WO2008031780A2

WO2008031780A2 - Method for producing fine-particle dispersions

Info

Publication number: WO2008031780A2
Application number: PCT/EP2007/059436
Authority: WO
Inventors: Sebastian Koltzenburg; Bernd Bechtloff; Richard Van Gelder; Dirk Franke
Original assignee: Basf Se
Priority date: 2006-09-13
Filing date: 2007-09-10
Publication date: 2008-03-20
Also published as: WO2008031780A3

Abstract

The invention relates to a method for producing fine-particle dispersions of a chemical compound which is poorly soluble in a dispersant, by the turbulent intermixing of at least two liquid flows described as medium A and medium B, of which at least the liquid flow described as medium A contains the chemical compound to be dispersed or a precursor thereof, in a mixing device provided with at least two inlets and an outlet. The liquid flows are supplied in such a way that the angle between the longitudinal axes of a volume flow of medium A and a volume flow of medium B is between 10° and 170°, and the volume flows have different surface cross-sections.

Description

Process for the preparation of finely divided dispersions

description

The present invention relates to a process for the preparation of finely divided dispersions by turbulent mixing of at least two liquid streams, of which at least one liquid stream designated as medium A contains the substance to be dispersed or a precursor thereof, and at least one liquid stream other than medium B denotes the dispersion medium contains, in a mixing device provided with at least two inlet openings and at least one discharge opening.

Dispersions are a system comprising at least two phases, one of which, the dispersing agent, being continuous and at least one other discontinuous phase, the dispersed phase, being finely dispersed therein (cf. Römpp Chemie Lexikon, Vol. 2, p. 1010, 9th edition (1990), Georg Thieme Verlag, Stuttgart). Dispersions can be present, for example, as emulsions (liquid / liquid) or as suspensions (solid / liquid).

There are numerous processes for the preparation of finely divided dispersions. Usually, the phase to be dispersed is finely divided by supplying energy in the dispersing agent. The energy can be supplied, for example, chemically, electrochemically, electrically, thermally or mechanically. Mechanical energy can be supplied, for example, by grinding or ultrasound.

Disperse systems can also be obtained by precipitation or condensation of the dispersed phase or one of its constituents or, in the case of reactive precipitation, by the formation of products in the dispersed phase.

Frequently, surface-active substances are also used in the preparation for stabilizing the dispersed phase.

An overview of suitable processes for preparing particularly finely divided dispersions with hydrophobic active substances as the dispersed phase is given by way of example. H. Muller et al. In "Emulsions and Nanosuspensions for the Formulation of Poorly Soluble Drugs", chapter 9.2., Medpharm Scientific Publishers, Stuttgart 1998.

EP-A-0169 discloses particulate pharmaceutical preparations of poorly water-soluble substances, the preparations being obtained by precipitation from a solution of the active substance after addition of a precipitation solution. In WO 93/10767 peptide drugs are described in which the drug is incorporated into a gelatin matrix in such a way that the forming particles are charge neutral. However, a disadvantage of such forms is their tendency to flocculate.

DE-A 4440337 describes the preparation of surfactant-stabilized finely divided suspensions. However, high surfactant concentrations may be physiologically questionable.

No. 4,826,689 describes a precipitation method in which amorphous spherical particles are obtained which are stabilized by no further addition or only slight additions of surfactants. The shear stability of such systems is low.

EP-A 275,796 describes the preparation of colloidal dispersible systems with submicron spherical particles.

WO 97/14407 describes the production of submicron particles by expansion from a solvent into a compressed gas, liquid or supercritical fluid in the presence of an amphiphile.

DE 3742 473 C2 describes finely divided preparations of solid particles of a cyclosporin and a stabilizer which maintains the degree of dispersion of the particles. The particle size of these preparations is in the submicron range.

WO 02/078674 describes the preparation of finely divided dispersions in the presence of amphiphilic copolymers, the particles being obtained by mixing a solution of the amphiphilic copolymer with a non-solvent. The mixing can be done either in a vortex mixer or in a device in which the streams of dissolved copolymer and non-solvent collide head-on.

C. Heyer and A. Mersmann, describe in Proc. 14th Int. Symp. Ind. Cryst. In 1999, the precipitation of finely divided pigment particles by mixing a solution of the pigment in sulfuric acid with a stream of water in a symmetrical Y-mixer.

S. Palakodaty et al. describe the precipitation of lactose particles by mixing an aqueous lactose solution with a supercritical fluid as a non-solvent by mixing the two liquids by means of a coaxial nozzle.

Another known possibility for the preparation of dispersions is the use of a microjet reactor for the production of azo colorants (EP-A-1 195 41 1), for the fine distribution of organic pigments (E PA-1 195 413) and for the preparation of liquid pigment preparations (EP-A- 1 195 414). In the microjet reactor used there is in Reactor space maintained a gas phase. The educts are injected by high-pressure nozzles to a common point of collision.

Disadvantages of this method are the difficult adjustment of the Eduktstrahlen to a common point of collision, problems in carrying out the experiment at unequal momentum currents, and the product separation from the gas phase or undesirable foaming. In particular, in the case of unequal pulse currents, the passage of medium A into the nozzle of medium B may occur, i. possibly to precipitate a component in front of the corresponding nozzle and thus to their constipation and total failure of the microjet reactor.

Also in the other known methods and arrangements such as symmetrical Y mixers, vortex mixers or coaxial nozzle mixers often occur problems. Thus, the targeted control of the process to produce uniform particle size distributions is often difficult.

The object of the present invention was to find an improved process for the preparation of finely divided dispersions.

Accordingly, a process for the preparation of finely divided dispersions by turbulent mixing of at least two liquid streams designated as medium A and medium B, of which at least one liquid stream designated as medium A contains the substance to be dispersed or a precursor thereof, in one with at least two inlet openings and at least a mixing device provided with a discharge opening, which is characterized in that the liquid flows are supplied in such a way that the angle α between the longitudinal axes of a volume flow of medium A and a volume flow of medium B is 10 to 170 °, and that the volume flows have different surface cross sections ,

According to a preferred embodiment, the angles between the longitudinal axes of the liquid flow flowing out through the outlet opening of the dispersion formed (and the longitudinal axes of the liquid streams entering the mixing device are greater than 90 °.

