The invention relates to hollow balls having shells comprising a sintered inorganic material, such as metals, metal oxides or ceramic, and to methods for producing lightweight structural components using such hollow balls. According to the object of the invention, the application area is to be widened, processing to form structural components is to be made technologically simpler and the properties of the hollow balls and of the structural components produced therewith are to be improved for specific applications. For this purpose, an additional solid functional layer is formed on a shell on the hollow balls. The functional-layer material can then be made able to flow and plastically and/or elastically deformed as a result of a physical and/or chemical treatment.

This is a nationalization of PCT/DE01/00349 filed Jan. 24, 2001 and published in German.
The invention relates to hollow balls having shells comprising a sintered inorganic material, such as metals, metal oxides or ceramics, and to methods for producing the hollow balls of lightweight structural components using such hollow balls.
EP 0 300 543 A1 and U.S. Pat. No. 4,917,857 have described a method for producing metallic and ceramic hollow balls. In this case, an aqueous suspension of a metallic or ceramic powder with an organic binder is applied to a ball-shaped core of a foamed polymer, and the polymer which forms the core is pyrolyzed during a heat treatment (400 to 500xc2x0 C.), during which treatment the gaseous components escape and what is referred to as a green body of sufficient stability is obtained.
This green body is then heated further, in order also to expel the organic constituents of the binder which have hitherto remained in place and to sinter the powder particles together to form a closed ball shell.
Furthermore, DE 197 50 042 C2 has described in particular the application of the pulverulent starting material together with a liquid binder to a core by using a rotor to roll it around.
The hollow balls with a shell which are obtained in this way and substantially comprise the powder material can be used for various applications.
One such application is described in DE 198 17 959 C1 for lightweight structural components. According to this document, such hollow balls, which are known per se, are to be mixed with a polymer adhesive to form a xe2x80x9cslurry of ballsxe2x80x9d, and this xe2x80x9cslurry of ballsxe2x80x9d is to be introduced into a mold or between two surface plates before the adhesive is cured. A certain limited time window in which the suitably pretreated balls have to be processed is available for this purpose before the adhesive cures.
Moreover, when mold bodies with difficult geometries, for example those with undercuts, are being filled, there are problems with completely filling the entire volume of the mold body with a xe2x80x9cslurry of ballsxe2x80x9d of this type.
After the adhesive (polyurethane or polyester based, an epoxy adhesive or PMMA) has cured, the adhesive forms a solid bond for the hollow balls forming a lightweight structural component of this type, but on the one hand this is not always completely successful on account of the possibility of segregation and on the other hand for some applications this is also undesirable.
However, if the hollow balls are introduced into a mold body first and then the more or less viscous adhesive is introduced, it is impossible to achieve a homogenous distribution of adhesive in the mold body.
Therefore, it is an object of the invention to improve hollow balls having shells of sintered inorganic material in such a way that their range of application is widened, processing to form structural components is technologically simplified and the properties of the hollow balls and of the structural components produced therewith are improved for specific applications.
The hollow balls according to the invention are based on conventional solutions but have at least one additional functional layer on the spherical shell, which consists of a sintered, at least predominantly inorganic material. The functional-layer material, components contained therein or components which are applied to a functional layer can be made able to flow, plastically and/or elastically deformed by means of a physical and/or chemical treatment. As a result, the shells and consequently also adjacent hollow balls can be fixed to one another in an adhesive and/or positively-locking manner.
The shells may consist of metal, a metal alloy, a metal oxide or a ceramic. They may be as far as possible free of organic constituents. Examples of suitable metals are iron, nickel, copper and light metal, e.g. titanium, aluminum or high-melting heavy metals, such as for example tungsten or molybdenum and alloys thereof.
The physical and/or chemical treatment and the selection of materials should preferably be such that at least the shells of the hollow balls do not become unstable during the treatment.
