also within the scope of the invention that in a further step the produced and possibly encapsulated emulsion is provided with a surface modification.

The invention is explained in more detail below on the basis of exemplary embodiments.

Examples 1 to 4 show the effects of varying individual parameters, while Examples 5 to 21 contain examples of possible encapsulation processes.

Example 1: Effect of gas pressure

The effect of the gas pressure was examined by colliding a liquid flow of oil and a liquid flow of water containing lecithin under different gas pressures in a room into which gas having different gas pressures was introduced through a gas inlet. The oil was pumped at a flow rate of 50 ml / min and the aqueous phase at a flow rate of 250 ml / min. The oil droplet size was determined by DLS. In all cases an oil droplet size of less than 500 nm was achieved. The results show that the oil droplet size decreases with increasing gas pressure. Pressure (bar) Oil droplet size (nm) 1 455 1.5 368 2 294 2.5 274 3 268

It can be concluded from this that the pressure acting on the system via the gas inlet has a direct influence on the oil droplet size.

Example 2: Effect of flow rate

The effect of the flow rate was examined by using different flow rates for the oil phase and the water phase while maintaining the ratio of the flow rates. A pressure in the space of 2 bar was used in all experiments. Oil flow rate (ml / min) Water flow rate (ml / min) Oil droplet size (nm) 10 50 596 20th 100 427 30th 150 348 50 250 294 100 500 257

The oil droplet size within the emulsion formed thus decreases with increasing flow rates.

Example 3: Diameter of the nozzles

The influence of the diameter of the nozzles was determined by testing various nozzle diameters while using an oil flow rate of 50 ml / min and a water flow rate of 250 ml / min and the gas pressure was 2 bar. Nozzle diameter (µm) Oil droplet size (nm) 200 294 300 318 400 567 500 785

The smaller the nozzle diameter, the smaller the oil droplet size within the emulsion formed.

Example 4: number of cycles

The oil and water phases were pre-emulsified and pumped through the two inlets in a closed cycle in order to determine the influence of the number of cycles on the oil droplet size within the emulsion. A flow rate of 250 ml / min and a gas pressure of 2 bar prevailed in the room. Number of cycles Oil droplet size (nm) 1 650 2 540 3 420 4th 355

The oil droplet size within the emulsion therefore also decreases with the number of cycles.

Encapsulation via a solvent / non-solvent process: Examples 5 to 8 Example 5: Coacervation

An essential oil to be encapsulated is emulsified at a flow rate of 67 g / min in the microjet reactor with an aqueous sodium caseinate solution (22.4 mg / ml) at a flow rate of 200 g / min in the microjet reactor. In the next step, this emulsion is processed at a flow rate of 200 g / min against an aqueous xanthan solution (0.25%) at 25 g / min. In this step, the oppositely charged side groups of the protein and the polysaccharide attach to each other. This interaction is strengthened by lowering the pH to pH 4 with 10% citric acid, whereby microcapsules are formed. The microcapsules are 50-100 µm in size.

Example 6: drying

An essential oil to be encapsulated is emulsified at a flow rate of 50 g / min in the microjet reactor in an aqueous whey protein isolate solution at a flow rate of 200 g / min. After adding 20% maltodextrin as a carrier material, the emulsion is spray-dried. Drying creates a powder that contains microencapsulated essential oil.

Example 7: Melt dispersion / matrix encapsulation

A fragrance to be encapsulated (15-30%) is dissolved in melted Compritol AO 888 at 85 ° C. This oil phase is emulsified at 68 ml / min in a 20 ° C. aqueous Tween 20 solution (0.5-1.5%) at 200 ml / min. The rapid cooling of the fat results in the formation of particles and thus matrix encapsulation of the fragrance when the emulsion is formed. The microcapsules are on average 5 µm (0.5% Tween 20) or 2 µm (1.5% Tween 20).

Example 8: Melt dispersion with modified surface

A fragrance to be encapsulated (15-30%) is dissolved in melted Compritol AO 888 at 85 ° C. This oil phase is emulsified at 68 ml / min in a 20 ° C. cold gum arabic solution (2.5%; 200 ml / min). Due to the rapid cooling of the fat, particles form immediately after the emulsion has formed.

These microcapsules are modified by processing this melt dispersion (200 ml / min) in the microjet reactor against a gelatin solution (2.5%; 150 g / min) at 50 ° C. By lowering the pH to pH 4 with 10% citric acid, the ionic interactions are strengthened and gelled by cooling.

Reactive encapsulation: Examples 9 to 18 Example 9:

A hydrophilic polyalcohol to be encapsulated (active ingredient) is added to an aqueous ammonia solution (1%) (water phase) and in the MJR reactor against an emulsifier-containing (polyetheralkyl-polymethylsiloxane) 1% encapsulation solution (TEOS) in Isoparaffin (oil phase) processed. With the same flow rate of the two solutions (50:50), a process pressure of 40 bar is set upstream of the nozzles.

The result is a stable emulsion, at whose phase boundary the encapsulation material is formed by hydrolysis of the precursors. The capsules can be separated by simple sedimentation or centrifugation and are between 5 and 10 µm in size.

Examples 10 and 11:

The method indicated in FIG. 1 is applied to the encapsulation substances OTMS, PTMS. With a constant flow rate, the microcapsules obtained have approximately the same properties with a reduced reaction time.

