EP3408015A1

EP3408015A1 - Method for producing emulsions

Info

Publication number: EP3408015A1
Application number: EP17706142.1A
Authority: EP
Inventors: Bernd BAUMSTÜMMLER; Hermann Schirra; Akif Emre TÜRELI
Original assignee: Instillo GmbH
Current assignee: Instillo GmbH
Priority date: 2016-01-25
Filing date: 2017-01-25
Publication date: 2018-12-05
Anticipated expiration: 2037-01-25
Also published as: ES2893124T3; DK3408015T3; WO2017129177A1; DE102016101232A1; KR20180101573A; EP3408015B1; JP2019508233A; CN108495708A; US20190030497A1; JP7031103B2; CN108495708B

Abstract

In order to provide a new method for producing emulsions, with which it is possible to achieve, with minimum energy input, oil droplets that are as homogeneous and as small as possible, it is proposed that at least two streams of immiscible liquids are pumped through separate openings of defined diameter in order to achieve flow velocities of greater than 10 m/s, and that the liquid streams meet at a collision point in a space, the resulting emulsion being discharged from the space through an outlet. By virtue of the kinetic energy, the collision of the liquid streams at high flow velocities, resulting in a disk-shaped collision plate forming at the collision point, create a homogeneous emulsion with an oil droplet size of less than 1 µm, which is accordingly also very stable. This requires no further energy input such as shear forces or high pressure.

Description

DESCRIPTION

Process for producing emulsions

The invention relates to a method for producing emulsions.

Emulsions are understood below to mean both colloidal emulsions and industrial emulsions, the latter differing from the colloidal emulsions by considerably larger particle dimensions in the micrometer range.

A variety of industries, such as the food, pharmaceutical and cosmetics industries, are in great demand for encapsulation, protection or targeted release of hydrophobic substances such as bioactive lipids, fragrances, 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 which 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 prepared. A disadvantage of emulsions is their instability, which relies on physicochemical mechanisms such as gravity separation, flocculation, coalescence, and Ostwald ripening. In oil-in-water emulsions, the most common cause of instability is gravity 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 methods are particularly high shear mixing (rotor / stator systems), high pressure homogenization, microfluidization, ultrasonic homoginazation or membrane emulsification Most of these processes require a high input of energy into the system in order to control the droplet size of the oil droplets formed, which can be applied in different ways, for example by heating, shearing, increasing pressure or Pressure reduction. The stability of the emulsion increases with decreasing droplet size. Emulsions with a Oltröpfchengröße of more than 10 μιη tend to go over in a short time in two separate phases, while at a Oltröpfchengröße of less than 1 μπι increases the stability of the emulsion with decreasing Oltröpfchengröße. However, with an oil droplet size of less than 1 μιη, a four times greater energy input is necessary to reduce the oil droplet size by 50%, which limits the minimum oil droplet size achievable. In addition, due to the energy input there is a risk of a temperature rise to temperatures above 70 ° C, at which a destruction of the emulsifiers may occur.

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.

In the microfluidization several passes are required even under high pressure conditions to bring the Oltröpfchengröße below 1 μπι. Since emulsion formation occurs in microchannels, blocking these microchannels is one of the most common problems with this method.

DE 10 2009 008 478 A1 describes a process in which a solvent / anti-solvent precipitation takes place in the presence of surface-active molecules, a microjet reactor corresponding to EP 1 165 224 B1 being used. Such a microjet reactor has at least two opposing nozzles, each with associated pump and supply line for spraying each of a liquid medium in a reactor chamber enclosed by a reactor chamber to a common collision point, wherein a first opening is provided in the reactor housing, through which a gas, a evaporating liquid, a cooling liquid or a cooling gas for maintaining the gas atmosphere inside the reactor, in particular at the collision point of the liquid jets, or for cooling the resulting products can be introduced, and provided a further opening for removing the resulting products and excess gas from the reactor housing is. Thus, through an opening in the reactor space, a gas, an evaporating liquid or a cooling gas is maintained to maintain a gas atmosphere in the interior of the reactor, in particular at the point of collision introduced the liquid jets, or for cooling the resulting products and the resulting products and excess gas through an opening from the reactor housing by pressure on the gas inlet te or by under pressure on the product and gas outlet side away. If a solvent / non-solvent precipitation, for example as described in EP 2 550 092 A1, is carried out in such a microjet reactor, 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 / nonsolvent precipitation means that a substance is dissolved in a solvent and collides as a liquid jet with a second liquid jet, wherein the solute is precipitated again. A disadvantage of solvent / Nonsolvent precipitation is the fact that the dissolved and reprecipitated substance is particulate in the solvent-Nonsolvent mixture after precipitation. In this case, the solvent content causes that for many particles time-dependent Ostwald ripening sets, which causes a growth of the particles.