It is also possible for a plurality of functional layers to be formed above one another in the manner of an onion skin, in which case the corresponding choice of materials may cover various applications. In this case, the treatment of such hollow balls may also be carried out in a plurality of steps specific to the particular application.
A hollow ball according to the invention with an additional solid functional layer which has been additionally applied, for example by application of a suspension to the shell, and dried or cured, represents an initial product which can be processed better and more easily than the conventional hollow balls, and these hollow balls save the final manufacturer of structural components a number of technological process steps.
It is possible to use hollow balls without a functional layer with an external diameter of 0.1 to 20 mm, preferably 0.5 to 5 mm. In this case, the shell may have a thickness which corresponds to 0.1 to 50%, preferably up to 10%, of the external diameter of the hollow balls.
The functional layer(s) according to the invention should have a thickness which, after the physical and/or chemical treatment of the hollow balls, ensures the appropriate functional effect, for example protection against corrosion or an adhesive bond between adjacent hollow balls. However, the thickness should advantageously be selected to be at least sufficiently great for it to be possible to achieve positively locking fixing of adjacent hollow balls during the plastic and/or elastic deformation.
It is generally sufficient for the thickness of a functional layer to be less than the thickness of the shell. The thickness of a functional layer should be no greater than 0.9 times, preferably 0.1 times to 0.5 times, the thickness of the shell of the corresponding hollow ball. This allows functions, such as for example the joining of adjacent hollow balls to form a lightweight structural component, protection against corrosion for the metal shells, electrical and magnetic properties, to be achieved.
Moreover, the mass of at least one functional layer or a plurality of these layers should not exceed the mass of the shell.
For positively locking fixing of adjacent hollow balls by means of the functional-layer material, it may be sufficient for at most 80% of the surface of the shell to be covered.
This allows the mass of a lightweight structural component produced from hollow balls to be reduced.
The hollow balls according to the invention should be able to flow freely and should not stick to one another, so that they can be processed without problems after storage and transport.
An additional sealing layer may be applied to the functional layer, in particular to provide temporary protection during transport and storage, so as to form very smooth, non-adhesive surfaces. By way of example, quick-drying, preferably water-soluble coatings or other more or less viscous liquids can be sprayed on. Suitable examples are cellulose or pectin solutions or polyvinyl alcohol.
The functional layers may be formed from a homogenous material but may also be formed from composites.
For example, for certain applications (e.g. for detection purposes), ferromagnetic and/or permanent-magnet particles may be embedded in the functional layer.
However, the functional layer may also be doped or formed with catalytically active elements or compounds. By way of example, platinum and/or Rhodium may be electro-deposited on a shell or a functional layer without the use of external current.
If organic materials or components are used for the functional layers, polymers which are selected from the group consisting of ethylene vinyl acetate copolymers (EVA), polyamides or polyesters, but also phenolic resin, cresol resin, furan resin or epoxy resin and/or binder based on latex or rubber, are particularly suitable. By way of example, a suitable epoxy resin is known under the trade name Terokal 5051 LV, and a rubber-based material is commercially available under the trade name Terostat 5190. Both products can be applied at temperatures of over 55xc2x0 C. and can then be cured by the introduction of energy. They then have a high strength and high rigidity. The rubber-based material may also be partially vulcanized. Both the abovementioned products have an electrical conductivity of approx. 106 xcexa9cm.
The substances known as xe2x80x9chot meltsxe2x80x9d, which are often ethylene vinyl acetate copolymers, are particularly suitable.
The composition of these materials can be set in such a way that they can be applied at relatively low temperatures (e.g.  less than 60xc2x0 C.) in the liquid phase and subsequently, after drying, can be activated, for example by means of heating. In this case, a specific softening or melting point, which should preferably be above 80xc2x0 C., particularly preferably above 100xc2x0 C., can be set very deliberately by means of a specific selection or composition.
