EP1929271A1 - Device for on-line process control during the production of emulsions or dispersions - Google Patents

Abstract

Disclosed is a device for on-line process control during the production of emulsions or dispersions. Said device comprises a vessel for accommodating an emulsion or dispersion, a stirring tool located in the vessel for generating a stirring input into the emulsion or dispersion, an apparatus for continuously measuring the stirring input, sensing probes located in the vessel for continuously measuring the temperature and the conductivity of the emulsion or dispersion, and a recording apparatus for continuously recording the stirring input, the temperature, and the conductivity.

Description

 Device for in-line process control in the production of emulsions or

dispersions

The invention relates to a device for in-line process control in the production of emulsions or dispersions, the use of such a device for determining suitable process parameters for the preparation of emulsions or dispersions and a method for determining suitable process parameters for the preparation of emulsions or dispersions.

The preparation of emulsions and dispersions is usually carried out batchwise in stirred reactors. The required amounts of the starting materials are metered into a mixing vessel and emulsified or dispersed with a high degree of stirring. As a rule, high-performance stirrers are used which allow the generation of cavitation forces. Alternatively, high pressure homogenization is often performed. A control of the emulsions produced and dispersions and of the process usually takes place only on the finished product of the corresponding mixture batch. A continuous review of the manufacturing process is usually not possible. Since the product can be analyzed only after completion of the corresponding batch mixture, the setting of advantageous or optimal process parameters for the preparation of the emulsions and dispersions is difficult. An optimized production is - if any - only consuming possible in numerous iterations. The determination of the interdependence of process parameters and products thus obtained, for example on the Rühreintrag, the temperature and the nature of the addition of the ingredients is not possible by known methods.

The object of the present invention is to provide an apparatus for in-line process control in the preparation of emulsions or dispersions, and a method for determining suitable process parameters for the preparation of emulsions or dispersions, wherein the disadvantages of the devices known from the prior art and Procedures should be avoided. The object is achieved according erfindungemäß by an apparatus for in-line process control in the production of emulsions or dispersions, comprising a vessel for receiving an emulsion or dispersion, arranged in the vessel agitator for stirring entry into the emulsion or dispersion, a device for continuous Measuring the stirring entry, measuring probes arranged in the vessel for the continuous measurement of the temperature and the conductivity of the emulsion or dispersion, and a recording device for the continuous recording of the stirring entry, the temperature and the conductivity.

The device can be used, for example, for the discontinuous production of emulsions and dispersions on a laboratory, pilot scale or production scale.

The object is further achieved by the use of such a device for determining suitable process parameters for the preparation of emulsions or dispersions.

The object is further achieved by a method for determining suitable process parameters for the preparation of emulsions or dispersions, in which, in a device as described above, the starting materials of the emulsions or dispersions are introduced jointly or separately into the vessel and mixed with stirring and the stirring entry, the conductivity and the temperature are measured continuously and, depending on the measured values obtained, if appropriate, the stirring input and / or the temperature of the vessel are changed.

The device according to the invention first comprises a vessel for receiving an emulsion or dispersion or ingredients of an emulsion or dispersion and for receiving measuring probes for the continuous measurement of the temperature and conductivity of the emulsion or dispersion. The measurement of temperature and conductivity can be done in a combined probe. In addition, the vessel is designed so that it can accommodate a stirring tool. The vessel may be open on one side (top) as in a stirred reactor. This is the usual case. It is also possible to design the vessel closed on all sides, with the exception of inlets and outlets and stirrer feedthroughs or feedthroughs for analytical sensors, the vessel is closed. The stirrer allows mechanical stirring into the emulsion or dispersion. In this case, the stirring tool according to an embodiment of the invention is designed so that it works without generating cavitation forces and without high-pressure homogenization. In preferred stirring tools, suitable stirring elements are arranged on a stirrer axis which is rotated. The stirring tool then has at least one stirring element driven by a stirring motor via a rotated agitator axis. The stirring tool may be so-called rotor / stator systems in which a rotor is moved by motor-driven operation. The stator is usually the housing, which may be provided with internals such as crushers. Suitable stirrers are, for example, paddle stirrers, which may optionally be provided with scrapers. In addition, kneaders and other suitable stirrers such as planetary stirrers, anchor stirrers, bar stirrers, propellers, blade stirrers, dissolver disks or Intermig can be used as an alternative. Other suitable stirrer configurations are known to those skilled in the art.

The stirring tool is preferably operated in such a way that the stirring entry into the emulsion or dispersion takes place without generation of cavitation forces and without high-pressure homogenization.

A homogenizer may additionally be provided in (for example near the bottom) or on the mixing vessel. The vessel can also have a circulation in which, for example, a homogenizer can be provided.

If necessary, grinding tools such as grinding beads or balls may also be present in the vessel. Suitable grinding tools are known in the art.

The vessel (mixing vessel) can have any suitable geometry, as long as it allows a suitable mixing of the flowable substances or mixtures or the phases of the emulsions and dispersions to be prepared. Suitable geometries are known to the person skilled in the art. The mixing vessel preferably has an essentially cylindrical shape on the inside, the axis of the stirring tool lying in the cylinder axis. The arrangement of the measuring probe or probes can be provided directly in the cylindrical space of the vessel. It is also possible to provide two cylindrical vessels which are parallel and spaced from each other and which communicate with each other at the lower end so as to mix in both of them by means of stirring can be made cylindrical vessels. Such an embodiment is described in the attached Figures 1 to 3.