For the purposes of the invention, finely divided means that the average particle size of the primary particles (d4.3, weight average) of the dispersed phase is <2 micrometers, preferably <1 micrometer. Particularly preferred are average particle sizes <0.8 micrometers, in particular less than 0.5 micrometers.

Suitable dispersions according to the invention are emulsions or suspensions. Preferably, the process is used to prepare suspensions.

Suitable substances to be dispersed are chemical compounds or mixtures of chemical compounds which are more natural, semisynthetic or of synthetic origin. Chemical compounds are substances whose smallest units, the molecules, are composed of at least two atoms of different elements. According to the invention, both substances having low molecular weights and oligomeric or macromolecular substances such as oligopeptides or polypeptides can be used as chemical compounds. In the case of compounds of semisynthetic or natural origin, mixtures may also be present. The compounds to be dispersed according to the invention are solid or liquid at room temperature. Preferably, solid or oily compounds are processed at room temperature.

Suitable chemical compounds are in principle all active substances and effect substances, for example biologically active compounds such as pharmaceutical, cosmetic or agrochemical active substances, for example insecticides, fungicides, herbicides or growth regulators, dietary supplements, inorganic or organic coloring agents or catalysts.

The method according to the invention can be carried out such that medium A contains the substance to be dispersed and medium B contains a non-solvent for the substance to be dispersed (process variant I), or in the sense of a reactive precipitation (process variant II), the media A and B and optionally further liquid streams Edukte for the substance to be dispersed or other auxiliaries such as Catalysts included.

According to process variant I, the substance to be dispersed is usually dissolved in the liquid used in medium A. But it can also be in the form of an emulsion, for example a melt emulsion. The liquid stream designated as medium B in this case contains any liquid which is a non-solvent for the substance to be dispersed.

The type of liquid used in the respective medium depends on the type of phase to be dispersed. The prerequisite is that the dispersion medium and the phase to be dispersed do not mix with one another under the process conditions, but form two separate phases. If the phase to be dispersed is hydrophobic, the dispersant is usually hydrophilic. If it is a hydrophilic phase to be dispersed, usually a hydrophobic dispersant is used. The formation of two phases can also be controlled via the pH, if the solubility of the phase to be dispersed in water is pH-dependent. For compounds whose solubility in an aqueous medium depends on the ionic strength, the formation of the dispersion can also be controlled by the ionic strength. Suitable liquids are, in addition to water, inorganic acids or bases, especially organic solvents. It is also possible to use mixtures, for example mixtures of different homogeneously miscible organic solvents or aqueous mixtures. The prerequisite is that a homogeneous solution of the liquid components is present in a mixture.

Suitable acids are, depending on the field of application, for example, mineral acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid or chlorosulfonic acid.

Suitable organic solvents are: alcohols having 1 to 10 C atoms, such as, for example, methanol, ethanol, n-propanol, isopropanol, butanols, such as n-butanol, sec-butanol, tert-butanol, pentanols, such as n-pentanol , 2-methyl-2-butanol, hexanols, such as 2-methyl-2-pentanol, 3-methyl-3-pentanol, 2-methyl-2-hexanol, 3-ethyl-3-pentanol, octanols, such as 2 , 4,4-trimethyl-2-pentanol, cyclohexanol; or glycols, such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, or glycerol; Polyglycols, such as polyethylene glycols or polypropylene glycols; Ethers, such as methyl isobutyl ether, tetrahydrofuran or dimethoxyethane; Glycol ethers, such as monomethyl or monoethyl ether of ethylene or propylene glycol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, butyl glycols or methoxybutanol; Ketones, such as acetone, diethyl ketone, methyl isobutyl ketone, methyl ethyl ketone or cyclohexanone; aliphatic acid amides such as formamide, dimethylformamide, N-methylacetamide or N, N-dimethylacetamide; Urea derivatives, such as tetramethylurea; or cyclic carboxylic acid amides, such as N-methylpyrrolidone, valero or caprolactam; Esters, such as carboxylic acid C1-C6-alkyl esters, such as butyl formate, ethyl acetate or propionic acid propyl ester; or carboxylic acid C, C, glycol ester; or glycol ether acetates such as 1-methoxy-2-propyl acetate; or phthalic or benzoic acid C1-C6 alkyl esters, such as ethyl benzoate; cyclic esters such as caprolactone; Nitriles, such as acetonitrile or benzonitrile; aliphatic or aromatic hydrocarbons, such as cyclohexane or benzene; or benzene substituted by alkyl, alkoxy, nitro or halogen, such as toluene, xylene, ethylbenzene, anisole, nitrobenzene, chlorobenzene, o-dichlorobenzene, 1, 2,4-trichlorobenzene or bromobenzene; or other substituted aromatics such as benzoic acid or phenol; aromatic heterocycles such as pyridine, morpholine, picoline or quinoline; and hexamethylphosphoric triamide, 1, 3-dimetyl-2-imidazolidinone, dimethyl sulfoxide and sulfolane. The solvents mentioned can also be used as mixtures.

Preferably, partially or completely miscible solvents are used as organic solvents with water. Which organic solvents are used also depends on the field of application of the dispersion or of the agent to be dispersed. In the case of agents to be dispersed, which are intended, for example, for use in pharmaceuticals, cosmetics, food supplements, the use of a physiologically relatively harmless solvent is recommended, while in purely technical applications a broader range can be applied.

Suitable are preferably organic, water-miscible solvents which are volatile and thermally stable and contain only carbon, hydrogen, oxygen, nitrogen and sulfur. Conveniently, they are at least 10 wt .-% miscible with water and have a boiling point below 200 ⁰ C, preferably below 100 ⁰ C, and / or have less than 10 carbon atoms. Preference is given to corresponding alcohols, esters, ketones, ethers and acetals. In particular, use is made of ethanol, n-propanol, isopropanol, butyl acetate, ethyl acetate, tetrahydrofuran, acetone, ethylene glycol, propylene glycol, 1,2-propanediol 1-n-propyl ether or 1,2-butanediol-1-methyl ether. Very particular preference is given to ethanol, isopropanol and acetone.