However, it is also possible to use powder coatings which are known per se, for example based on phenolic or epoxy resin, as functional-layer material. These coatings may be applied in powder form to the heated hollow balls, for example in a fluidized bed; temperatures at which the powder adheres to the shells of the hollow balls but at which the powder coating powder does not melt leading to running should be maintained. The individual powder particles can adhere with a more or less uniform distribution to the shell surface and, after cooling, the hollow balls can readily be transported and stored without sticking to one another. The temperature is only increased again, until the powder softens or melts, during the production of lightweight structural components. During the melting, a uniform coating coverage can be formed over the entire surface, but in this case, given a suitable densely packed arrangement of the hollow balls or the application of a pressure (compacting) to the hollow balls, surface regions of hollow balls which are in direct contact with one another can be kept free of functional-layer material (e.g. free of coating).
A functional layer may, for example, be formed from an organic or inorganic binder, in and/or on which particles, preferably metals or polymers, are held adhesively. These particles can be deformed during a final thermal processing.
Polymers may also contain pulverulent inorganic elements and compounds and may then in particular fulfill binder functions for the elements or compounds, in addition to other functions, such as corrosion prevention and/or insulation.
Examples of suitable inorganic elements or compounds are metals, colored pigments, metal compounds, metal alloys and/or those which have magnetic or ferromagnetic properties.
If pulverulent elements or compounds are used for the functional layers, they can be applied to the shells as a suspension with a binder. In addition to organic binders, it is also possible to use inorganic binders. By way of example, metal salt solutions or water glass can be used to at least temporarily bind metal, metal oxide, ceramic or glass powder. Examples of suitable glasses are enamels or soldering glasses, for example lead- or boron-containing glasses, the latter having a relatively low softening and melting point.
The functional layer may advantageously consist of a metal or contain a metal which is able to form an intermetallic compound with a metallic shell material or a second functional-layer material. This is possible, for example, with tin and copper. Various aluminides may also be formed in this way.
However, it is also possible to form metal alloys if suitable metals are included in a functional layer or in functional layer and shell.
Particularly in the case of porous shells, it may be advantageous to select a combination of materials which allows infiltration. In this case, the functional-layer material can be infiltrated into the porous shell, or shell material can be infiltrated into the functional layer, in order to obtain a continuous covering. This allows the external diameter of the hollow balls to be influenced.
Moreover, porous ceramics or metals which are difficult to sinter can be provided with a dense surface.
It is also possible fore the functional layer to contain various additives. Examples are solders, fluxes, sintering aids, blowing agents and swelling agents.
By way of example, the functional layer may be formed from a pulverulent metal or may contain a metal of this type and also a blowing agent. During a heating operation, metal foam which is able to at least partially fill cavities in a bed of hollow balls is formed by means of the functional layer.
It is possible for a very wide range of metal powders of pure metals (e.g. Si, Al or Cu), but also alloys, for example with Mn, to be used.
Suitable blowing agents are metal hydrides, carbonates or hydrates. Pulverulent titanium hydride may preferably be used.
Within the functional layer, the concentration of the blowing agent in the functional layer should be greater in the inner wall than outside, in order to advantageously influence the formation of foam.
Particularly in the case of a plurality of different functional layers which are formed one above the other, a combination of physical and chemical treatments may be appropriate. By way of example, removal or activation may be carried out by means of a chemical route, followed by plastic deformation by means of a heat treatment.
Compared to known solutions, hollow balls according to the invention with a shell which is substantially formed from metal can advantageously be produced by providing a substrate material which is volatile when heated, for example STYROPOR (a proprietary trade name for expandable polystyrene), with a covering layer. This covering layer is formed from a liquid which contains a binder and base-metal powder parts, sintering being carried out after a drying operation. In conventional methods, problems occur because ball-shaped semifinished products which have been prepared in this way do not have sufficient strength during the sintering, since, as the temperatures rise, the binder action generally drops considerably. The binder used is expelled by evaporation or pyrolysis, so that the strength is reduced. The sintered wall thickness which have formed can be damaged and depressed even at low pressures and forces, so that individual hollow balls which have been prepared in this way are destroyed. It is difficult to get rid of these damaged or destroyed hollow balls. This drawback can be combated by adding an additive which decomposes when heated to the mixture which contains the binder and the base-metal powder. An additive of this type may be dissolved in the liquid of the mixture or may be present in colloidal form.