In the drawing, Figures 1 and 2 show mutually perpendicular cross-sectional views through the vessel according to the invention. FIG. 3 shows a plan view of the vessel. Figure 4 shows the schematic structure of the isolated stirrer. FIG. 5 shows the schematic structure of the device according to the invention. FIGS. 6 to 10 show plots of the conductivity versus the measuring time or temperature. The figures will be explained in more detail below.

FIG. 1 and FIG. 2 show cross sections through the vessel provided in the device according to the invention. The vessel has a jacket for temperature control, through which a temperature control liquid can be passed. In Figure 1, the supply and discharge for the temperature control, in particular coolant or heating means are shown left top and bottom right. The corresponding inlets and outlets are also shown in Figure 2 below and above as (dashed) circles, while they are recognizable in Figure 3 left and right of the vessel. As is apparent from Figures 1 to 3, two cylindrical recesses of different diameters are provided in the cooling / heating jacket, which are interconnected in the lower region. This is apparent in particular from FIG. In FIG. 2, to the left, the smaller diameter cylindrical aperture and, to the right, the larger diameter cylindrical aperture, which are interconnected in the lower region, are shown. The left port accepts the temperature and conductivity probe, while the right port picks up the agitator. Both the probe and the stirring tool are inserted from above. The corresponding openings are shown in Figure 3 from above. During operation, mixing of the emulsions / dispersions is achieved by the stirring tool, so that the mixed emulsion / dispersion also flows past the measuring probe in the left-hand cylindrical opening.

The (mixed) vessel used according to the invention can be selected in size according to the respective practical requirements. On the laboratory scale, the internal volume (free volume) of the (mixed) vessel is preferably 50 ml to 10 l, more preferably 100 ml to 5 l, in particular 300 to 1000 ml. In the pilot plant scale, the internal volume is preferably 5 to 100 ml, more preferably 10 to 50 1. On a large-scale or production scale, the volume or Take up capacity preferably more than 20 tons, for example more than 50 tons.

On a laboratory scale, for example (mixed) vessels can be used, in which the height of the cylindrical recesses is about 13 cm. The inner diameter of the

Recesses are for example 15 and 48 mm. Including the entire vessel

For example, the jacket has an outer diameter of 92 mm. In the overall cylindrical embodiment of the vessel shown, the outer diameter including shell is preferably 50 to 350 mm. The diameter of the larger cylindrical opening is preferably 25 to 300 mm.

FIGS. 1 to 3 show a temperature control jacket through which a temperature control medium flows. However, other suitable devices for controlling the temperature of the vessel may be provided.

It is also possible, for example continuously, to take part of the contents of a mixing vessel on a production scale and feed it to a device according to the invention. In this case, for example, the stirring entry in both vessels can be adapted to each other. It is also possible to determine advantageous process parameters in the device according to the invention and then to transmit them to the production in a timely manner.

The device according to the invention is used in particular for the discontinuous production of emulsions or dispersions. In this case, the container shown is charged with the ingredients of the emulsions or dispersions through the openings arranged above, and the finished dispersion or emulsion is also removed through this opening. Other geometries of the vessel, the loading and unloading are known in the art. The device for in-line process control can also be integrated into already existing conventional stirring vessels in pilot plant or production scale, for example subsequently.

If the stirring is carried out via a stirring element driven by a stirring motor via a rotated agitator axis, the stirrer axis preferably has an electrical insulation in its course in such a way that the stirring element and the stirring motor are electrically insulated from one another. An exemplary embodiment of this insulation is shown schematically in FIG. R stands for the stirrer axis, S stands for the stirrer axis mounted shrink tubing made of non-conductive plastic material, and M is a pushed onto the shrink tubing metal sleeve. By lying between the stirrer axis and the metal sleeve shrink tubing electrical insulation of the stirrer axis is effected. The insulation prevents possible interference with the conductivity / temperature measurement.

Figure 5 shows the schematic structure of the entire device by way of example. The stirring tool Ru has a magnetic belt Ma, which in turn serves as a signal generator for a rotational speed sensor Dr. From the stirring tool, the stirrer axis protrudes into the vessel. Furthermore, a measuring probe for measuring the temperature and conductivity Le also protrudes into the vessel. Both the speed sensor and the measuring probe are connected to a control and recording device St, which in turn is controlled by a computer Re, and transmits the data to the computer. A monitor Mo can be used to check the control of the temperature and speed as well as the measurement of the parameters. Not shown is an input unit, such as a keyboard, with which the computer and the control unit can be controlled. Usually also output media are provided for the information. Both the control of the stirring motor and optionally of pumps or metering devices for the ingredients of the emulsions or dispersions and the measured value recording can be controlled via a central computer. The evaluation of the obtained measured values (parameters) preferably also takes place via a central computer.

The continuous recording of the stirring, the temperature and the conductivity can be done with the help of the computer, but also via other suitable media such as printers or plotters. In this case, the stirring entry and optionally the temperature of the vessel are computer controlled, and the continuous recording and optionally evaluation of the Rühreintrags, the temperature and the conductivity is also computerized.

