The present invention relates to a process for producing briquetted and pressed granular material and the use thereof for coloring building materials, such as concrete and asphalt, and organic media, such as paint systems, plastics and colored pastes.

The present invention relates to a process for producing briquetted and pressed granular material and the use thereof for coloring building materials, such as concrete and asphalt, and organic media, such as paint systems, plastics and colored pastes.
The processing of pigment granules requires that the pigments be ground to primary particles in order to achieve the optimal color effect. The resulting powders formed create a large amount of dust and, owing to their finely-divided state, tend to adhere and stick in dosing plants. In the case of toxicologically harmful substances, during the processing precautions must therefore be taken to avoid danger to humans and the environment owing to the dust formed. But even in the case of safe, inert substances such as, for example, iron oxide pigments, avoidance of irritation due to dust is being increasingly demanded by the market.
The aim when handling pigments is accordingly avoidance of dust and improved dosing as a result of good flow properties, in order to achieve a color effect of even quality for use in building materials and organic media. This aim is more or less achieved by applying granulation processes to pigments. Here pelletizing and spray granulation are generally used. Compacting processes have hitherto been less suitable, owing to the limited dispersibility of the granular material obtained thereby.
In principle, in the case of pigments the market demands two diametrically opposing properties for the use of pigment granules: mechanical stability of the granular material and good dispersibility. The mechanical stability is responsible for good transport properties during transport between manufacturer and user as well as for good dosing and flow properties in the pigments in use. It is produced by high adhesive forces and is dependent, for example, on. the quantity of binder or even on the compacting pressure during forming. On the other hand, the dispersibility is influenced by a thorough grinding prior to granulation (wet grinding and dry grinding), by the mechanical energy during the incorporation (shear forces) and by dispersing agents, which immediately lower the adhesive forces in the dry granular material during the incorporation into a medium. The use of larger quantities of dispersing agents in pigments is limited, however, owing to the cost ratio of additive to pigment. A high proportion of additive moreover causes a corresponding decrease in the coloring strength or in the scattering power. As the variations in coloring strength are generally less than xc2x15%, the use of additives is also restricted even if these are acting simultaneously as adhesion promoters and dispersing agents. Furthermore, the additives must not unfavorably alter the properties in use of end products such as building materials, plastics and paints: for example, the strength or the setting properties in concrete, the compressive strength or abrasion resistance in asphalt and the strength or the notch impact resistance in plastics and the elastic properties in elastomers (polymers).
Suitable production processes according to prior art for pigment granules are, for example, spray granulation (spray drying by disk or nozzle) and pelletizing (mixers, fluid-bed granulators, disks or drums).
The spray-drying granulation starts from pigment suspensions with the use of binders. Relevant processes are described in various protective rights; here water-soluble binders are used. Thus in DE-A 3 619 363, EP-A 0 268 645 and EP-A 0 365 046 the processes start from organic substances such as, for example, lignosulphonates, formaldehyde condensates, gluconic acids, sulphated polyglycol ethers, whereas in DE-A 3 918 694 and U.S. Pat. No. 5,215,583 the processes start from inorganic salts such as, for example, silicate and phosphate. A combination of spray granulation and pelletizing has also been described in EP-A 0 507 046. In DE-A 3 619 363 (column 3, lines 44-47) and EP-A 0 268 645 (column 7, lines 18, 19) the use of a compacting process is adopted. In this process a strong coherence of the particles is achieved by application of pressure, so that a good transportability but at the same time decreased properties of dispersibility are produced.
In EP-A 0 257 423 and DE-A 3 841 848, spray granulation using polyorganosiloxanes as hydrophobic, lipophilic additives is described. The spray-dryer mentioned generally leads to small particle sizes, that is, to a high proportion of fine material. This means that a significant proportion of the material is not obtained from the dryer as immediately usable granular material, but is first retained as fine material in the filter and has then to be returned to the process. The aftertreatment carried out to render the material hydrophobic, in the case of spray-dried products, results in granular material which flows very well but is exceptionally dusty.
EP-A 0 424 896 discloses the production of fine granular material low in dust, in a production operation in known intensive mixers. A low content of waxes in combination with emulsifier and wetting agents is used here by creating an aqueous dispersion. In the course of this water contents of from 20% up to over 50% are generally obtained. These granular materials must first of all be dried and separated from oversize and undersize material.
DE-A 31 32 303 describes inorganic pigment granules which are free-flowing and low in dust, which are mixed with binders rendered liquid by the action of heat and are granulated by a screening process with the use of a screening aid (pressure). About 10 to 20% of the throughput accumulates as fine material of  less than 0.1 mm.