As medium A, supercritical fluids can also be used. In addition to supercritical carbon dioxide, many commonly used organic solvents such as isopropanol (T _c = 31 ^o C, p _c = 7.4 MPa), ethanol (T _C = 216 ° C, p _c = 6.5 MPa) or others used in medium A. Solvent or solvent mixtures prior to mixing with the medium B are in the supercritical state.

The phase to be dispersed in process variant I is preferably dissolved in the medium A as described above. Optionally, the substance to be dispersed in the chosen solvent by heating, optionally under elevated pressure, are brought into solution.

The concentration of the substance to be dispersed in medium A depends on the solubility of the substance to be dispersed in the chosen medium. To achieve the highest possible space-time yields, the concentration is selected as high as possible, ie close to the solubility limit.

The inventive method is carried out so that at least one liquid flow of the medium A and at least one liquid flow of the medium B are such turbulent mixed with each other, that the angle α between the longitudinal axes of the flow rates of medium A and medium B at an angle of 10 to 170 ° , preferably 30 to 155 °, particularly preferably 90 to 140 °. The angle between the liquid streams entering the mixing device and the liquid streams leaving the mixing device is more than 90 °.

For the method according to the invention, it is essential that the area cross section of the volume flows of medium A and medium B is chosen differently. The ratio of the surface cross sections of the inlet openings is preferably 0.01 to 0.9, particularly preferably 0.1 to 0.8. The absolute size of the surface sections depends on the size of the device and can be from 0.03 mm ² to 1000 mm ² . How the ratio is to be chosen in each individual case depends on the selected material system and can be determined by the specialist in each individual case.

The ratio of the sum of the area cross sections of the inlet openings to the area average of the discharge opening can be 0.1 to 5, preferably 0.2 to 3.

The throughput of the volume flows also depends on the size of the device. It can be from 1 to 50,000 l / h.

The ratio of the pulse currents of medium A and medium B is chosen so that it represents a numerical value of 0.01 to 0.9, preferably 0.1 to 0.8. Pulse flow is the product of mass flow and velocity.

Overall, the flow parameters are chosen so that after mixing the various streams turbulent flow occurs. For the particular system selected, the person skilled in the art can determine these parameters, taking into account the densities and other parameters.

The temperature of medium A may be 20 to 300, preferably 50 to 250 ⁰ C.

The temperature of medium B may be 0 to 100, preferably 5 to 30 ⁰ C.

The pressure loss in the mixing device is in the range of 0.01 to 200 MPa, preferably 0.1 to 20 MPa. In addition, a pressure holding device may be provided at the output. The holding pressure can be 0.01 MPa to 20 MPa.

According to one embodiment of the invention, the method can also be performed as reactive precipitation. The media A and B and optionally further streams then contain the starting materials for the desired in the final dispersion dispersed phase before and optionally further auxiliaries such. Catalysts. The resulting after mixing the educt liquid streams chemical compound is then not soluble in the resulting liquid medium.

For example, medium A may contain a solution of barium chloride and medium B may consist of sulfuric acid, so that after mixing, a precipitation of barium sulfate occurs. Another example is the precipitation of titanium dioxide. Furthermore, double metal cyanide compounds can be obtained, for example, by mixing a zinc acetate with a cobalt tricyan solution.

The present invention also relates to an apparatus for carrying out the method according to the invention.

The two or more, expediently 2 to 7, inlet openings open into the mixing device and are distributed over the inner circumference that they are not coaxial are aligned. Non-coaxial means that the liquid streams do not meet head-on, parallel or tangential.

In the figure 1, the mixing device with the position of the angle α and ß is shown schematically. The angle α denotes the angle between the volume flows of medium A and B and, if appropriate, further liquid flows. The angle β is the angle of the inlet openings with respect to the axis of the discharge opening in the direction of the discharge opening.

The angle β may be 95 to 175 °, preferably 15 to 155 °.

FIG. 2 shows a further schematic embodiment of the invention.

The inlet openings can be designed with an angular, an oval or a round cross-section. Preferred is a round cross-section.

In addition to the inlet openings for the media A and B, inlet openings for further liquids can also be provided, for example liquids for influencing the pH or the ionic strength or reagents necessary for reactive precipitation.

The device is further provided with pumps, in particular high-pressure pumps, in order to press the liquid streams through the inlet openings.

The geometry of the mixing zone can be arbitrary, but advantageous are molds which allow no or only small dead volumes, such. cylindrical shapes.

The volume of the mixing zone must be limited to such an extent that a turbulent flow state is maintained. The mixing zone itself can be thermostated by an enclosing housing.

The mixing zone can also be followed by a flow tube. The flow tube is preferably a double-walled, controlled in order to control endo- and exothermic chemical reactions or physical processes.

The mixing zone of the mixing device according to the invention is almost completely filled with liquid phase during operation. The educts enter a mixing zone in which highly turbulent flow conditions exist. The subject matter of the invention is also a mixing device for carrying out the method according to the invention, which is characterized in that two or more inlet devices each with associated pump and supply line for introducing in each case a liquid medium in one of a housing Mixing zone of a mixing device are provided, which is provided with at least one outlet opening for discharging the resulting dispersion from the mixing device. The axes of the entry devices are not aligned coaxially with each other.

According to a preferred embodiment, the mixing device is also equipped with a temperature measuring device for determining the mixing temperature in the mixing zone.

The discharge can also be followed by a conventional mixer or any dispersing unit. The further dispersion can be effected by shear forces or by real comminution. Methods or dispersing agents for this purpose are known to the person skilled in the art.

All components of the mixing device according to the invention are expediently made of glass, plastic or metal, preferably of alloyed stainless steel, Hastelloy or titanium.

In one embodiment of the invention, the process may be carried out in the presence of an amphiphilic compound. The amphiphilic compound exerts the function of a protective colloid in order to avoid agglomeration of the primary particles of the substance to be dispersed.

Suitable amphiphilic compounds may be low molecular weight, oligomeric or polymeric substances. Which amphiphilic compound is chosen usually depends on whether the dispersion is to be used for industrial applications or whether physiological compatibility is desired.

The amphiphilic compound may, depending on its solubility, be supplied in the dispersing medium or in the solvent present in medium A or in another stream.