With the device according to the invention, ready-formulated emulsions and dispersions can be examined for their temperature and shear behavior. Furthermore, critical parameters can be determined and optimized in the preparation of the emulsions and dispersions. In the preparation of dispersions, the pigment addition is usually critical. With the device according to the invention it can be determined in a simple manner how much pigment can be introduced into an emulsion and when the pigment addition ideally takes place. Furthermore, the training a LC phase in an emulsion are determined time-resolved. Different stirrer speeds can be used to determine scaling-up parameters during production. The formation of LC gel networks can be determined by the conductivity at different temperatures. Similarly, the influence of low or high speeds can be observed here.

In the preparation of pilot scale or production scale emulsions and dispersions, the progress of blending or emulsification or dispersion at any stage of the process and at any stage in the process can be accomplished in real time with no time delay, ie. H. be analyzed in-line, and in the stirred tank itself, so that appropriate measures such as adjustment of the stirring, the temperature, or addition (time, speed, amount) of emulsion or dispersion components, can be controlled to the production of emulsions or dispersions to optimize.

Overall, the continuous determination of one or more of the mentioned parameters allows a continuous process control and a continuous control of the composition of the emulsion or dispersion. The quality assurance in the production is thus considerably improved or simplified. This is particularly important in pharmaceutical products of high importance.

The device according to the invention allows, for example, the ideal in-line process control for the preparation of oil-in-water emulsions or water-based dispersions. During production, important parameters such as peripheral speed of the stirrer, temperature of the emulsion / dispersion and conductivity of the emulsion / dispersion are continuously recorded automatically. The conductivity data, which are determined during the emulsification process, allow a very good interpretation of the emulsion structure as a function of temperature and stirring intensity. The conductivity of an emulsion / dispersion is directly related to its degree of dispersion, viscosity and structure.

Determination of the degree of dispersion by in-line conductivity measurements of dispersions

As the degree of dispersion increases, the conductivity of an emulsion / dispersion or the mobility of the ions in the aqueous phase decreases, since with increasing degree of dispersion the Viscosity after Einstein's relationship is increasing. There is thus an equilibrium between viscosity and degree of dispersion in an emulsion / dispersion.

If, for example, a pigment is added to an O / W emulsion, the conductivity decreases after the addition of this pigment. If the stirring speed during the pigment addition is sufficiently high, an equilibrium sets in almost immediately after pigment addition. As the pigment addition increases, the pigment distribution lasts longer with the same stirring power. If the balance is very slow, it is advisable to increase the peripheral speed. As can be seen from FIG. 6, the in-line measurement of the device according to the invention reflects this process very well. FIG. 6 shows a pigment addition to an emulsion. At the points marked with the arrows, 2 g of pigment were added to the emulsion with stirring. The conductivity was determined as a function of the measuring time. The curve indicates after which time an equilibrium is reached (slope of the curve approaches zero). It can be seen that, after the last addition of pigment, the conductivity continues to decrease continuously. This means that before the last pigment addition, the maximum amount of pigment compatible in equilibrium was added at the chosen stirrer speed. Thus, the present invention allows the indirect measurement of pigment dispersion and the measurement of the amount of pigment that can be dispersed in an emulsion.

emulsions

In emulsions, however, the conductivity does not necessarily decrease with increasing degree of dispersion. Here it can also increase with increasing degree of dispersion. This

Phenomenon particularly occurs when ionogenic emulsifiers are used.

As the degree of dispersion of the oil droplets increases, so does an ever larger one

Interface occupied by emulsifiers. About the dissociation of the counterion of

Emulsifier increases the ion concentration in the water phase and thus the conductivity of the emulsion. A typical example of how the conductivity of an O / W emulsion stabilized by ionic emulsifiers increases is shown in FIG

Conductivity applied as a function of the measuring time. The individual arrows indicate different additions in the preparation of an emulsion. First, it is assumed that demineralized water. Xanthan gum was added at the first point marked with an arrow. At the second point marked with an arrow, the oil phase was added. At the third point marked with an arrow was with the emulsion is cooled to form an LC phase. Based on the conductivity, the formation of the LC phase can be followed well.

Detection of structure formations

Oil-in-water emulsions are often stabilized by liquid crystalline gel networks. These are formed depending on the melting point of the mixing emulsifiers in the temperature range below 60 ° C.

From which temperature the formation begins and at which temperature it is completed, can be followed very well with the device according to the invention.

Thus, it is possible to detect the critical temperature at which optimal homogenization is to take place or, for example, preservatives are preferably incorporated. FIG. 8 shows the determination of the critical gel network temperature during cooling. It is the conductivity as a function of the temperature applied. At low temperature there is a LC gel network. Preservatives are preferably added at these temperatures in which an LC gel network is present since smaller amounts are required for good efficacy. At the temperature at which the conductivity increases, the particle size can be reduced again by post-homogenization. About the transition temperature to the LC gel network also statements about the water resistance of, for example, sunscreen agents are possible. A transition at about 30 ° C means a non-waterproof composition.

FIG. 9 shows the influence of the stirring speed on the required emulsification time. In each case the conductivity is plotted as a function of the measuring time. For an emulsion which was prepared with a stirrer speed of 3.15 m / s, a stable emulsion forms after about 2000 s, while at a stirrer speed of 1.44 m / s more than 3000 s are required. Thus, with the device according to the invention, optimum stirrer speeds and thus scaling-up parameters can be determined.