The decomposition of the additive may take place during the sintering, in which case the supplementary decomposition products which are formed from the additive form additional binder constituents for the base-metal powder, in the form of solid bodies, during the period of the heat treatment involved in the sintering. This process runs in the opposite direction to the reduced binder action of the actual binder as the temperature rises, and the binder function is gradually taken over by the supplementary decomposition products formed from the additive.
The hollow ball with a metallic shell which is present after the sintering can then subsequently be provided with at least one functional layer, as has already been described in various exemplary forms.
The additive, which is present in the form of a suspension together with the liquid, the binder and the base-metal powder, may advantageously be a metal salt or a metal hydroxide; it is also possible for a plurality of such salts and/or metal hydroxides to be present. As a result of the temperature being increased over the course of the heat treatment involved in the sintering, a metal oxide is formed from a metal salt (the oxide formation may advantageously take place in an oxidizing atmosphere). The metal oxide, which is formed in the form of solid bodies as a supplementary decomposition product, of a metal salt then acts as a binder between the base-metal powder parts and increases the strength of the shell which forms on a hollow ball, while the binder which is substantially composed of organic components is decomposed through pyrolysis.
However, sintering can also be carried out in an inert atmosphere, e.g. nitrogen or argon.
By way of example, copper acetate, nickel acetate, iron oxalate, nickel carbonate, nickel acetylacetonate or copper acetilacetonate are suitable. These compounds should preferably be used dissolved up to their saturation limit in a liquid. During the drying which is carried out prior to the sintering, the dissolved additives are concentrated in the liquid on account of the surface tension thereof at the locations of contact with the base-metal powder parts, and after the drying remain in place as a solid substance together with the organic binder constituents which were present in the liquid and, on account of the increase in volume at the locations of contact with the base-metal powder parts, increase the strength of the shells of the hollow ball so as to protect it against pressure and vibration.
The strength of the hollow balls is also achieved as a result of the supplementary decomposition products, which are formed during the sintering process, remain as solid bodies and have been obtained from the additive, being accumulated in concentrated form in each case at all the contact locations between the base-metal powder parts. This accumulation takes place as a result of the surface tension of the liquid at the contact locations of the individual base-metal powder parts before the drying.
The fact that the binder function is taken over by the decomposition products formed from the additive during heating, while at the same time the binder function of the binder of the base-metal powder parts is reduced in the opposite direction, has a particularly advantageous effect for thin-walled hollow balls.
The additive used may advantageously be metal salts of organic acids, since during decomposition of an additive of this type and of the binder, only carbon, oxygen and/or hydrogen are released and discharged to atmosphere, and substances of this type are generally harmless to people, environment and technology.
The metal salts are advantageously selected from readily reducible metals, such as copper, iron, nickel, cobalt, tin, molybdenum, tungsten and/or silver, and accordingly, in the case of a base-metal powder based on iron, are eminently suitable for sintering, these metals also being suitable alloying elements, since they can also be used for sintered steels.
To produce the suspension from which the covering layer which may subsequently form the protective shell of a hollow ball after the sintering, the solvent used may, for example, be water, alcohol or similar liquids. If, by way of example, alcohol is used as the liquid, this alcohol is particularly advantageously suitable since the generally organic binder is readily soluble in alcohols.