Examples 12, 13, and 14:

The method given in FIG. 1 is applied to variable flow rates. By varying the flow rate, ratios of the disperse phase (active substance) to the oil phase of 30:70, 40:60 and 60:40 can be achieved. The size of the microcapsules obtained increases as the proportion of disperse phase (active substance solution) increases.

Examples 15 and 16.

The method indicated in FIG. 1 is applied to an encapsulation solution containing TEOS with the modification that the concentration of the emulsifier used was reduced to 50% or 25% of the original concentration. The microcapsules obtained are larger than those obtained according to Example 1.

Example 17:

The procedure outlined in Figure 1 is applied to a different encapsulation chemistry. A 20% solution of an aqueous active substance to be encapsulated, which contains 10 meq of NH2 of the encapsulation component HMDA, is processed in the MJR against a 1% emulsifier solution in isoparaffin. The emulsion obtained in this way is by adding 40 meq COCl a 20% trimesoyl chloride solution cured in Isopar. The capsules obtained are 2 to 30 µm in size.

Example 18:

The method given in Example 17 is used with the modification that the capsule hardening by means of trimesoyl chloride solution takes place in situ by continuously introducing the solution into the reactor chamber via the fifth opening of the MJR reactor. The capsules obtained have approximately the same properties as those obtained according to Example 9.

Oil-soluble actives: Examples 19-20 Example 19:

The procedure given in Example 5 is applied to oil-soluble encapsulants. An oil-soluble active substance to be encapsulated is added to a 20% solution of the encapsulation material (OTMS) in isoparaffin and mixed by stirring at room temperature for 5 min. The solution obtained in this way is processed in the MJR reactor at a process pressure of 40 bar against a 2% aqueous emulsifier solution. The result is a stable, homogeneous emulsion which, by adding the catalyst dibutyltin laurate (0.5%), hardens the capsules, which can be separated after hardening by means of centrifugation or sedimentation.

Example 20:

The method given in Example 19 is used with the modification that the capsule hardening takes place in situ by means of dibutyltin laurate by continuously introducing the solution into the reactor chamber via the fifth opening of the MJR reactor. The capsules obtained have approximately the same properties as those obtained according to Example 19.

Melt dispersion / matrix encapsulation: Example 21

Example 21: Step 1:

Melting a polymer (e.g. PEGs, waxes, fats, ...) By choosing the material to be melted, either a hydrophilic or an oleophilic melt can be generated.

Step 2a:

Stirring solid active ingredients into the melt (e.g. surfactants, peroxo compounds, enzymes, ...)

Step 2b (as an alternative to step 2a):

Stirring the liquid active ingredients into the melt

Step 3a:

Transferring the modified melt into the MJR process using a cold non-solvent as a second liquid stream with precipitation of loaded polymeric microspheres

Step 3b (as an alternative to step 3a):

Mixing the modified melt with a warm non-solvent (pre-emulsion). This pre-emulsion is introduced into the MJR on the right and left with a flow rate ratio of 1: 1. Using the cooling effect of the inert carrier gas, the loaded polymer is precipitated on a microscale.

Step 3c (as an alternative to step 3a or step 3b):

The modified melt is mixed with part of the heated non-solvent to reduce the melt viscosity. The mixture is precipitated with the cold residual non-solvent in the MJR process with precipitation of the polymer beads.

Claims (11)

1. A method for preparing emulsions, wherein in a first step, at least one pre-emulsion is prepared from at least two non-intermixable liquids, and then in a second step, in a microjet reactor, at least two liquid streams of the at least one pre-emulsion are pumped through separate nozzles with defined diameters, characterized in that the pressure of the liquid jets is between 5 and 500 bar, in order to achieve flow velocity of the liquid streams of more than 10 m/sec., and in that the liquid streams collide at a collision point in a space, wherein the space is filled or pressurized with gas and the gas pressure in the space is 0.05 to 30 bar.
2. The method according to claim 1, characterized in that the diameter of the nozzles is identical or different, and is 10 to 5,000 µm, preferably 50 to 3,000 µm, and particularly preferably to 100 to 2,000 µm.
3. The method according to claim 1 or 2, characterized in that the flow velocity of the liquid streams is identical or different and is more than 20 m/sec., preferably more than 50 m/sec., and particularly preferably to more than 100 m/sec.
4. The method according to one of claims 1 to 3, characterized in that the distance between the nozzles is less than 5 cm, preferably less than 3 cm and particularly preferably less than 1 cm.
5. The method according to one of claims 1 to 4, characterized in that the gas pressure in the space is 0.2 to 10 bar and preferably 0.5 to 5 bar.
6. The method according to one of claims 1 to 5, characterized in that the gas is heated or cooled before entering the space, in order to influence the temperature in the space.
7. The method according to one of claims 1 to 6, characterized in that a solvent is introduced into the space via another inlet.
8. The method according to one of claims 1 to 7, characterized in that a pressure of less than 100 bar, preferably less than 50 bar, and particularly preferably less than 20 bar prevails in the space during collision.
9. The method according to one of claims 1 to 8, characterized in that the liquid streams and/or the resulting emulsion are guided through a heat exchanger, in order to control the temperature of the liquid streams prior to the collision or the temperature of the emulsion after the collision, respectively.
10. The method according to one of claims 1 to 9, characterized in that the prepared emulsion is encapsulated in a further step.
11. The method according to one of claims 1 to 10, characterized in that in a further step, the prepared and possibly encapsulated emulsion is provided with a surface modification.