FIG. 10 shows the behavior of the LC gel network formation at different production temperatures. It is the conductivity as a function of the temperature applied. A first LC-gel network was made at 80 ⁰ C, a second LC Gel network at 65 ⁰ C. For the gel network produced at a higher temperature results in lower temperatures, a lower conductivity, as shown in Figure 10.

The above examples show that with the device according to the invention and the method according to the invention a multiplicity of practically relevant process parameters for the production of emulsions and dispersions can be found. Critical parameters can be easily determined. By varying the stirring entry, the emulsion quality can be assessed as a function of the stirrer speed. The measured data, stirrer speed, conductivity and temperature are determined directly in the (mixing) vessel.

According to the invention, it is possible to investigate the production of emulsions and dispersions which have very different volume fractions of the disperse phase. The dependence of the viscosity of an emulsion or dispersion on the volume fraction of the disperse phase usually corresponds to an exponential function. The important viscoelastic region in which it is possible to work according to the invention is the region in which the viscosity increases very sharply with increasing volume fraction of the disperse phase. In a biphasic emulsion, the weight ratio of the phases is preferably in a range of 1:15 to 15: 1, preferably 1: 5 to 5: 1, preferably 1: 2 to 2: 1, especially 1: 1.5 to 1.5 : 1 chosen. Especially in the case of oil / water emulsions (OAV), water / oil emulsions (W / O) and polyol / oil emulsions (P / O), the proportions by weight of the corresponding phases are preferably in this range.

In the preparation of the emulsions and dispersions, it is also possible initially to work with high viscosity and subsequently by low-viscosity dilution. The setting of a finely divided emulsion or dispersion is achieved in the high-viscosity range, while the dilution to the final concentration then takes place. For a description of the viscoelasticity, reference may be made to Römpp, Chemielexikon, 9th edition, keyword "viscoelasticity".

By maintaining the specified ratio of the two phases, a very strong mixing effect can be achieved even with the entry of low shear energies. Without wishing to be bound by theory, the microemulsion obtained by mixing the phases can be understood as a system of two interpenetrating networks, so that the microemulsion exhibits single-phase behavior. About the conductivity statements about the phase volume ratio are possible. By measuring the conductivity, it is therefore easy to determine changes in the emulsion composition or in the phase volumes. The process control is carried out in-line, for example on a production scale, for example up to the ton scale in the range of, for example, 1 to 20 tons of emulsion or dispersion, ie continuously during the manufacturing process. This makes it possible to react immediately to deviations of the compositions of the emulsions or dispersions, so that ultimately identical batches can be obtained. For example, by controlling the stirring, the production of the emulsions and dispersions can be controlled. The process control is carried out by the described measurements, for example, directly in the stirred reactor or mixing vessel, so that a production or quality control for example, a commercial product results.

In addition to the temperature of the (mixed) Gefaßes and the supply of starting materials for the emulsions and dispersions can be computer controlled. All process parameters can be controlled and controlled via a central computer. The measured values supplied by the sensors are also preferably fed to the computer as described and evaluated computer-aided.

The (mixed) vessel may be constructed of any suitable material. Examples of suitable inert materials are plastics, steels such as V2A or V4A steel or copper. Suitable materials or materials are known in the art.

The selection of the stirring tool, the size of the (mixing) vessel and so on is carried out according to the practical requirements and is to be determined by simple preliminary tests. The device according to the invention can be inexpensively adapted to a variety of applications by selecting suitable stirring tools. The in-line process control according to the invention can also be integrated into known mixing vessels on a production scale.

The apparatus and method of the present invention are applicable to a variety of emulsions or dispersions. In particular, emulsions according to the invention or multiple emulsions are prepared. Examples are OW emulsions, WO emulsions, PO emulsions, multiple emulsions, LC gels, liposomes or pearlescent concentrates. According to the invention, a wide variety of particle sizes are accessible in the emulsions. In addition to normal emulsions can also nanoemulsions having emulsion droplets having a mean diameter in the range of 5 to 1000 microns, preferably 15 to 300 nm. The production of nanodispersions is also possible.

For the preparation of an aqueous active substance carrier nanodispersion which contains at least one pharmaceutical, cosmetic and / or food-technological active ingredient, the active substance and the lipid-based active substance carrier and at least one emulsifier which forms lamellar structures can first be mixed at a temperature above the melting or softening point of the active ingredient carrier , In this case, a phase B is formed. Then, this phase B can be mixed with an aqueous phase A at a temperature above the melting or softening point of the active ingredient carrier.

The active ingredient carrier particles used are lipid-based particles. These include lipids and lipid-like structures. Examples of suitable lipids are the mono-, di- and triglycerides of the saturated straight-chain fatty acids having 12 to 30 carbon atoms, such as lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, cerotic, meleinic, as well as their esters with other polyhydric alcohols such as ethylene glycol , Propylene glycol, mannitol, sorbitol, saturated fatty alcohols having 12 to 22 carbon atoms, such as lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, saturated wax alcohols having 24 to 30 carbon atoms, such as lignoceryl alcohol, ceryl alcohol, cerotyl alcohol, myrizyl alcohol. Preference is given to mono-, di-, triglycerides, fatty alcohols, their esters or ethers, waxes, lipid peptides or mixtures thereof. In particular, synthetic mono-, di- and triglycerides are used as individual substances or in the form of a mixture, for example in the form of a hard fat. Glycerol trifatty acid esters are, for example, glycerol trilaurate, glycerol trimyristate, glycerol palmitate, glycerol tristearate or glycerol tribehenate. Suitable waxes are, for example, cetyl palmitate and Cera Alba (bleached wax, DAB 9). Polysaccharides with or in individual cases or polyalkyl acrylates, polyalkyl cyanoacrylates, polyalkyl vinyl pyrrolidones, acrylic polymers, polylactic acids or polylactides can also be used as lipids.