Suitable physiologically acceptable protective colloids may be natural polymers such as polypeptides, for example, such as beef, pork or fish gelatin, casein or caseinates, or polypeptide-containing mixtures such as milk powder from whole milk or skimmed milk. Other suitable natural or semisynthetic polymers are polysaccharides such as starches or starch derivatives, for example dextran or dextrins, pectins, gum arabic, alginic acids or alginates such as, for example, ammonium, alkali or alkaline earth alginates, chitosan, lignosulfonates or cellulose derivatives such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose , or mixtures of said protective colloids. Preferably, the polypeptide used is one of the gelatin types mentioned, in particular acidic or basic degraded gelatin having bloom numbers in the range from 0 to 250, very particularly preferably gelatin A 100, A 200, B 100 and B 200 and low molecular weight, enzymatically degraded gelatin types with the Bloom number 0 and molecular weights of 15,000 to 25,000 D such as Collagel A and Gelitasol P (Stoess, Eberbach) and mixtures of these types of gelatin.

Further preferred polypeptides are also casein or caseinates, especially in the form of their sodium and potassium salts.

Examples of suitable synthetic protective colloids are furthermore polymers based on the following monomers:

2-methyl-N-vinylimidazole, acrylamide, acrylamidomethylpropanesulfonic acid, acrylonitrile, acrylic acid, aminopropyl vinyl ether, butanediol monoacrylate, butanediol monomethacrylate, butanediol monovinyl ether, butyl acrylate, butyl methacrylate, diethylaminoethyl vinyl ether, diethylene glycol monovinyl ether, dimethylaminoethyl acrylate, dimethylaminoethyl acrylate metochloride, dimethylaminoethyl methacrylate, dimethylaminoethyl methacrylate quaternized with methyl chloride, dimethylaminopropyl methacrylamide, ethyl acrylate , Ethylene glycol monovinyl ether, ethylhexyl acrylate, ethylhexyl methacrylate, ethyl methacrylate, ethylvinyl ether, hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate, isobutyl acrylate, isobutyl methacrylate, isopropylacrylamide, maleic anhydride, methacrylic acid, methacrylic anhydride, methyl acrylate, methyl methacrylate, methyl vinyl ether, N-methyl-N vinylacetamide, N-vinylcaprolactam, N-vinylimidazole, N-vinylpiperidone, N-vinylpyrrolidone, phenoxyethyl acrylate, Polytetrahydrofuran 290 divinyl ether, styrene, styrenesulfonic acid, tert-butylacrylamide, tert-butyl acrylate, tert-butyl methacrylate, vinyl (2-ethylhexyl) ether, vinyl acetate, vinyl formamide, vinyl isobutyl ether, vinyl isopropyl ether, vinyl propyl ether and vinyl tert-butyl ether and esters the acrylic acid or methacrylic acid with oligo- or polyethylene oxide, eg Monomethylpoly- ethylene oxide acrylic acid or methacrylic acid esters in which the polyethylene oxide has a number average molecular weight of about 300 to about 5,000 g / mol.

Ionizable monomers may optionally be completely or partially neutralized before, during or after the polymerization.

The term polymers includes both homo- and copolymers. Here, the skilled person can control the desired properties of the protective colloid by selecting suitable monomers and their relative proportions in the polymer. Suitable copolymers are both random and alternating systems, block copolymers or graft copolymers. The term copolymers comprises polymers which are made up of two or more different monomers or in which the incorporation of at least one monomer into the polymer chain reacts in different ways. lisieren, as is the case for example with the stereo block copolymers. The hydrophilicity or hydrophobicity required for the application can be set by the person skilled in the art by the choice of suitable monomers with appropriate hydrophilicity or hydrophobicity and by their relative amounts.

The concentration of the protective colloids can be selected so that the weight ratio of protective colloid to the substance to be dispersed is 9: 1 to 1: 1, preferably 4: 1 to 2: 1.

Furthermore, low molecular weight surface-active compounds can be used. As such surface-active compounds are particularly suitable amphiphilic compounds or mixtures of such compounds. Both ionic and nonionic compounds come into consideration. In principle, all surfactants with an HLB value of 5 to 20 come into consideration. Suitable surface-active substances are, for example: esters of long-chain fatty acids with ascorbic acid, mono- and diglycerides of fatty acids and their oxyethylation products, esters of monofatty acid glycerides with acetic acid, citric acid, lactic acid or diacetyltartaric acid, polyglycerol fatty acid esters, such as e.g. the monostearate of triglycerin, sorbitan fatty acid esters, propylene glycol fatty acid esters, 2- (2'-stearoyl lactyl) lactic acid salts and lecithin. Preferred surfactants are ascorbyl palmitate or sodium dodecyl sulfate diacetyltartaric acid esterified with monoglycerides. For physiologically acceptable applications, ascorbyl palmitate is particularly preferred.

According to another embodiment of the invention, water-insoluble polymers may also be added to the solvent for the phase to be dispersed, so that in the resulting dispersion the forming discontinuous phase is a dispersion of the active ingredient or effect substance in a polymer matrix. Of particular interest are polymers which are soluble in organic, water-miscible solvents, and are not or only partially soluble in water or aqueous solutions or water solvent mixtures at temperatures between 0 and 240 ⁰ C. The following polymers are exemplified without, however, being limiting.

Thus, natural or semi-synthetic polymers such as gutta percha, celluloic ethers such as e.g. Methylcellulose (substitutional ridge 3-10%), ethylcellulose, butylcellosis, cellulose esters, e.g. Cellulose acetate, or starches or starch derivatives.