From DE 10 2009 036 537 B3 a device for emulsifying at least two liquids is known, which comprises an emulsion reactor having an outlet for removing the emulsion resulting from the mixing of the liquids and in which a plurality of for injection to substantially a common Collision point aligned nozzles is provided, each nozzle is associated with a respective supply line and a pump which pumps a liquid from an associated tank through the supply line in the emulsion reactor.

The object of the invention is therefore to provide a novel process for the preparation of emulsions, which also enables the preparation of asymmetric emulsions.

This object is achieved in that in a first step at least one pre-emulsion of at least two immiscible liquids is generated and then in a second step at least two liquid streams of the at least one pre-emulsion are pumped through separate openings with a defined diameter to flow rate of the liquid streams of more than 10 m / s and that the liquid streams meet at a collision point in a room. Since in a variety of emulsions, namely the asymmetric emulsions in which the oil and the water phase are not present in a ratio of 1: 1, it has been found in the invention advantageous to first produce a preemulsion 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 streams into a device in which both streams of liquid meet at a collision point in a space, for example a microjet reactor.

Due to the collision of the liquid streams at high flow rates, which forms a plate-shaped collision plate in the collision point, a homogeneous emulsion is achieved with an oil droplet size of less than 1 μιη due to the kinetic energy, which is also very stable accordingly. There is no further input of energy, e.g. Shear forces needed. It can be carried out in the aqueous phase at temperatures between 0 ° C and 100 ° C, preferably at temperatures between room temperature and 70 ° C, more preferably at temperatures between room temperature and 50 ° C. The pressure of the liquid jets is between 5 and 5,000 bar, preferably between 10 and 1,000 bar, and more preferably between 20 and 500 bar.

Since the collision takes place in the room, there is no danger of blocking, as is the case with microchannels. Through the diameter of the openings, 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 through the outlet from the room. Thus, there is a continuous process. In order to obtain the smallest possible droplets of oil droplets, it is possible to pass an emulsion already obtained under the same conditions through both inlets in the room, which may optionally be repeated several times.

It is also possible to connect the outlet of the space with the gas inlet of a second space in which further liquid streams are introduced into the emulsion formed, for example, to change the surface properties of the emulsion. If two streams of liquid collide, they preferably enclose an angle of 180 °, with three streams of liquid the angle is preferably 120 °, etc. With three streams of liquid, two liquids are not miscible with each other, etc.

It is preferred according to the invention that the diameter of the openings is identical or different and 10 to 5,000 μπι, preferably 50 to 3,000 μπι and particularly preferably 100 to 2,000 μπι. It is possible to work with openings of different diameters, for example, on one side of an opening with a diameter of 100 μπι and on the other side of an opening with a diameter of 300 μπι. Of course, the diameter of the openings on both sides can be the same.

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

Again, one of the liquid streams may have a higher flow rate than the other liquid stream, for example on the one hand 50 m / s and on the other hand 100 m / s. Again, it is possible that the flow rates of both liquid streams are equal.

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

Preferably, the distance between the openings is less than 5 cm, preferably less than 3 cm, and more preferably less than 1 cm.

Belonging to the invention is also that the space is filled with gas or applied.

Gas, in particular inert gas or inert gas mixtures, but also reactive gas can be supplied through a gas inlet in the room. It is preferred that the gas pressure in the space is 0.05 to 30 bar, preferably 0.2 to 10 bar, and more preferably 0.5 to 5 bar.

Also via the gas pressure, the droplet size can be influenced.

It may be useful to heat or cool the gas prior to entering the room to affect the temperature in the room.

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

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

An embodiment of the invention is that during the collision in the room, a pressure of less than 100 bar, preferably less than 50 bar and more preferably less than 20 bar prevails.

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

Finally, it is within the scope of the invention that a microjet reactor is used to carry out the process.

Such a microjet reactor is known from EP 1 165 224 Bl.

Due to the method used in the microjet reactor of the collision of the beams under elevated pressure, the droplet size of the emulsion is dependent on the system and operating parameters, in particular the nozzle size in the microjet reactor and the pump pressure of the pumping pumps for the two fluid streams. In contrast to the customary use of microjet reactors in the method according to the invention by the collision energy no precipitation reactions are caused in the microjet reactor, but emulsions are formed.

In the context of the invention is also that in a further step, the emulsion produced is encapsulated.

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 will be explained in more detail by means of exemplary embodiments.

Examples 1 to 4 show the effects of variation of 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 space in 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 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 investigated by using different flow rates for the oil phase and the water phase with a constant flow rate ratio. A pressure in the room of 2 bar was used in all experiments.

The Oltröpfchengröße within the emulsion formed thus decreases with increasing flow rates.

Example 3: Diameter of the openings

The influence of the diameter of the orifices was determined by testing different orifice 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.

The smaller the opening 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 into a closed cycle to determine the influence of the number of cycles on oil droplet size within the emulsion. A flow rate of 250 ml / min and a gas pressure of 2 bar prevailed in the room.