The amount of the active substance carrier particles, based on the total aqueous active ingredient carrier dispersion, is preferably 0.1 to 30% by weight, particularly preferably 1 to 10% by weight. In addition to the lipids, dispersion stabilizers can be used. They may, for example, in amounts of 0.01 to 10 wt .-%, preferably 0.05 be used to 5 wt .-%. Examples of suitable substances are surfactants, in particular ethoxylated sorbitan fatty acid esters, block polymers and block copolymers (such as poloxamers and poloxamines), polyglycerol ethers and esters, lecithins of various origins (for example egg or soya lecithin), chemically modified lecithins (for example hydrogenated lecithin) as well Phospholipids and sphingolipids, mixtures of lecithins with phospholipids, sterols (for example cholesterol and cholesterol derivatives and stigmasterol), esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols (for example sucrose monostearate), sterically stabilizing substances such as poloxamers and poloxamines (polyoxyethylene-polyoxypropylene) Block polymers), ethoxylated sorbitan fatty acid esters, ethoxylated mono- and diglycerides, ethoxylated lipids and lipids, ethoxylated fatty alcohols or fatty acids and charge stabilizers or charge carriers such as dicetyl phosphate, phosphatidylglycerol and saturated and unsaturated fatty acids, sodium cholate, sodium glycol cholate, sodium taurocholate or mixtures thereof, amino acids or peptizers such as sodium citrate (see JS Lucks, BW Müller, RH Müller, Int. J. Pharmaceutics 63, pages 183 to 189 (1990)), viscosity-increasing substances such as cellulose ethers and esters (for example methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose), polyvinyl derivatives such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetate, alginates, polyacrylates (for example Carbopol), Xanthans and pectins.

As aqueous phase A, water, aqueous solutions or mixtures of water with water-miscible liquids such as glycerol or polyethylene glycol can be used. Further additional components for the aqueous phase are, for example, mannose, glucose, fructose, xylose, trehalose, mannitol, sorbitol, xylitol or other polyols, such as polyethylene glycol, and electrolytes, such as sodium chloride. These additional components can be used in an amount of 0.5 to 60, for example 1 to 30 wt .-%, based on the aqueous phase A.

If desired, it is also possible to use viscosity-increasing substances or charge carriers, as described in EP-B-0 605 497.

Emulsifiers that form lamellar structures can be natural or synthetic

Products are used. The use of surfactant mixtures is possible. Examples of suitable emulsifiers are the physiological bile salts such as sodium cholate,

Sodium dehydrocholate, sodium deoxycholate, sodium glycocholate, sodium taurocholate. Animal and plant phospholipids such as lecithins with their hydrogenated forms as well as polypeptides such as gelatin with their modified forms can also be used.

Suitable synthetic surfactants are the salts of sulfosuccinic acid esters, polyoxyethylene acid betanesters, acid betanesters and sorbitan ethers, polyoxyethylene fatty alcohol ethers, polyoxyethylene stearate esters and corresponding blend condensates of polyoxyethylene-methopolyoxypropylene ethers, ethoxylated saturated glycerides, partial fatty acid glycerides and polyglycides. Examples of suitable surfactants are Biobase® EP and Ceralution® H.

Examples of suitable emulsifiers are also glycerol esters, polyglycerol esters, sorbitan esters, sorbitol esters, fatty alcohols, propylene glycol esters, alkylglucositesters, sugar esters, lecithin, silicone copolymers, wool wax and mixtures thereof or derivatives. Glycerol esters, polyglycerol esters, alkoxylates and fatty alcohols and isoalcohols can be derived, for example, from castor fatty acid, 12-hydroxystearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, stearic acid, myristic acid, lauric acid and capric acid. In addition to the stated esters, succinates, amides or ethanolamides of the fatty acids may also be present. Particularly suitable fatty acid alkoxylates are the ethoxylates, propoxylates or mixed ethoxylates / propoxylates.

Emulsifiers are also generally used to prepare the cosmetic emulsions according to the invention. Examples of suitable emulsifiers are glycerol esters, polyglycerol esters, sorbitan esters, sorbitol esters, fatty alcohols, propylene glycol esters, alkylglucoside esters, sugar esters, lecithin, silicone copolymers, wool wax and their mixtures and derivatives. Glycerol esters, polyglycerol esters, alkoxylates and fatty alcohols and isoalcohols can be derived, for example, from castor fatty acid, 12-hydroxystearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, stearic acid, myristic acid, mauric acid and capric acid. In addition to the stated esters, succinates, amides or ethanolamides of the fatty acids may also be present. Particularly suitable fatty acid alkoxylates are the ethoxylates, propoxylates or mixed ethoxylates / propoxylates. It is also possible to use emulsifiers which form lamellar structures. Examples of such emulsifiers are the physiological bile salts such as sodium cheolate, sodium dehydrocheolate, sodium deoxycheolate, sodium glycochelate, sodium taurochalate. Animal and vegetable phospholipids like Lecithins with their hydrogenated forms as well as polypeptides such as gelatin with their modified forms can also be used.