Furthermore, synthetic polymers can be used. Suitable synthetic core polymers are polymers based on the following monomers:

Acrylamide, allyl methacrylate, alpha-methylstyrene, butadiene, butanediol dimethacrylate, Butanediol divinyl ether, butanediol dimethacrylate, butanediol monoacrylate, Butandiolmono- methacrylate, butanediol monovinyl ether, butyl acrylate, butyl methacrylate, Cyclohexylvi- vinyl ether, diethylene glycol divinyl ether, diethylene glycol monovinyl ether, ethyl acrylate, ethyl diglycol acrylate, ethylene, Ethylenglycolbutylvinylether, ethylene glycol dimethacrylate, ethylene glycol divinyl ether, ethylhexyl acrylate, ethylhexyl methacrylate, ethyl methacrylate, ethyl vinyl ether, glycidyl methacrylate, hexanediol divinyl ether, hexanediol monovinyl ether, Isobutene, isobutyl acrylate, isobutyl methacrylate, isoprene, methyl acrylate, methylenebisacrylamide, methyl methacrylate, methyl vinyl ether, n-butyl vinyl ether, N-methyl-N-vinylacetamide, N-vinylcaprolactam, N-vinylimidazole, N-vinylpiperidone, N-vinylpyrrolidone, octadecyl vinyl ether, phenoxyethyl acrylate, Polytetrahydrofuran 290-divinyl ether, propylene, styrene, tert-butylacrylamide, tert-butyl acrylate, tert-butyl methacrylate, tetraethylene glycol divinyl ether, triethylene glycol dimethyl acrylate, tri ethylene glycol divinyl ether, triethylene glycol divinyl methyl ether, trimethylolpropane trimethacrylate, trimethylolpropane trivinyl ether, vinyl (2-ethylhexyl) ether, vinyl 4-tert-butyl benzoate, vinyl acetate, vinyl chloride, vinyl dodecyl ether, vinylidene chloride, vinyl isobutyl ether, vinyl isopropyl ether, vinyl propyl ether, vinyl tert-butyl ether

The term polymers includes both homo- and copolymers. In this case, the person skilled in the art can control the desired water insolubility of the core polymer by selecting suitable monomers and their relative proportions in the polymer. It goes without saying that the hydrophilic monomers mentioned in the above list have this desired insolubility only in combination with at least one further hydrophobic monomer and therefore can not be used as homopolymer as the core polymer.

Suitable copolymers are both random and alternating systems, block copolymers or graft copolymers. The term copolymers encompasses polymers which are made up of two or more different monomers, or in which the incorporation of at least one monomer into the polymer chain can be implemented in various ways, e.g. in the case of stereo block copolymers. The required for the application of hydrophilicity or hydrophobicity can be adjusted by the skilled person by the choice of suitable monomers with appropriate Hydrohilie or hydrophobicity and by their relative amounts.

The phase to be dispersed may also be a solution of a solid compound in an oily substance. Suitable physiologically acceptable oils are, for example, fish oil, peanut oil, soybean oil, rapeseed oil or nuclear oils. Depending on the field of application, mineral oils are still suitable.

With the aid of the method according to the invention and the device according to the invention, it is generally possible to prepare finely divided dispersions. As already stated, both dispersions of hydrophobic chemical compounds in one hydrophilic dispersants, as well as dispersions of hydrophilic chemical compounds in a hydrophobic dispersant.

Preferably dispersions of compounds sparingly soluble in water can be prepared by the process according to the invention.

The term "water-soluble" according to the invention also comprises virtually insoluble substances and means that for a solution of the substance in water at 20 ⁰ at least 30 to 100 g of water is required per g of substance C. In virtually insoluble chen substances are at least 10,000 g Water per g of substance needed.

The process of the invention can be used for the preparation of dispersions containing sparingly soluble in water pharmaceutical active ingredients. Corresponding active ingredients are, for example: benzodiazepines, antihypertensives, vitamins, cytostatics - especially taxol, anesthetics, neuroleptics, antidepressants, antiviral agents, antibiotics, antifungals, fungicides, chemotherapeutics, urologics, antiplatelet agents, sulfonamides, antispasmodics, hormones, immunoglobulins, sera, thyroid medicines, Psychotropic drugs, antiparkinson agents and other antihyperkinetics, ophthalmics, neuropathy preparations, calcium metabolism regulators, muscle relaxants, anesthetics, lipid-lowering agents, liver therapeutics, coronary agents, cardiacs, immunotherapeutics, regulatory peptides and their inhibitors, hypnotics, sedatives, gynecologics, gout, fibrinolytics, enzyme preparations and transport proteins, enzyme inhibitors , Emetics, circulation-promoting agents, diuretics, diagnostics, corticoids, cholinergics, biliary tract therapeutics, antiasthmatics, broncholytics, beta-blockers, calcium antagonists, ACE inhibitors, arteriosclerosis anti-oxidants, antiphlogistics, anticoagulants, antihypotonics, antihypoglycemics, antihypertensives, antifibrinolytics, antiepileptics, antiemetics, antidotes, antidiabetics, antiarrhythmics, antianemics, antiallergics, anthelmintics, analgesics, analeptics, aldosterone antagonists, weight loss agents. In detail, pharmaceutical active ingredients are, for example:

Analgesics / antirheumatics such as codeine, diclofenac, fentanyl, hydromorphone, ibuprofen, indomethacin, levomethadone, morphine, naproxen, pritramide, piroxicam, tramadol, antiallergic agents such as astemizole, dimetinden, doxylamine, loratadine, meclocine, pheniramine, terfenadine, antibiotics / chemotherapeutics such as erythromycin, Framycetin, fusidic acid, rifampicin, tetracycline, thiazetazone, tyrothricin, anticonvulsants such as carbamazepine, clonazepam, mesuximide, phenytoin, valproic acid, antifungals such as clotrimazole, ficonazole, itraconazole, calcium antagonists such as darodipine, isradipine, corticoids such as aldosterone, betametasone, Budesonide, dexamethasone, fluocortolone, fludrocortisone, hydroxycortisone, methylprednisolone, prednisolone, hypnotics / sedatives such as benzodiazepine, cyclobarbital, methaqualone, phenobarbital, immunosuppressive agents such as azathioprine, cyclosporine, topical anesthetics such as benzocaine, butanilacaine, etidocaine, lidocaine, oxybuprocaine, tetracaine, Migraines such as dihydroergotamine, ergotamine, lisurid, methylated sergid, narcotics such as droperidol, etomidate, fentanyl, ketamine, methohexital, propofol, thiopental, ophthalmic agents such as acetazolamide, betaxolol, bupranolol, carbachol, carteolol, cyclodrin, cyclopentolate, diclofenamide, edoxodine, homatropin, levobununol, pholedrine, pindolol, timolol, tropicamide, Herbal medicines such as Hypernicum, Urtica folia, Artichoke, Agnus castus, Cimicifuga, Devil's claw, Besenginster, Peppermint oil, Eucalyptus oil, Celandine, Ivy, Kava-kava, Echinacea, Valerian, Sabal, Hypericum, Milk thistle, Ginkgo biloba, Aloe barbadensis, Allium sativum , Panax ginseng, Serenoa repens, Hydrastis canadensis, Vaccinium macrocarpon or mixtures thereof, protease inhibitors such as. These include, for example, saquinavir, indinavir, ritonavir, nelfinavir, palinavir or combinations of these protease inhibitors, sex hormones and their antagonists, anabolic steroids, androgens, antiandrogens, estradiols, gestagens, progesterone, estrogens, antioestrogens such as tamoxifen, vitamins / antioxidants such as carotenoids or caro - tinoid analogues or lipoic acid, cytostatics / antimetastatics such as busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbacin, dactinomycin, estramustine, etoposide, flurouracil, ifosfamide, methotrexate, paclitaxel, vinblastine, vincristine, vindesine.