EP-A 0 144 940 discloses pigment granules low in dust which, starting from filtration sludge containing about 50% water, through the addition thereto of 0.5 to 10% of surfactants as well as mineral oil or waxes liquefying at 50 to 200xc2x0 C., are mixed until lubrication point is reached. The procedure is carried out in intensive mixers, and if necessary the mixture is granulated and dried. Water is present in the end product in a quantity of 10 to 15%, which is disadvantageous for introduction into plastics.
Other processes are also limited in their application. Spray granulation, owing to the formation of droplets, requires the use of free-flowing and hence highly fluid suspensions. Consequently, for the drying process a greater quantity of water has to be evaporated than from highly pressed-out filtered pigment pastes during the frequently applicable fluid-bed drying. This leads to high energy costs. In the case of pigments previously produced by calcination, spray granulation involves an additional processing step with high energy costs. Moreover, in spray granulation a greater or lesser proportion of fine material accumulates, which has to be returned to the production unit.
Pelletizing, too, frequently exhibits disadvantages. Starting from pigment powder, it may be carried out in mixers under conditions of high turbulence, in the fluid-bed process or else by disk granulation and drum granulation. Common to all these processes is that the requirement for binder, in most cases water, is high, so that drying has to follow as an additional processing step. Here, too, granular materials of differing size are obtained, especially if insufficient binder is available for the quantity of powder or if the actual distribution is not optimal. Then a certain fraction may be too large for use as granular material, while on the other hand fractions which are excessively small and hence dust-forming are still present. A classifying of the granular material formed is therefore necessary, with oversize and undersize material being returned.
Disk granulation leads to granular materials having a wide particle size spectrum. Where this is undesirable because of the poor dispersibility of excessively large particles, the granulation process has to be monitored through intensive supervision by staff and the production of granular material has to be optimised by manual control of the quantity of grains. This is generally also followed by a classification and return of oversize and undersize material.
Extrusion processes from pastes lead to the formation of relatively solid granular materials during drying; owing to their size, these do not guarantee an optimal dispersibility.
DE-A 42 14 195 describes a process for coloring asphalt using inorganic pigment granules, with oils being used as binders. It is a simple granulation process.
In DE-A 4 336 613 and DE-A 4 336 612 inorganic pigment granules are produced from pigments by mixing with binders, compacting, rough grinding and granulating. The granular materials thus produced are not transportable satisfactorily by pneumatic means; during transportation a large quantity of dust is formed, which is undesirable.
It was accordingly the object of the present invention to provide a process which avoids the hitherto described disadvantages of spray granulation, extrusion granulation or pelletizing in their application to inorganic pigments and which provides sufficiently stable granular material which can be dosed, is low in dust and has a dispersibility as far as possible equally good as that of the powders used hiltherto.
It has now been found that this object can be met by a multistep combination of the processing steps mixing, compacting, separation and optionally rounding.
The invention provides a process for producing briquetted and pressed granular material from inorganic pigments and auxiliary substances, which is characterised in that
a) one or more inorganic pigments are mixed with one or more of the auxiliary substances promoting processability,
b) this mixture is subjected to a pressing or briquetting step,
c) this pressed or briquetted product is comminuted,
d) the comminuted product is divided up into two or more fractions,
e) the fraction wherein at least 85% of the particles are larger than 80 xcexcm, preferably larger than 100 xcexcm, or are between 80 and 2000 xcexcm, preferably between 100 and 1000 xcexcm, is removed and optionally rounded in an additional step and the other fraction or fractions is/are transferred out of the process or returned.
Prior to step c) the pressed or briquetted product may be divided up preferably into two fractions (intermediate step x), in order then to comminute the coarse fraction, wherein at least 85% of the particles are larger than 500 xcexcm, preferably 600 xcexcm, in step c), and to divide the other, fine fraction, once again into two or more fractions in step d), separate from or together with the product from step c).
Preferably only the fine fraction from intermediate step x) is divided up into two or more fractions in step d), while the coarse fraction from intermediate step x) is comminuted in step c) and is then transferred out of the process as product.
Intermediate step x) may be carried out preferably by pneumatic classification or screening (mechanical separation). Preferably screening machines are used.
The comminuted product in d) is particularly preferably divided up into two fractions, with the fine fraction smaller than 80 xcexcm being transferred out or returned to the process and the coarse fraction larger than 80 xcexcm optionally being rounded in an additional step.
The comminuted product may also preferably be divided up into three fractions in step d), with the fine fraction and the coarse fraction being transferred out of the process or returned to the process and the middle fraction between 80 and 2000 xcexcm, particularly preferably between 100 and 1000 xcexcm, most preferably between 100 and 500 xcexcm, optionally being rounded in an additional step.