Suitable synthetic surfactants are the salts of sulfosuccinic, Polyoxiethylensäurebethanester, Säurebethanester and sorbitan, Polyoxiethylenfettalkoholether, Polyoxiethylenstearinsäureester and corresponding mixture condensates of Polyoxiethylen-methpolyoxipropylenethern, ethoxylated saturated glycerides, partial fatty acid glycerides and polyglycides. Examples of suitable surfactants are Biobase ^® EP and Ceralution ^® H.

Lipids and emulsifiers are preferably used in a weight ratio of 50: 1 to 2: 1, preferably 15: 1 to 30: 1.

The pharmaceutical, cosmetic and / or food-technological active ingredients are, based on the phase B, preferably used in an amount of 0.1 to 80 wt .-%, particularly preferably 1 to 10 wt .-%.

The following are exemplary pharmaceutical active ingredients listed, which can be used for example in free form, as a salt, ester or ether:

Analgesics / antirheumatics such as morphine, copdein, piritamide, fentanyl and fentanyl derivatives, levomethadone, tramadol, diclofenac, ibuprofen, indomethacin, naproxen, piroxicam, penicillamine; Antiallergic agents such as pheniramine, dimetinden, terfenadine, asternizole, loratidine, doxylamine, meclozin, bamipin, clemastine; Antibiotics / chemotherapeutics such as polypetid antibiotics such as colistin, polymyxin B, teicplanin, vancomycin; Antimalarials such as quinine, halofantrine, mefloquine, chloroquine, antivirals such as ganciclovir, foscarnet, zidovudine, acyclovir and others such as dapsone, fosfomycin, fusafungi, trimetoprim; Anticonvulsants such as phenytoin, mesuximide, ethosuximide, primidone, phenobarbital, valproic acid, carbamazepine, clonazepam; Antifungals such as internally: nystatin, natarrycin, amphotericin B, flucytoan, miconazole, fluconazole, itraconazole; external also: clotrimazole, econazole, tioconazole, fenticonazole, bifonazole, oxiconazole, ketoconazole, isoconazole, tlnattate; Corticoids (internals), such as aldosterone fludrocortisone, betametasone, dexametasone, triamcinolone, fluocortolone, hydroxycortisone, prednisolone, prednylidene, cloprednol, methylprednisolone; Dermatics, such as antibiotics: tetracycline, erythromycin, neomycin, gentamycin, clindamiycin, framycetin, tyrothricin, chlortetracycline mipirocin, fusidic acid; Antivirals as above, also: podohyllotoxin, vidarabine, tromantadine; Corticoids as above, also: amcinonide, flupredniden, alclometasone, clobetasol, diflorasone, halcinonide, fluocinolone, clocortolone, flumetasone, difluocortolone, fludroxycortide, halometasone, desoximtasone, fluocinolide, fluocortinbutyl, flupredniden, prednicarbate, desonide; Diagnostics such as radioactive isotopes such as Te99m, InI 11 or 1131 covalently linked to lipids or lipids or other molecules or in complexes, highly substituted iodine-containing compounds such as lipids; Hemostatic agents, such as bleeding factors VIII, DC; Hypnotics, sedatives such as cyclobarbital, pentobarbital, phenobarbital, methaqualone, benzodiazepines (flurazepam, midazolam, netrazepam, lormetazepam, flunitrazepam, trazolam, Brotizolam, temazepam, loprazolam); Pituitary and hypothalamic hormones, regulatory peptides and their inhibitors such as corticotrophin, tetracosactide, chorionic gonadotropin, urofollitropin, urothonototropin, somatropin, metergoline, bromocriptine, terlipressin, desmopressin, oxrtocin, argipressin, ornipressin, leuprorelin, triptorelin, gonadorelin, buserelin, nafarelin, goselerin, somatostatin; Immunotherapeutics and cytokines, such as dimepranol-4-acetatamidobenzoate, thymopentin, α-interferon, β-interferon, filgrastim, interleukins, azathioprine, ciclosporin; Local anesthetics, such as internally: butanilicain, mepivacaine, bupivacaine, etidocaine, lidocaine, articaine, prilocaine; external also: propipocaine, oxybuprocaine, etracaine, benzocaine; Migraine agents such as proxibarbal, lisuride, methysergide, dihydroergotamine, clonidine, ergotamine, pizotifen; Anesthetics such as methohexital, propofol, etomidate, ketamine, alfentanil, thiopental, droperidol, fentanyl; Parathyroid hormones, calcium metabolism regulators such as dihydrotachysterol, calcitonin, clodronic acid, etidronic acid; Opthalmics such as atropine, cyclodrin, cyclopentolate, homatropin, tronicamide, scopolamine, pholedrine, edoxudine, idouridin, tromantadine, acyclovir, acetazolamide, diclofenamide, carteolol, timolol, metipranolol, betaxolol, pindolol, befunolol, bupranolol, levobununol, carbachol, pilocarpine, clonidine , Neostigmine; Psychotropic drugs, such as benzodiazepines (lorazepam, diazepam), clomethiazole; Thyroid therapeutics such as 1-thyroxine, carbimazole, thiamazole, propylthiouracil; Sera, immunoglobulins, vaccines such as immunoglobulins in general and specific such as hepatitis types, rubella, cytomegalovirus, rabies; TBE, varicella zoster, tetanus, Rhesus factors, immune serums such as botulism antitoxin, diphtheria, gas gangrene, snake venom, scorpion venom, vaccines such as influenza, tuberculosis cholera, diphtheria, hepatitis types, TBE, rubella, hemophilus influenzae, measles, neisseria, mumps, poliomyelitis, Tetanus, rabies, typhus; Sex hormones and their inhibitors, such as anabolic steroids, androgens, antiandrogens, progestogens, estrogens, antiestrogens (tamoxifen etc.); Cystostatic agents and metastasis inhibitors such as alkylating agents such as Nimustin, Melphalan, Carmustine, Lomustine, Cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, busulfan, treosulfan, predninmustine, thiotepa,