Furthermore, it is also possible to process vitamins and other active ingredients for dietary supplements or dietetic agents, for example carotenoids such as .beta.-carotene, astaxanthin, cantaxanthin or isorenearatin, and also coenzyme Q10.

Suitable active ingredients include pigments for cosmetic or pharmaceutical applications such as zinc oxide or titanium dioxide.

Cosmetic active substances can also be processed, for example cosmetic fats and oils such as peanut oil, jojoba oil, coconut oil, almond oil, olive oil, palm oil, castor oil, soybean oil or wheat germ oil or for essential oils such as mountain pine oil, lavender oil, rosemary oil, pine needle oil, pine needle oil, eucalyptus oil , Peppermint oil, safflower oil, bergamot oil, turpentine oil, lemon balm oil, sage oil, juniper oil, lemon oil, aniseed oil, cardamom oil; Peppermint oil, camphor oil etc. or for mixtures of these oils.

Furthermore, water-insoluble or insoluble UV absorbers such as, for example, 2-hydroxy-4-methoxybenzophenone (Uvinul® M 40, BASF), 2,2 ', 4,4'-tetrahydroxybenzophenone (Uvinul® D 50), 2, 2'-dihydroxy-4,4'-dimethoxybenzophenone (Uvinul® D49), 2,4-dihydroxybenzophenone (Uvinul® 400), 2-cyano-3,3-diphenylacrylic acid 2'-ethylhexyl ester (Uvinul® N 539), 2 , 4,6-trianilino-p- (carbo-2'-ethylhexyl-1 '-oxi) -1, 3,5-triazine (Uvinul ^® T 150), 3- (4-methoxybenzylidene) camphor (Eu Solex ^® 6300, Merck), N, N-dimethyl-4-aminobenzoic acid 2-ethylhexyl ester (Eusolex® 6007), salicylic acid 3,3,5-trimethylcyclohexyl ester, 4-isopropyl-dibenzoylmethane (Eusolex® 8020), 2-ethylhexyl p-methoxycinnamate and 2-isoamyl p-methoxycinnamate, and mixtures thereof. Likewise, agrochemicals can be processed.

Furthermore, coloring agents such as inorganic or organic pigments can be processed according to the invention. Examples of pigments are those from the group of the perylenes, perinones, quinacridones, for example unsubstituted quinacridone of the beta or gamma phase or quinacridone mixed crystal crude pigments, quinacridonequinones, anthraquinones, anthanthrones, benzimidazolones, disazocondensation pigments, azo pigments, indanthrones, phthalocyanines, such as chlorinated CuPc, unchlorinated alpha- or beta-phase CuPc, metal-free phthalocyanines or phthalocyanines with other metal atoms such as aluminum or cobalt, dioxazines, for example triphendioxazines, aminoanthraquinones, diketopyrrolopyrroles, indigo pigments, thioindigo pigments, thiazine indigo pigments, isoindolines, isoindolinones , Pyranthrones, isoviolanthrones, flavanthrones and anthra-pyrimidines, individually, in mixtures or as mixed crystals, eg from two or three such pigments, into consideration. Carotenoids such as β-carotene can also be used as organic pigment.

As the dispersant for pigments, preferred are acids such as sulfuric acid, for example, 96% by weight sulfuric acid, monohydrate or oleum; Chlorosulfonic acid and polyphosphoric acid, used individually or in mixture. These acids can also be used as mixtures with one or more organic solvents. In the process according to the invention, in the preparation of pigment dispersions it is also possible to use customary auxiliaries, for example surfactants, non-pigmentary and pigmentary dispersants, fillers, setting agents, resins, waxes, defoamers, antidusting agents, extenders, colorants for shading, preservatives, drying retardants, additives for controlling rheology, wetting agents, antioxidants, UV absorbers, light stabilizers, or a combination thereof. The total amount of auxiliaries added may be from 0 to 40% by weight, preferably from 1 to 30% by weight, in particular from 2.5 to 25% by weight, based on the crude pigment.

The process according to the invention is also suitable for all azo colorants which can be prepared by azo coupling reactions, for example azo pigments from the series of monoazo pigments, disazo pigments, β-naphthol and naphthol AS pigments, laked azo pigments, benzimidazolone pigments, disazo condensation pigments and metal complexazo pigments; and for azo dyes from the series of cationic, anionic and nonionic azo dyes, in particular mono-, dis- and polyazo dyes, formazan and other metal complex azo dyes and anthraquinone azo dyes. The process of the invention also relates to the preparation of precursors of the actual azo colorants by azo coupling reaction. For example, by means of the process according to the invention precursors for laked azo colorants, ie leachable azo colorants, for disazo condensation pigments, ie monoazo colorants which can be linked via a bifunctional group or, for example, via an acid chloride-extendable disazo colorants, for formazan dyes, or other heavy metal-containing, for example, copper, chromium, nickel, or cobalt-containing azo colorants, ie, heavy metal complexable azo colorants. The azo dyes are especially the alkali salts or ammonium salts of the reactive dyes and the acidic wool dyes or nouns cotton dyes of the Azore series. As azo dyes are preferably metal-free and metallizable mono-, dis- and polyazo dyes, and azo dyes containing one or more sulfonic acid groups into consideration.