The granular materials preferably have a residual water content of less than 4 wt. %, particularly preferably less than 2 wt. %. This can be obtained if necessary by after-drying.
The rounding step under e) is preferably carried out with the dust fraction removed.
The product formed by the rounding in step e) may preferably in addition be coated with auxiliary substances.
If a rounding step under e) is carried out, afterwards preferably a coarse fraction having particle sizes of  greater than 1500 xcexcm can be separated and optionally returned to the process.
The inorganic pigments used are preferably iron oxide, titanium dioxide, chromium oxide, rutile mixed phase pigments and mixtures of these pigments with carbon black.
The inorganic pigment granules have bulk densities preferably of between 0.5 and 4.0 g/cm3, particularly preferably between 0.5 and 2.0 g/cm3. The granules mixed with carbon black have bulk densities preferably of from 0.3 to 1.5 g/cm3.
Both inorganic and organic substances may be used as auxiliary substances.
The auxiliary substances used are preferably water, salts selected from among the phosphates, carbonates, nitrates, sulphates, chlorides, silicates, aluminates and borates, formates, oxalates, citrates and tartrates; polysaccharides, cellulose derivatives such as, for example, cellulose ethers, cellulose esters, phosphonocarboxylic acids, modified silanes, silicone oils, oils from biological cultivation (for example, rape oil, soy bean oil, maize oil, olive oil, coconut oil, sunflower oil), refined petroleum oils based on paraffins and/or on naphthenes, synthetically produced oils, alkylphenols, glycols, polyethers, polyglycols, polyglycol derivatives, protein fatty acid condensation products, alkylbenzenesulphonates, alkylnaphthalenesulphonates, lignosulphonates, sulphated polyglycol ethers, melamine formaldehyde condensates, naphthalene formaldehyde condensates, gluconic acid, polyhydroxy compounds or aqueous solutions thereof.
In addition, during mixing preferably emulsifiers, wetting agents and dispersing agents may be added in a quantity of from 0.01 to 5 wt. %, preferably from 0.01 to 3 wt. %, referred to the weight of the pigment used.
Suitable emulsifiers are in particular emulsifiers having HLB values of 7 to 40, particularly 8 to 18, for use in building materials containing aqueous systems, such as concrete, and consisting of alkyl or acryl groups and hydrophilic intermediate and end groups such as, for example, amides, amines, ethers, hydroxyl, carboxylate, sulphate, sulphonate, phosphate, amine salt, polyether, polyamide, polyphosphate. The substances may be used, according to their HLB value, individually or in combination.
Suitable wetting agents are in particular alkylbenzenesulphonates, fatty alcohol sulphates, fatty alcohol ether sulphates, fatty alcohol ethoxylate, alkylphenol ethoxylate, alkane sulphonates, olefin sulphonates.
Preferably melamine sulphonates, naphthalene sulphonates, metal soaps, polyvinyl alcohols, polyvinyl sulphates, polyacrylamides, fatty acid sulphates are used as dispersing agents.
To increase the stability or to assist in the processing of the granular material it may be beneficial finally to coat the granular materials with an additional layer. This layer can be produced by applying inorganic salts in solution, polyols, oils or waxes or polyethers, polycarboxylates or cellulose derivatives, preferably carboxymethyl celluloses.
Preservatives may also be added to the granular materials during mixing, in a concentration of from 0.01 to 1 wt. %, referred to the weight of the pigment. Examples which may be mentioned are formaldehyde-releasing compounds, phenolic compounds or isothiazolinone preparations.
Surprisingly,auxiliary substances for the pressed and briquetted granular materials, in particular if these are intended for incorporation into aqueous building materials systems such as cement mortar or concrete, can be not only water-soluble substances but also substances insoluble in water such as, for example, oils.
The auxiliary substances are added preferably in quantities of from 0.001 to 10 wt. %, particularly preferably from 0.01 to 5 wt. %, most preferably from 0.1 to 3 wt. %, referred to pigment used.
The auxiliary substances can be added preferably compounded with other additives such as, for example, wetting agents, metal soaps, et cetera.
The pressing or briquetting step b) is preferably carried out by means of a roll press or matrix press and preferably at line forces of from 0.1 to 50 kN/cm, preferably 0.1 to 20 kN/cm.
In the pressing or briquetting (compacting, step b)) an important value is the pressing force (kN) per cm of roll width (line force). During compacting between rolls, a linear transfer of the pressing force is assumed, as a pressing surface cannot be defined and therefore a pressure (kN/cm2) cannot be calculated.