Antimetabolites such as cytarabine, fluorouracil, methotrexate, mercaptopurine, tioguanine, alkaloids such as vinblastine, vincristine, vindesine; Antibiotics such as aclarubicin, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mitomycin, plicamycin,

Complexes of subgroup elements (for example, Ti, Zr, V, Nb, Ta, Mo, W, Pt) such as carboplatin, cisplatin and metallocene compounds such as titanocene dichloride amsacrine, dacarbazine, estramustine, etoposide, hydroxycarbamide, mitoxynthrone, procarbazine, temiposide, alkylamidophospholipids (described in JM Zeidler, F. Emling, W. Zimmermann and HJ Roth, Archiv der Pharmazie, 324 (1991), 687)

Etherlipids such as hexadecylphosphocholine, dmofosine and analogs described in R. Zeisig, D. Arndt and H. Brachwitz, Pharmacy 45 (1990), 809-818.

Suitable active ingredients are, for example, also dichlorphenac, ibuprofen, acetylsalicylic acid, salicylic acid, erythromycin, ketoprofen, cortisone, glucocorticoids.

Also suitable are cosmetic active ingredients which are particularly susceptible to oxidation or hydrolysis, for example polyphenols. Catechins (such as epicatechin, epicatechin-3-gallate, epigallocatechin, epigallocatechin-3-gallate), flavonoids (such as luteolin, apigenin, rutin, quercitin, fisetin, kaempherol, rhametin), isoflavones (such as genistein, daidzein, glycitein, Prunetin), coumarins (such as daphnetin, umbelliferone), emodin, resveratrol, oregonin.

Suitable are vitamins such as retinol, tocopherol, ascorbic acid, ribofiavine, pyridoxine. Also suitable are whole extracts from plants, which i.a. contain the above molecules or classes of molecules.

The active substances are, according to one embodiment of the invention, light protection filters. These can be used as organic sunscreen at room temperature

(25 ⁰ C) in liquid or solid form. Suitable light protection filters (UV filters) are, for example, compounds based on benzophenone, diphenyl cyanoacrylate or

Amino benzoic acid. Concrete examples are (INCI or CTFA designations)

Benzophenone-3, Benzophenone-4, Benzophenone-2, Benzophenone-6, Benzophenone-9, Benzophenone-1, Benzophenone-11, Etocrylene, Octocrylene, PEG-25 PABA,

Phenylbenzimidazole sulfonic acid, ethylhexyl methoxycinnamate, ethylhexyl dimethyl PABA, 4-methylbenzylidene camphor, butyl methoxydibenzoylmethane, ethylhexyl salicylates, homosalates, and methylene-bis-benzotriazolyl tetramethylbutylphenol (2,2'-methylene-bis- {6- (2H-benzoetriazol-2-yl) -4- (1, 1 , 3, 3-tetramethylbutyl) -phenol}, 2-

Hydroxy-4-methoxybenzophenone-5-sulfonic acid and 2,4,6-trianilino-p- (carbo-2'-ethylhexyl-1-oxi) -l, 3, 5-triazine.

Other organic sunscreen filters are octyltriazone, avobenzone, octylmethoxycinnamates, octylsalicylates, benzotriazoles and triazines.

According to a further embodiment of the invention, anti-dandruff agents are used as active ingredients, as they are usually present in cosmetic or pharmaceutical formulations. An example of this is Piroctone Olamine (1-hydroxy-4-methyl-6- (2,4,4-dimethylpentyl) -2 (1H) -pyridone, preferably in combination with 2-aminoethanol (1: 1)). Other suitable agents for the treatment of dander are known in the art.

Other possible ingredients of the emulsions are hydrophilic coated micropigments, electrolytes, glycerol, polyethylene glycol, propylene glycol, barium sulfate, alcohols, waxes, metal soaps, magnesium stearate, vaseline or other ingredients. For example, it is also possible to add perfumes, perfume oils or perfume flavors. Suitable cosmetic agents, for example polyphenols and compounds derived therefrom. Suitable vitamins are retinol, tocopherol, ascorbic acid, riboflavin and pyridoxine.

As active ingredients, for example, all oxidation-sensitive active ingredients such as tocopherol come into consideration.

According to a further embodiment of the invention, organic dyes are used as active ingredients or instead of active substances.

All known and suitable water-in-oil emulsions or oil-in-water emulsions can be prepared by the process according to the invention. These can be used after the emulsifiers described and other ingredients. Furthermore, the preparation of polyol-in-oil emulsions is possible. Any suitable polyols can be used here. In the emulsions, the proportions of the two main phases can be varied within wide limits. For example, from 5 to 95% by weight, preferably from 10 to 90% by weight, in particular from 20 to 80% by weight, of the respective phases are present, the total amount being 100% by weight.