The formation of the covering layer may be applied to the ball-shaped substrate made from STYROPOR (a trade name for expandable polystyrene) or styrene in prefoamed form by means of wet powder-spraying processes or slip casting, the substrate body being completely decomposed by degassing and pyrolysis after the drying and sintering, and the gaseous components which are formed escaping to the outside, so that the metallic shell formed may be completely hollow on the inside.
The organic binder used may be a binder comprising one or more organic binders which is present in the liquid together with the base-metal powder part and the additives.
During the abovementioned accumulation of the additive at the contact points of the base-metal powder parts, the additive in the liquid is dissolved on an atomic and/or molecular size level and/or distributed homogeneously. During the drying, the additive which is present in the liquid forms a solid substance between the contact points of the base-metal powder parts. However, it is not yet decomposed during the drying step. The accumulation of the solid substance formed from the additive at the contact points between the base-metal powder parts is retained after the drying step, and the binding of the base-metal powder parts to one another can be strengthened in this way, so that the strength of the dried covering layer can be increased simply because of the increase in volume which has occurred at the contact points of the base-metal powder parts. The hollow ball, which is substantially formed from the dried covering layer, is already considerably less sensitive to impact, vibrations and jolting, even prior to sintering, than is the case in known solutions.
Metal salts of metals whose oxides can readily be reduced can very particularly advantageously be used. Examples of such metals are copper, iron, nickel, cobalt, tin, molybdenum, tungsten and silver. By way of example, metal salts which are selected from the group consisting of hydroxides, carbonates, acetates, formates, oxalates and/or acetylacetonates may expediently be used for forming shells of hollow balls.
The binder can be removed from the dried hollow ball which is provided with the covering layer during a further heat treatment carried out in a oxidizing atmosphere at temperatures of approx. 600xc2x0 C. In the process, all the organic binder constituents decompose, as does the additive which has been added, the latter forming a supplementary decomposition product, generally metal oxides and/or metal hydroxides, which is in the form of solid bodies. The additive, which is now in the form of solid bodies, can now assume the role of the organic constituents of the binder, which has lost its molecular structure of the organic binder system predominantly as a result of pyrolysis, and the organic molecules for the most part escape in the form of a gas. The thermodynamic stability of individual organic products which have been subjected to the pyrolysis means that a binder residue often remains, which initially substantially comprises aromatic hydrocarbon compounds and can therefore still perform a binding function between the base-metal powder parts. The reduction in the binder action can be very substantially compensated for by the decomposition products of the binder which have formed, since, by way of example, metal oxides which are formed as decomposition products can act as binders.
During the sintering, as the temperature rises first of all the binder, apart from binder residues, becomes volatile, followed by the substrate material which is used. The decomposition temperatures of the substrate material and of the additive are normally below the melting point of the additive and of the respective base-metal powder parts.
During the sintering, the binding action of metal oxides increases as the temperature rises, in particular on account of their small particle size, whereas the binding action of the binder which has become volatile, apart from a few residual binder residues, decreases in the opposite direction as the sintering time progresses.
In one configuration of the inventive method for producing hollow balls with metallic shells, in the case of sintering in a reducing atmosphere, it is possible for alloying constituents for the base-metal powder parts, which are likewise in solid from as an intermediate product, to be formed the in this case from the supplementary decomposition products of the additive. The melting point of a supplementary product which is formed from the binder should in this case be lower than the melting point of the respective base-metal powder.
As has already been mentioned, after the sintering operation at least one functional layer can be applied to the metallic, stable shell which has now formed, for example in a fluidized-bed reactor.
However, it is also possible for a metal layer to be electro-deposited, without the use of external current, directly on the metallic shell or on an intervening, appropriate functional layer; metals which are suitable for acting as a catalyst may be particularly recommended for this metal layer. In this case, it is advantageous for the surface of the shell or functional layer to be formed with a relatively great roughness or porosity, in order to correspondingly increase the size of the surface area.
However, functional layers can also be applied and formed in the fluidized bed or in an apparatus as described, for example, in DE 197 50 042 C2.