The compaction is preferably carried out at low line forces. The line forces applied are in general preferably within the lower range of the commercially available equipment, between 0.1 and 50 kN/cm is preferred. The line forces are most preferably from 0.1 to 20 kN/cm. An example of commercially available equipment is the Pharmapaktor 200/50 from the firm Bepex GmbH, Leingarten/Germany.
The additional separating step x) is carried out preferably using screening machines such as, for example, drum screens, oscillating screens and vibrating screens.
The comminution can be effected by means of all the conventional commercial comminution units, such as crushers, toothed roll crushers, rolls equipped with frictional devices and screen granulators.
The comminution step c) is carried out preferably using screen granulators or screen-type mills, wherein the material is pressed through a passing, screen having a mesh size of from 0.5 to 4 mm, particularly preferably from 0.5 to 2.5 mm, most preferably from 1 to 2 mm (so-called crushers). As is generally known, the motion of the rotors is circulating or oscillating, at a peripheral speed of from 0.05 m/sec to 10 m/sec, preferably from 0.3 to 5 m/sec. The distance between rotor and screen or breaker plate is from 0.1 to 15 mm, preferably from 0.1 to 5 mm, most preferably from 1 to 2 mm.
An example of the comminuting equipment which can be used is the Flake Crusher from the firm Frewitt, Fribourg/Switzerland.
After the comminution, the fine material smaller than 80 xcexcm is separated off. The quantity of this fine material is preferably from 10 to 50 wt. %, particularly preferably 10 to 30 wt. %. The fine material is preferably returned to step b). The remaining fraction is free-flowing, can be dosed, is stable, low in dust and readily dispersible. A further optimization can be achieved by additional rounding.
The rounding step e) is preferably carried out on a rotary disk, in a rotary drum or dragee drum, drum screens or similar units or in a fluid bed or in a screening plant. Here the dust fraction can be removed preferably by suction or, in the fluid bed, transported away with the air.
One of the advantages of the process according to the invention is that it is possible to start from dried and if necessary ground pigment powders. This is in particular especially economic when the pigment is produced by calcination. In the case of spray granulation, for example, a further slurrying and thereafter an additional drying step are necessary. It is moreover very expensive as regards energy to evaporate off again the water used for slurrying.
The process according to DE-A 4 336 613 or DE-A 4 336 612 leads, through pelletizing on the rotary disk, to round particles which are however inhomog,eneous. They consist of a compact core and an external layer or layers formed thereon, which can become abraded. These products consequently form dust, especially when transported pneumatically, and the flow properties are not particularly good. The products obtained by the process according to the invention do not have these disadvantages, as they consist of homogeneous compact particles of uniform density and strength.
The granular materials produced by the process according to the invention are used for coloring building materials such as, for example, concrete, cement mortar, plasters and asphalt, and for coloring organic media such as paints, plastics and pigment pastes and for producing disperse dyes and slurries.
The granular materials produced according to the invention are particularly suitable for incorporation into dry cement mortar mixtures and into plasters.
In the multistep process according to the invention it is important that in the first step a sufficiently cohesive homogeneous material is produced by adding the auxiliary substance in a mixer. The briquetting or pressing then takes place in the second step.
The invention also provides a process for coloring building materials such as concrete or asphalt using inorganic pigments, which is characterised in that inorganic briquetted or pressed granular materials made from inorganic pigments and auxiliary substances, which have been produced by the process according to the invention, are mixed with the building material in a quantity of from 0.1 to 10 wt. %, preferably 1 to 5 wt. %, referred to cement.
Another preferred use of the granular materials produced according to the invention is in disperse dyes and slurries.
The invention further provides a process for coloring organic media such as paint systems, plastics and pigment pastes using inorganic pigments, which is characterised in that inorganic briquetted or pressed granular materials made of inorganic pigments, which have been produced by the process according to the invention, are mixed with the organic medium in a quantity of from 0.1 to 10 wt. %, referred to organic medium.
The test of the dispersibility in building materials is carried out in cement mortar by the following method by measurement of the coloring strength on prisms produced from white cement:
Cement-quartz sand ratio 1:4; water-cement value 0.35; level of pigmentation 1.2%, referred to cement; mixer used, obtained from RK Toni Technik, Berlin, having 5 l mixing tub, structural type 1551, speed of rotation 140 rev/min; batch: 500 g cement. After 100 s, 3 samples of mixture (300 g) are taken and test pieces (5xc3x9710xc3x972.5 cm) are prepared under pressure (300 bar). Curing of the test pieces: 24 hours at 30xc2x0 C. and 95% atmospheric humidity with subsequent drying for 4 hours at 60xc2x0 C. Color data measurement by Dataflash 2000, Datacolor International, Cologne, 4 measuring points per stone, per pigment mixture 12 measuring points. The average values obtained are compared with the values of a reference sample. The color difference Eab and the coloring strength (reference sample=100%) were assessed (DIN 5033, DIN 6174). The dispersibility is described as good at a difference in coloring strength of up to 5% compared with the reference sample, and as satisfactory at a difference of up to 10%.