The described P / O emulsion can also be emulsified in water or a water-in-oil emulsion. This results in a polyol-in-oil-in-water emulsion (P / O / W emulsion) containing at least one described emulsion and additionally at least one aqueous phase. Such multiple emulsions may correspond in structure to the emulsions described in DE-A-43 41 113 and DE-A-43 41114.

When introducing the P / O emulsion according to the invention into water or aqueous systems, the weight ratio of the individual phases can be varied within wide limits. In the finally obtained P / O / W emulsion, the weight fraction of the P / O emulsion is preferably from 0.01 to 80% by weight, particularly preferably from 0.1 to 70% by weight, in particular from 1 to 30% by weight. %, based on the total P / O / W emulsion.

When introducing the P / O emulsion according to the invention into an O / W emulsion, the proportion of the P / O emulsion is preferably 0.01 to 60% by weight, particularly preferably 0.1 to 40% by weight, in particular 1 to 30 wt .-%, based on the final P / O / W emulsion. In the O / W emulsion used for this purpose, the oil content is preferably 1 to 80% by weight, particularly preferably 1 to 30% by weight, based on the O / W emulsion used. Instead of a P / O emulsion, a W / O emulsion can also be introduced, which leads to a W / O / W emulsion. The individual phases of the emulsions may still have conventional ingredients known for the individual phases. For example, the individual phases may contain further pharmaceutical or cosmetic active substances which are soluble in these phases. The aqueous phase may contain, for example, organic soluble sunscreen, hydrophilically coated micropigment, electrolytes, alcohols, etc. Also, any or all of the phases may contain solids which are preferably selected from pigments or micropigments, microspheres, silica gel, and the like. The oil phase may contain, for example, organically modified clay minerals, hydrophobically coated (micro) pigments, organic oil-soluble light protection filters, oil-soluble cosmetic agents, waxes, metal soaps such as magnesium stearate, vaseline or mixtures thereof. As (micro) pigments, titanium dioxide, zinc oxide and barium sulfate as well as wollastonite, kaolin, talc, Al ₂ O ₃ , bismuth oxychloride, micronized polyethylene, Mica, ultramarine, eosin, azo dyes. Titanium dioxide or zinc oxide, in particular, are customary in cosmetics as light protection filters and can be applied particularly smoothly and evenly to the skin by means of the emulsions according to the invention. Microspheres or silica gel can be used as carriers for drugs, and waxes can be used, for example, as a base for polishes.

The water phase may also contain glycerol, polyethylene glycol, propylene glycol,

Ethylene glycol and similar compounds and derivatives thereof.

The use of customary auxiliaries and additives in the emulsions is the

Specialist known.

As the aqueous phase, water, aqueous solutions or mixtures of water with water-miscible liquids such as glycerol or polyethylene glycol can be used. Further, electrolytes such as sodium chloride may be contained in the aqueous phase. If desired, it is also possible to use viscosity-increasing substances or charge carriers, as described in EP-B-0605 497.

Claims

claims

1. An apparatus for in-line process control in the preparation of emulsions or dispersions, comprising a vessel for receiving an emulsion or dispersion, an arranged in the vessel agitator for stirring entry into the emulsion or dispersion, a device for continuously measuring the Rühreintrags, in measuring probes arranged in the vessel for the continuous measurement of the temperature and the conductivity of the emulsion or dispersion; and a recording device for the continuous recording of the stirring, the temperature and the conductivity.

2. Apparatus according to claim 1, characterized in that the stirring tool driven at least one of a stirring motor via a rotated agitator axis

Has stirring element and the measurement of the Rühreintrags carried out by measuring the speed of the stirrer axis.

3. A device according to claim 2, characterized in that the stirrer axis in its course has an electrical insulation of the type that stirring element and

Stirring motor are electrically isolated from each other.

4. Device according to one of claims 1 to 3, characterized in that it serves for the discontinuous production of emulsions or dispersions in the laboratory, Technikums- or Produktionsmaßstäb.

5. Device according to one of claims 1 to 4, characterized in that it comprises a device for tempering the vessel.

6. Device according to one of claims 1 to 5, characterized in that it comprises a computer as a control unit and the Rühreintrag and optionally the temperature of the vessel are computer controlled.

7. Apparatus according to claim 6, characterized in that the continuous recording and optionally evaluation of the Rühreintrags, the temperature and the conductivity is computer-aided.

8. Use of a device according to one of claims 1 to 7 for the determination of suitable process parameters for the preparation of emulsions or dispersions.

9. A method for determining suitable process parameters for the preparation of emulsions or dispersions, characterized in that in a device according to one of claims 1 to 7, the starting materials of the emulsions or dispersions are introduced jointly or separately into the vessel and mixed under stirring and mixing the stirring , the conductivity and the temperature are measured continuously and, depending on the measured values obtained, if appropriate, the stirring input and / or the temperature of the vessel are changed.

10. The method according to claim 9, characterized in that the temporal change in the conductivity at different Rühreinträgen or as a function of additions of starting materials of the emulsion or dispersion or the dependence of the conductivity of the temperature, optionally determined at different production temperatures.