To produce lightweight structural components using hollow balls according to the invention, a mold body or a structure which forms the outer cladding of the lightweight structural component is filled with these hollow balls, which as far as possible fill the entire internal volume.
After the filling operation and optional compacting of the otherwise untreated hollow balls, a physical and/or chemical treatment, in which the functional-layer material is softened at least until it can be plastically and/or elastically deformed, is carried out in at least one further method step.
The compacting can be carried out by simple pressure compacting, but can more advantageously be carried out by means of vibratory compacting, in which case a compacting operation may advantageously also be carried out at least from time to time during the subsequent physical and/or chemical treatment.
The physical treatment may involve heating of the functional-layer material which is brought about by introduction of energy; the softening point and if appropriate also the melting point of this material should be lower than that of the material which forms the shell.
The heated material which is able to flow adapts itself to the surface form of the hollow balls, which are packed together as tightly as possible and are in virtually punctiform contact with one another. After the cooling, during which the functional-layer material can also solidify again, adjacent hollow balls are fixed at least in a positively-locking manner, secure adhesive bonding not being absolutely imperative.
The flow of the functional-layer material allows cavities which have remained between the hollow balls to be at least partially filled with this material. This makes it possible to influence forces acting on the hollow ball and to avoid undesirable stresses in the shells.
Moreover, it is possible to ensure that between the contact points or surfaces of adjacent hollow balls, the functional-layer material is completely displaced and the shells bear directly against one another, so that the stability and strength of the lightweight structural component can be increased.
The heating may be effected, for example, by convection using hot gases or liquids which are guided through the bed of the hollow balls, or by thermal radiation, inductively or via the correspondingly heated mold wall.
A chemical treatment may preferably be carried out using a solvent which is suitable for the functional-layer material and is introduced in liquid or vapor into the filled mold. A solvent of this type is used to soften the functional-layer material, so that this material is once again temporarily plastically deformable. After the solvent has been extracted or evaporated off, which can be achieved by suction and/or heating, the functional-layer material can solidify again and maintain the shape which it has adopted.
In the case of a mixture of a plurality of components from which the functional layer has been formed, it may be sufficient to soften one component using the solvent and/or by supplying energy sufficiently for it to become plastically deformable.
It is possible to use organic solvents in order to at least partially dissolve and soften corresponding polymers or functional layers which contain polymers and/or organic components which are contained therein.
Functional-layer materials whose volume increases as a result of the treatment, for example by foaming, are particularly advantageous. This makes it possible to compensate for diameter tolerances of the shells of the hollow balls and if appropriate also to advantageously influence the properties, in particular the damping and elasticity of the lightweight structural component.
Such materials may be foamable polymers, polymers which contain blowing agents, glasses or metals which contain pulverulent blowing agents.
For example, a metal powder, which may have been bound using an organic binder, may additionally be mixed with a suitable pulverulent blowing agent, so that given suitable heating a metal foam is formed around the shell. Examples of suitable blowing agents are metal hydrides, carbonates or hydrates. By way of example, titanium hydride powder can be used for aluminum.
However, in the case of a chemical treatment it is also possible to add swelling agents in order to increase the volume of the functional-layer material. For example, swellable polymers may be applied to shells as functional-layer material and, after a structure which forms the outer cladding of a lightweight structural component has been filled, an organic or inorganic swelling agent can be added. Following the increase in volume which is produced as a result of swelling, the structure is sealed off in a gas tight manner and the hollow balls-are stabilized by the functional-layer material.
Examples of polymers of this type are those which are known as xe2x80x9csuperabsorbersxe2x80x9d. These polymers can be swollen using water or aqueous solutions, resulting in a significant increase in volume. This is maintained for as long as the water is stored in the polymer.
If, by way of example, a lightweight structural component of this type having a gas tight and water tight cladding is used, the swollen polymer can fix the individual hollow balls, if appropriate filling up the cavities.