The dispersibility in asphalt was tested by the following method:
The pigment/granular pigment together with a road bitumen of the type B 80 (commercial product from Shell AG) and aggregrates is mixed in a heatable laboratory mixer (Rego mixer) at 180xc2x0 C. for 60 seconds. Test pieces are prepared from the mixture by Marshall""s method (xe2x80x9cThe Shell Bitumen Handbook, Shell Bitumen U.K., 1990, pages 230-232). Differences in shade in the Marshall test pieces are assessed calorimetrically against a preset comparative sample (Minolta Chromameter II, standard illuminant C, Cielab System, DIN 5033, DIN 6174) by comparison of the red values a*. Differences in the a* values of less than 0.5 units are indistinguishable visually.
The flow properties were tested by assessing the behavior on discharge from a funnel of 100 ml in volume and having a 6 mm opening, in accordance with ASTM Test D 1200-88. If the material flows freely, the flow properties are described as good. If a flow of material does not take place or does so only after tapping, the flow properties are considered to be inadequate.
The determination of the fine material as screen oversize is carried out on a VA screen in accordance with DIN 4188, having 80 xcexcm mesh size on an air-jet screening machine of the type Alpine 200 LS. 20 g of the sample to be tested is used. The fine material is removed by suction for a running time of 5 minutes and the quantity of coarse fraction on the screen is reweighed.
The dispersibility of plastics is determined in accordance with a test in DIN 53 775, part 7: xe2x80x9cTesting of coloring materials in plasticized polyvinyl chloride (PVC-P) materials; determination of the dispersing hardness by two roll millingxe2x80x9d:
The pigment to be tested is dispersed in PVC on a mixing roll at 160xc2x15xc2x0 C. The rolled sheet obtained is divided and one half is then exposed to increased shear forces by rolling at room temperature. The measure of the dispersibility in the case of colored pigments is the color difference xcex94E in accordance with CIELAB (DIN 5033, 6174) between hot- and cold-rolled PVC sheets, and in the case of white pigments is the difference of the standard tristimulus values Y (DIN 5033) between hot- and cold-rolled PVC sheets. A readily dispersible pigment can be dispersed even at low shear forces, whereas the increased shear forces on rolling at low temperature are required in order to disperse a relatively indispersible pigment. The rule is therefore: the smaller the color difference xcex94E or the difference in the standard tristimulus values Y, the better does the pigment disperse. The dispersibility is of great importance particularly in the case of granular materials, as the particles of granular material to be dispersed in the plastics material have first of all to be divided. For granular materials a dispersibility is sought which is as good as that of the corresponding pigment powders, so that the characteristic values xcex94E or Y for powders and granular material should not differ greatly.
The measurement of fine dust particles for determining the stability of granules is carried out in accordance with DIN 55992. The dust-forming properties of the granules can be determined using a Heubach xe2x80x9cDustmeterxe2x80x9d. The quantity of fine dust particles issuing from a rotating drum, through which a stream of air of a specific intensity is passed is determined gravimetrically by means of a glass fibre filter. By carrying out measurements after varying periods of exposure the progress of the formation of dust can be determined as a function of mechanical stress.

Process for producing briquetted and pressed granular material and use thereof


A test system for characterizing the compatibility of bioactive substances with polyvinylpyrrolidones in a solid dispersion consisting of one or more bioactive substances and 1,3-bis(1-pyrrolidonyl)butane.

The present invention relates to a test system for characterizing the compatibility of bioactive substances with polyvinylpyrrolidones in a solid dispersion consisting of one or more bioactive substances and 1,3-bis(1-pyrrolidonyl)butane. The invention further relates to a method for characterizing the compatibility and to the use of 1,3-bis(1-pyrrolidonyl)butane as solvent in a test system of this type.
Solid dispersions, that is to say homogeneous extremely fine disperse phases of two or more solids, and the special case thereof called xe2x80x9csolid solutionsxe2x80x9d (molecularly disperse systems) and their use in pharmaceutical technology are generally known (cf. Chiou and Riegelman, J. Pharm. Sci., 60, 1281-1300 (1971)).
Solid solutions can be produced by melting processes or by the solution process.
A particularly suitable polymeric auxiliary for producing such solid dispersions or solid solutions is polyvinylpyrrolidone (PVP). PVP-based solid solutions of bioactive substances can be produced particularly advantageously by melt extrusion as described, for example, in EP-A 240904.