The oil droplet size within the emulsion thus 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 Na-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 gum solution (0.25%) at 25 g / min. In this step, the oppositely charged side groups of the protein and the polysaccharide are attached to each other. Lowering the pH to pH 4 with 10% citric acid enhances this interaction, creating microcapsules. The microcapsules are 50-100 μπι large.

Example 6: Drying

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

Example 7: Melt Dispersion / Matrixyer Encapsulation

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

Example 8: Melt Dispersion with Modified Surface

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

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

Reactive Encapsulation: Examples 9 to 18

Example 9:

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

The result is a stable emulsion, at the phase interface, the encapsulating material is formed by hydrolysis of the precursors. The capsules can be separated by simple sedimentation or Zentrifugati on and are between 5 and 10 μπι large.

Examples 10 and 11:

The procedure given in FIG. 1 is applied to the encapsulating substances OTMS, PTMS. At constant flow rate, the microcapsules obtained have approximately the same properties with reduced reaction time.

Examples 12. 13 and 14:

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

Examples 15 and 16.

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

Example 17:

The method given in Figure 1 is applied to another encapsulation chemistry. A 20%) solution of an aqueous active substance to be encapsulated containing 10 meq H 2 of the encapsulation component HMDA is processed in MJR against a 1% emulsifier solution in isoparaffin. The emulsion thus obtained is made by adding 40 meq COC1 a 20% Trimesoyl chloride solution cured in Isopar. The resulting capsules are 2 to 30 μιη large.

Example 18:

The procedure given in Example 17 is followed with the modification that capsule hardening is carried out by means of trimesoyl chloride solution in situ by continuous introduction of the solution into the reactor chamber via the fifth opening of the MJR reactor. The resulting capsules have approximately the same properties as obtained according to Example 9.

Oil Soluble Actives: Examples 19 to 20 Example 19:

The procedure given in Example 5 is applied to oil-soluble encapsulants. An oil-soluble active ingredient to be encapsulated is placed in a 20% solution of the encapsulating material (OTMS) in isoparaffin and mixed at room temperature for 5 minutes by stirring. The solution thus obtained 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, the addition of the catalyst dibutyltin laurate (0.5%), the curing of the capsules which can be separated after curing by centrifugation or sedimentation.

Example 20:

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

Melt Dispersion / Matrix Encapsulation: Example 21 Example 21:

Step 1 :

Melting of a polymer (e.g., PEGs, waxes, fats, ...)

By choosing the substance to be melted, either a hydrophilic or an oleophilic melt can thus be generated.

Step 2a:

Stirring the 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 MXR process using a cold non-solvent as a second liquid stream to precipitate loaded polymeric microspheres

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

Mix 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 action of the inert carrier gas, the loaded polymer is microscopically precipitated.

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

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

Claims

1. A process for the preparation of emulsions, characterized in that in a first step at least one pre-emulsion of at least two immiscible liquids is generated and then in a second step at least two liquid streams of the at least one pre-emulsion are pumped through separate openings of defined diameter, to achieve flow velocity of the liquid streams of more than 10 m / s and that the liquid streams meet at a collision point in a room.

2. The method according to claim 1, characterized in that the diameter of the openings is identical or different and 10 to 5,000 μπι, preferably 50 to 3,000 μπι and particularly preferably 100 to 2,000 μπι.

3. The method according to claim 1 or 2, characterized in that the

Flow rate of the liquid streams is identical or different and more than 20 m / s, preferably more than 50 m / s and more preferably more than 100 m / s.

4. The method according to any one of claims 1 to 3, characterized in that the distance between the openings is less than 5 cm, preferably less than 3 cm and more preferably less than 1 cm.

5. The method according to any one of claims 1 to 4, characterized in that the space is filled with gas or applied.

6. The method according to any one of claims 1 to 5, characterized in that the gas pressure in the space 0.05 to 30 bar, preferably 0.2 to 10 bar and particularly preferably 0.5 to 5 bar.

A method according to any one of claims 1 to 6, characterized in that the gas is heated or cooled before it enters the room to influence the temperature in the room.

8. The method according to any one of claims 1 to 7, characterized in that a solvent is introduced through a further inlet into the room.

9. The method according to any one of claims 1 to 8, characterized in that during the collision in the room, a pressure of less than 100 bar, preferably less than 50 bar and more preferably less than 20 bar prevails.

10. The method according to any one of claims 1 to 9, characterized in that the

Liquid streams and / or the resulting emulsion are passed through a heat exchanger to control the temperature of the liquid streams before the collision and the emulsion after the collision.

11. The method according to any one of claims 1 to 10, characterized in that a microjet reactor is used for carrying out the method.

12. The method according to any one of claims 1 to 11, characterized in that in a further step, the emulsion prepared is encapsulated.

13. The method according to any one of claims 1 to 12, characterized in that in a further step, the produced and possibly encapsulated emulsion is provided with a surface modification