The azo colorants, pigment dispersions and pigment preparations prepared according to the invention are suitable for coloring natural or synthetic high molecular weight organic materials, such as, for example, cellulose ethers and esters, such as ethylcellulose, nitrocellulose, cellulose acetate or cellulose butyrate, natural resins or synthetic resins, such as polymerization resins or condensation resins, for example aminoplasts , in particular urea and melamine

Formaldehyde resins, alkyd resins, acrylic resins, phenolic resins, polycarbonates, polyolefins such as polystyrene, polyvinyl chloride, polyethylene, polypropylene, polyacrylonitrile, polyacrylic acid esters, polyamides, polyurethanes or polyesters, rubber, casein, latices, silicones and silicone resins, individually or in mixtures. The abovementioned high molecular weight organic compounds can be present as plastic compositions, cast resins, pastes, melts or in the form of spinning solutions, paints, glazes, foams, inks, inks, mordants, paints, emulsion paints or printing inks. The azo colorants, finely divided pigments and pigment preparations prepared according to the invention are also suitable as colorants in electrophotographic toners and developers, such as 2.B. One or

Two-component powder toners (also called one- or two-component developers), magnetic toner, liquid toner, polymerization toner and special toner.

Furthermore, catalysts according to the invention can be processed as the phase to be dispersed.

Preferred fields of use are pharmaceutical formulations, food supplements, animal nutrients, cosmetics.

The dispersions can also be converted into powder form by conventional methods. For example, solid products can be obtained by the conventional molding drying methods such as spray drying, spray granulation or freeze-drying (see also: O. Krischer, W. Käst: The Scientific Foundations of Trocknungstechnik, Vol. 1, Springer-Verlag GmbH, 1997). Optionally, a portion of the dispersant may be removed prior to the drying step by thermal processes, eg, thermal concentration, or by membrane processes, eg ultrafiltration. With the aid of the process according to the invention, it is possible to prepare finely divided dispersions of chemical compounds of poorer solubility in the particular dispersant selected having improved particle size distribution. The method offers the advantage that the process parameters can be stably reliably controlled.

Examples

For Examples 1 to 6 according to the invention, a mixing device according to the invention made of Hastelloy C4 and having the following parameters was used:

Asymmetrical Y-nozzle; Angle α = 120 °, angle β = 120 °

Fluid stream A: active ingredient solution

Liquid stream B: protective colloid solution

Example 1 Diameter Inlet Liquid stream A: 0.61 mm Diameter Inlet Liquid stream B: 1.3 mm

Diameter discharge opening: 2 mm

Examples 2 to 6

Diameter Inlet Liquid stream A: 0.25 mm Diameter Inlet Liquid stream B: 0.7 mm Diameter Discharge opening: 1.6 mm

Comparative Examples B to F: Symmetrical Y-Nozzle Diameter Inlet Liquid Stream A: 0.5 mm Diameter Inlet Liquid Stream B: 0.5 mm Diameter Discharge: 1.0 mm

The respective mass flows were determined for each mixing device by means of CFD simulations (CFD: Computational Fluid Dynamics). The mass flows were chosen such that the integral of the dissipation rate in the mixing volume was constant for both mixing devices.

The particle size determination was carried out by quasi-elastic light scattering.

example 1

A β-carotene solution in isopropanol was turbulently mixed with varying mass flows as liquid stream A with an aqueous fish gelatin solution as liquid stream B in the apparatus described above. FIG. 3 shows the resulting particle sizes as a function of the mass flows. Comparative Example A

Analogously, a β-carotene solution was mixed with a fish gelatin solution in a device in which the liquid streams were fed coaxially. The resulting particle sizes as a function of the mass flows are also shown in FIG.

Example 2

55 g of crystalline β-carotene were suspended in a solution consisting of 1 g of dl-α-tocopherol and 350 g of iso-propanol. and mixed at a mixing temperature of 165 ° - 175 ° C with 633.5g of iso-propanol, the resulting molecular disperse solution was immediately thereafter using an asymmetric nozzle with 7785.4g of an aqueous casein solution, in addition to 106.2g sodium caseinate still 159.2 g glucodex 6 was mixed. The entire process took place at a pressure of 60 bar. The set flow rates were: suspension pump: 1, 82kg / h, solvent pump: 2,84kg / h and protective colloid pump: 34,9kg / h.

The dispersion resulting from this experiment is characterized by advantages in the particle size distribution and also shows no high drug losses and instabilities. The proportion of particles smaller than 1000 nm in diameter was 94%.

Comparative Example B

55 g of crystalline β-carotene were suspended in a solution consisting of 1 g of dl-α-tocopherol and 350 g of iso-propanol. and mixed at a mixing temperature of 165 ° - 175 ° C with 787.5g iso-propanol, the resulting molecular disperse solution was immediately thereafter using a symmetrical nozzle with 7699.3g of an aqueous casein solution, in addition to 105.0g sodium caseinate still 157.5 g glucodex 6, mixed. The entire process took place at a pressure of 60 bar. The adjusted flow rates were: suspension pump: 0.83 gk / h, solvent pump: 1.61 kg / h and protective colloid pump: 15.7 gk / h. The dispersion resulting from this experiment has a poorer particle size distribution and, in addition to significant losses of active substance, also exhibits phase separation instabilities. The proportion of particles smaller than 1000 nm in diameter was 73%.

Example 3

24g of crystalline clotrimazole were suspended in 210g iso-propanol / water (1: 1). and dissolved at a temperature of 165 ° - 175 ° C, the resulting molecular Disperse solution was immediately thereafter using an asymmetric nozzle with 4044.4 g of an aqueous casein solution containing 55.9 g of sodium. Caseinate mixed. The entire process took place at a pressure of 60 bar. The set flow rates were: suspension pump: 1, 97kg / h and protective colloid pump: 34.5kg / h.

The dispersion resulting from this experiment is characterized by advantages in the particle size distribution. The proportion of particles with a diameter less than 400 nm was 100%.