However, there are minimum requirements on the amounts employed to produce melt extrudates. If only relatively small amounts of active ingredient are available, it cannot be predicted with certainty whether an active ingredient will form solid solutions with PVP whether in the melt or in coprecipitates. However, it is precisely when drug products based on new active ingredients are being developed that only relatively small amounts of the active ingredient are frequently available so that the possibility of prediction with the aid of a simple test system appears to be extremely desirable.
It is likewise desirable to be able to make predictions concerning the stability of solid solutions or solid dispersions. This is because, depending on the compatibility of active ingredient and PVP, the previously homogeneous disperse phase may become inhomogeneous, or the active ingredient may recrystallize. Such phase separation or recrystallization is, of course, unwanted because of the change in the homogeneity and the release characteristics associated therewith.
It is an object of the present invention find a test system which makes it possible in a simple manner to characterize the compatibility of bioactive substances and PVP in a solid dispersion.
We have found that this object is achieved by the test system defined at the outset. We have also found a method for characterizing the compatibility of bioactive substances with polyvinylpyrrolidones in a solid dispersion, which comprises dispersing or dissolving the bioactive substance in 1,3-bis(1-pyrrolidonyl)butane, and assessing the resulting dispersion or solution spectroscopically.
The test system according to the invention consists, on the one hand, of one or more bioactive substances and, on the other hand, of 1,3-bis(1-pyrrolidonyl)butane as solvent or dispersant.
The preparation of 1,3-bis(1-pyrrolidonyl)butane is known per se. Thus, for example, Breitenbach et al., Naturwissenschaften 42, 1955, 155;440, describe the dimerization of N-vinylpyrrolidone under acidic reaction conditions and subsequent hydrogenation of the resulting 1,3-bis(1-pyrrolidonyl)-1-butene to 1,3-bis(1-pyrrolidonyl)butane. 1,3-Bis(1-pyrrolidonyl)butane is a colorless oily liquid with a boiling point of 205-215xc2x0 C. (0.2 mbar). DE-A 196 41 437 discloses that 1,3-bis(1-pyrrolidonyl)butane (also called DHVP hereinafter) is suitable as solvent or solubilizer for cosmetic or pharmaceutical active ingredients.
The test system is suitable in principle for all pharmaceutical active ingredients, crop protection agents, food supplements or cosmetic active ingredients. It is also possible to examine the compatibility of detergent enzymes or dyes with PVP. The miscibility of non-bioactive formulation aids such as sugars, sugar alcohols or other polymeric aids can also be examined. Suitable polyvinylpyrrolidones (PVP) are all types of PVP with Fikentscher K values of from 10 to 110.
Compatibility means for the purpose of this invention the tendency of a substance to form a stable homogeneous solid dispersion with PVP, this solid dispersion being, in particular, a solid solution, that is to say a molecular dispersion of the components in one another.
To carry out the method according to the invention, a solution or dispersion of the active ingredient or mixtures of active ingredients in DHVP is prepared. The ratios of the amounts can in principle be chosen without restriction and naturally depend essentially on the properties of the active ingredient. However, it is advisable to choose the concentration ranges in the test system so that they correspond to active ingredient contents typical of extruded forms, that is to say generally from 0.1 to 70, preferably 10 to 30% by weight of active ingredient, based on the total weight of the test system. However, it is also possible in the individual case to prepare solutions or dispersions with a concentration of 60% by weight or even higher. It is preferred to carry out test series with increasing active ingredient contents. The active ingredient(s) are weighed out, mixed with the appropriate amounts of DHVP and preferably stirred, normally with a typical laboratory magnetic stirrer at 5 to 200 rpm. If a substance does not dissolve at room temperature, the test system can also be heated. The heating is preferably carried out so as to correspond approximately to the heating rate in a subsequent melt formulation, that is to say at 0.5 to 5xc2x0 C./min. The test system is preferably heated to a maximum of 140xc2x0 C. However, it is also possible in the individual case to heat to the boiling point of DHVP. The test system is then allowed to cool to room temperature.
The prepared test systems are assessed spectroscopically. This preferably takes place visually using a microscope, for example using a conventional laboratory microscope with a resolution of 0.04 N.A. It is found in this way whether clear solutions or dispersions form. The recrystallization behavior is also assessed. The recrystallization behavior immediately after cooling to room temperature is an important criterion especially for test systems in which the active ingredient has been induced to dissolve by heating. Test systems in which the active ingredient does not recrystallize immediately after stopping the stirring or after cooling are investigated for long-term stability:
leaving to stand at room temperature for 24 hours
after storage for 1 month, 3 months, 6 months in climate zone 2 (25xc2x0 C., 60% relative humidity) and climate zone 4 (20xc2x0 C., 70% relative humidity)
stress storage at 40xc2x0 C., 75% relative humidity for up to 6 months.
Investigation is always of whether the active ingredient has recrystallized out of the solution.
It is also possible to examine the test systems for their amorphous nature with the aid of confocal Raman spectroscopy.
The method of differential scanning calorimetry is likewise suitable.
It has emerged that conclusions can be drawn directly from the recrystallization behavior from a DHVP solution about the stability of a solid solution of an active ingredient with polyvinylpyrrolidones obtained by melt extrusion or by coprecipitation. There is a good correlation between the stability of a solution of the active ingredient in DHVP and the stability of an active ingredient-containing PVP melt extrudate or coprecipitate. It is also possible from the dissolving behavior of the active ingredient in DHVP to draw conclusions directly about the tendency of a substance to form solid solutions with PVP, specifically in relation both to a suitable temperature profile for melt processes such as extrusion and to the amount of active ingredient which can be incorporated.
This means that the test system makes it possible to predict in a straightforward manner the compatibility of bioactive substances with polyvinylpyrrolidones, in particular of products obtainable by melt processes.
There has been investigation of, for example, the dissolving behavior of acetylcysteine, acetylsalicylic acid, anipamil HCl, bentazone, benzocaine, bezafibrate, biperiden, Butazolidin, captopril, carbamazepine, chloramphenicol, cromoglicic acid, clotrimazole, caffeine, cyclosporin, diazepam, diclofenac sodium, dilliazon, diltiazem, dimetridazole, diphenhydramine HCl, 5,5-diphenylhydantoin, erythromycin stearate, esuprone, fenofibrate, flecainide, furosemide, fluconazole, gallopamil HCl, glibenclamide, hydrochlorothiazide, ibuprofen, indometacin, itraconazole, ketoprofen, melperone, metazachlor, nalixidic acid, naftidrofuryl, nexopamil, nifedipine, nitrendipine, nitrofurantoin, oxybutynin, paracetamol, pentoxifylline, paroxetine, prazosin, propafenone HCl, pseudoephedrine HCl, ranitidine HCl, riboflavin, selegiline HCl, sulfamethazine, sulfamethoxazole, sulfathiazole, theophylline, tolbutamide, triamterene, trimethoprim, zotepine.

Test system for characterizing the compatibility of bioactive substances and polyvinylpyrrolidone


Methods, systems, and apparatus, including computer programs encoded on a computer storage medium, for reducing audio noise are disclosed. In one aspect, a method includes the actions of receiving first audio data of a user utterance. The actions further include determining an energy level of second audio data being outputted by the loudspeaker. The actions further include selecting a model from among (i) a first model that is trained using first audio data samples that each encode speech from one speaker and (ii) a second model that is trained using second audio data samples that each encode speech from either one speaker or two speakers. The actions further include providing the first audio data as an input to the selected model. The actions further include receiving processed first audio data. The actions further include outputting the processed first audio data.

Speech processing is the study of speech signals and the processing methods of signals. The signals are usually processed in a digital representation, so speech processing can be regarded as a special case of digital signal processing, applied to speech signals. Aspects of speech processing includes the acquisition, manipulation, storage, transfer and output of speech signals.


A process for producing and purifying succinic acid comprises growing a succinate salt-producing microorganism on an inexpensive substrate containing carbohydrate, other nutrients, sodium ions and tryptophan under a CO.sub.2 partial pressure until most of the carbohydrate is converted to succinate. The fermentation broth is then electrodialyzed to recover and concentrate the succinate salt in an aqueous stream which is subjected to water-splitting electrodialysis to form base and a succinic acid product. The resulting succinc acid product is treated first with a strongly acidic ion exchanger in the acid form to remove any sodium or other cations and then treated with a weakly basic ion exchanger in the free base form to remove any sulfate ions or sulfuric acid and to obtain a highly purified succinic acid product.

Succinic acid and its derivatives are widely used as specialty chemicals for applications in polymers, foods, pharmaceuticals, and cosmetics. Furthermore, succinic acid is a valuable 4-carbon intermediate useful for the production of 1,4-butanediol, tetrahydrofuran, and gammabutyrolactone.
Although the succinate ion is a common intermediate in the metabolic pathway of several anaerobic microorganisms, there are no examples of any prior art fermentation that produces succinate in large amounts or with high yields. For example, succinate is a key intermediate for anaerobic fermentations by propionate-producing bacteria, but it is only produced in low yields and in low concentrations.