Comparative Example C

24g of crystalline clotrimazole were suspended in 210g iso-propanol / water (1: 1) and dissolved at a temperature of 165 ° -175 ° C, the resulting molecular dispersion solution was immediately thereafter using a symmetrical nozzle with 4070.6 g of an aqueous casein solution containing 56.3 g of sodium. Caseinate mixed. The entire process took place at a pressure of 60 bar. The adjusted flow rates were: suspension pump: 0.99kg / h and protective colloid pump: 17.5kg / h. The dispersion resulting from this experiment has a worse particle size distribution. The proportion of particles smaller than 400 nm in diameter was 79%.

Example 4

48g of crystalline ketoconazole were suspended in 210g iso-propanol / water (1: 1) and dissolved at a temperature of 165-175 ° C, the resulting molecular disperse solution was immediately thereafter using an asymmetric nozzle with 4300.4g an aqueous casein solution containing 59.5 g of sodium. Caseinate mixed. The entire process took place at a pressure of 60 bar. The set flow rates were: suspension pump: 1, 97kg / h and protective colloid pump: 33.3kg / h. The dispersion resulting from this experiment is characterized by advantages in the particle size distribution. The proportion of particles smaller than 1000 nm in diameter was 99%.

Comparative Example D

48 g of crystalline ketoconazole were suspended in 210 g of isopropanol / water (1: 1) and dissolved at a temperature of 165 ° -175 ° C., the resulting molar Culinary disperse solution was immediately mixed using 4422.3 g of an aqueous casein solution containing 61.1 g of sodium caseinate using a symmetrical nozzle. The entire process took place at a pressure of 60 bar. The set flow rates were: suspension pump: 0.98kg / h and protective colloid pump: 17.0kg / h.

The dispersion resulting from this experiment has a worse particle size distribution. The proportion of particles smaller than 1000 nm in diameter was 95%.

Example 5

48g of crystalline cinnarizine were suspended in 210g iso-propanol / water (1: 1). and dissolved at a temperature of 165 ° - 175 ° C, the resulting molecular dispersion solution was immediately thereafter using an asymmetric nozzle with 4630.6 of an aqueous casein solution, the 63.1 sodium. Caseinate mixed. The entire process took place at a pressure of 60 bar. The set flow rates were: suspension pump: 1, 92kg / h and protective colloid pump: 34.5kg / h. The dispersion resulting from this experiment is characterized by advantages in the particle size distribution.

The proportion of particles smaller than 1000 nm in diameter was 99%.

Comparative Example E

48g of crystalline cinnarizine were suspended in 210g iso-propanol / water (1: 1). and dissolved at a temperature of 165 ° - 175 ° C, the resulting molecular dispersion solution was immediately thereafter using a symmetrical nozzle with 4553.4g of an aqueous casein solution containing 62.1g of sodium. Caseinate mixed. The entire process took place at a pressure of 60 bar. The adjusted flow rates were: suspension pump: 0.94kg / h and protective colloid pump: 16.6kg / h. The dispersion resulting from this experiment has a significantly worse particle size distribution. The proportion of particles smaller than 1000 nm in diameter was 60%.

Example 6 48 g of crystalline 17-.beta.-estradiol were suspended in 210 g of isopropanol / water (1: 1). and dissolved at a temperature of 165-175 ° C, the resulting molecular disperse solution was immediately thereafter using an asymmetric nozzle with 4204.3 g of an aqueous casein solution containing 57.3 g of sodium. Caseinate mixed. The entire process took place at a pressure of 60 bar. The adjusted flow rates were: suspension pump: 2.13kg / h and protective colloid pump: 34.7kg / h.

The dispersion resulting from this experiment is characterized by advantages in the particle size distribution. The proportion of particles with a diameter less than 400 nm was 97%.

Comparative Example F

48 g of crystalline 17-.beta.-estradiol were suspended in 210 g of isopropanol / water (1: 1) and dissolved at a temperature of 165.degree.-175.degree. C., the resulting molecular disperse solution being immediately thereafter using a symmetrical nozzle with 4768.8 g of an aqueous casein solution containing 65.0 g of sodium caseinate. The entire process took place at a pressure of 60 bar. The set flow rates were: suspension pump: 0.93kg / h and protective colloid pump: 17.2kg / h.

The dispersion resulting from this experiment has a worse particle size distribution. The proportion of particles smaller than 400 nm in diameter was 87%.

Claims

claims

1. A process for the preparation of finely divided dispersions of a poorly soluble in a dispersion medium chemical compound by turbulent mixing at least two designated as medium A and medium B liquid streams, of which at least one designated as medium A liquid stream containing the chemical compound to be dispersed or a precursor thereof in a mixing device provided with at least two inlet openings and a discharge opening, characterized in that the liquid streams are supplied in such a way that the angle between the longitudinal axes of a volume flow of medium A and a volume flow of medium B is 10 ° to 170 ° , and that the volume flows have different area cross sections.

2. The method according to claim 1, characterized in that the ratio of

Area cross sections of the inlet openings of medium A to medium B is 0.01 to 0.9.

3. Process according to claim 1 or 2, characterized in that water or aqueous mixtures are used as the dispersant.

4. The method according to any one of claims 1 to 3, characterized in that the angles between the longitudinal axes of the effluent through the outlet opening liquid flow of the dispersion formed and the longitudinal axes of the entering into the mixing device liquid flows are greater than 90 °.

5. The method according to any one of claims 1 to 4, characterized in that medium A contains an organic solvent as a solvent for the substance to be dispersed

6. The method according to any one of claims 1 to 5, characterized in that medium A contains as solvent a concentrated acid.

7. The method according to any one of claims 1 to 6, characterized in that in addition a protective colloid is added.

8. The method according to any one of claims 1 to 7, characterized in that in addition an amphiphilic compound is added.

9. A device for carrying out a method according to one of claims 1 to 8, characterized in that the liquid streams are supplied via two or more inlet openings so that the angle between the Longitudinal axes of a volume flow of medium A and a volume flow of medium B is 10 ° to 170 °, and that the inlet openings have different surface cross sections.

10. The device according to claim 9, characterized in that the ratio of

1 1. Apparatus according to claim 9 or 10, characterized in that the angle between the longitudinal axes of the effluent through the outlet opening

Liquid flow of the dispersion formed and the longitudinal axes of the entering into the mixing device liquid flows are greater than 90 °.