Succinate is also produced by anaerobic rumen bacteria. These bacteria include Bacteroides ruminicola (hereafter written B. rumincola) whose growth and metabolism is described by Howlett, et al., Applied Environ. Microbiol., 32, 274-283 (1976) and Bacteroides amylophilus (hereafter written B. amylophilus) whose culture and growth are described by Caldwell, et al., J. Bacteriol., 98, 668-676 (1969) and by Hamlin, et al., J. Bacteriol., 72, 548-554 (1956).
Although the rumen bacteria give higher yields of succinate than do the propionate-producing bacteria, the reported fermentations were run in very dilute solutions and gave a variety of products in generally low yields. Moreover, the rumen organisms tend to lyse after a comparatively short fermentation time, thereby, leading to unstable fermentations.
In 1961, Anderson and Ordal isolated a facultative anaerobe, Cytophaga succinicans, which produced succinate, acetate, and formate from dextrose with fixation of carbon dioxide, J. Bact., 81, 139 (1961). However, this organism produced succinate in such low concentrations that it would not be economically feasible to recover succinic acid from the fermentation medium. Similar results were observed with the Bacteroides fragilis obtained from the gastrointestinal tract, Caspari, et al., Arch. Microbiol., 135, 16-24 (1983).
In order to develop a commercially attractive process to produce succinic acid by fermentation, several important fermentation and product purification criteria need to be accomplished. The fermentation should be high yield (wt%) and produce a high product concentration using inexpensive raw materials and nutrients. Since anaerobic fermentations are run at neutral or near neutral pHs, salts of organic acids rather than the acids themselves are produced. The fermentation broth also contains cells, protein and other undesirable materials. The desired product from the process is the purified acid which can be used for specialty or commodity chemical manufacture. Hence, a high yield, economical fermentation process has to be integrated with an efficient recovery and purification process.
Electrodialysis (ED) is a well known separation process where ionized compounds are separated from non-ionized or weakly ionized compounds in aqueous solutions based on transport through ion exchange membranes in an electric field. The process has been used in a commercial scale in the chlor-alkali, desalination, metal-processing, wastewater treatment, pharmaceutical and food processing industries. Since in a fermentation broth the succinate salt is ionized, whereas the carbohydrates and proteins and amino acids are either non-ionized or weakly ionized, recovery and purification of succinate salt from the fermentation broth by electrodialysis is feasible.
Recently, several papers and patent applications have been published on recovery and purification of lactate from fermentation broths by conventional electrodialysis. However, in these examples, broth was either thoroughly cleaned to remove cells and proteins prior to electrodialysis or when broth containing cells was used the membrane fouled and led to a loss of efficiency. Prigent (6) disclosed a method for production of lactate from fermenting whey where the broth was filtered by ultrafiltration to remove the cells and then electrodialyzed. Hongo, Nomura and Iwahara (7) used a whole broth of Lactobacillus delbrueckii IFO 3534 in their electrolysis cum electrodialysis apparatus, but discovered that the efficiency was poor due to membrane fouling. These workers (8) then devised a complicated fermentation process where the cells were immobilized in alginate beads and the cell free broth was fed to the electrodialyzer. Bacterial cells are very small and to remove cells by high speed centrifugation and/or ultrafiltration is expensive both in process capital and power requirements. Cell immobilization in alginate beads is also very expensive.
It is conceivable that conventional electrodialysis, as described previously, if selective can be used to recover and concentrate succinate salt from a cell-free fermentation broth. For most specialty and commodity chemical uses of succinic acid, the acid form is required. Recent development of high efficiency bipolar membranes (9,10,11,12) for use in water-splitting electrodialysis membrane stacks, make it feasible to produce acid and base from a salt. Thus, we theorized that the desirable succinic acid and the corresponding base might be produced from the succinate salt. The base could then be recycled to the fermentation process.
The succinic acid product, after water-splitting ED, will have cationic, anionic and amino acid impurities. Ion exchange resins are capable of removing ionically charged species from solutions. Since some of the impurities in the succinic acid are ionically charged, careful selection of ion exchangers might allow removal of the impurities without removing the succinic acid itself. Cation exchangers will remove positively charged ions having a specific ionic strength. Anion exchangers will remove negatively charged ions having a specific ionic strength. Therefore, we theorized that proper selection of the types of ion exchangers, order of use, and the operating parameters may allow the removal of the succinic acid stream impurities.
For a succinic acid fermentation process to be economically attractive to produce specialty and commodity chemicals, development of a low cost fermentation and purification process is necessary. The fermentation should use low cost substrates and nutrients, the rate of fermentation should be high (high productivity), and the product concentration in the fermentation broth should be high. In addition, proper integration of an efficient and economical purification process with the fermentation is necessary.

Process for the production and purification of succinic acid