After the cladding has been opened and the water has been removed by drying, if necessary this assembly can be dissolved again and, if desired, the hollow balls can likewise be removed again.
However, it is also possible for metals, alloys or glasses without blowing agent to be used as supporting-layer material, but at least the softening point and if possible also the melting point should be below those of the shell material. In the case of alloys, at least one significant alloying component should satisfy this requirement.
The heat treatment may in this case be continued until the functional-layer material melts and the hollow balls are soldered together. In this case, it is advantageously also possible for at least one solder and optionally also a suitable flux to be included or embedded in the functional layer. A functional layer of this type may in this case consist, for example, of pure tin or bound tin powder.
An iron shell or a shell which consists of stainless high-strength and heat-resistant steel may, for example, be coated with a copper alloy which forms the functional layer.
Particularly in the case of relatively reactive shell materials, such as for example iron or aluminum, the functional layers advantageously act to prevent oxidation. They also form protection against corrosion in the case of components produced from hollow balls.
If adjacent shells or the functional material is/are to be sintered during the heat treatment, it is also possible for in each case suitable sintering aids to be included or embedded in the functional-layer material.
If adjacent shells are to be sintered together at their contact points, the functional-layer material has to either have been expelled or displaced sufficiently through plastic deformation, and the shell outer walls must be in direct contact with one another when or once the sintering temperature is reached.
It may also be advantageous if the inner wall of the mold body has been coated with a parting agent or the inner wall of the mold body or that the structure which forms the outer cladding of a lightweight structural component has been coated with a material which is also suitable for the functional layer prior to the filling with hollow balls.
This makes it possible to ensure easy demolding of the lightweight structural component or a smoother surface of a component of this type or a stronger bond between the hollow-ball packing and the outer cladding.
It is possible to use metal shells, metal or other hollow bodies as structures which forms the outer cladding and can be filled with the hollow balls according to the invention.
If a lightweight structural component is produced in a mold body, the surface of the demolded lightweight structural component is substantially formed by the shells of the outer hollow balls, the size of the shells of the hollow balls substantially determining the roughness of the surface. This surface may be laminated, coated or provided with coverings.
A demolded lightweight structural component can, as a semifinish lightweight structural component, be subjected to a further or final treatment. The semifinished lightweight structural component, which is easy to handle, can be sintered, resintered or infiltrated in order for the remaining cavities to be filled.
A preliminary product which has been prepared in this way may, for example, be used as a core in a mold of a plastics injection-molding machine and plastics can be injection-molded around it. As an alternative to the plastic, the outer cladding around a preliminary product of this type may also be formed from a metal or a metal alloy using a suitable process. This can be achieved, for example, by dipping into a melt or by build-up welding or using a metal-spraying process which is known per se.
A lightweight structural component or a semi-finished lightweight structural component may, if appropriate, be deformed by bending or pressing. However, it can also undergo material-removing machining. In these cases, however, a strong bond between the hollow balls should be ensured, which can be achieved, for example, with the aid of the functional-layer material which is able to withstand the deformation without the lightweight structural component breaking during the deformation.
For these cases, it is advantageously possible to use a functional-layer material which either cures in a number of stages or can be plastically deformed over a prolonged period using a known temperature range, so that the deformation of the lightweight structural component can be carried out after the treatment and before the complete curing which may take place.
The lightweight structural components may be produced in batches, for example in mold bodies, or continuously or quasi-continuously. The latter option is advantageous in particular for the production of semi-finished products.

Hollow balls and a method for producing hollow balls and for producing light-weight structural components by means of hollow balls

Fraunhofer-Gesellschaft Zur Foerderung der Angewandten Forschung E.V.


The present invention is concerned with a pharmaceutical composition suitable as a depot formulation for administration via intramuscular or subcutaneous injection, comprising:

This application is a National Stage application under 35 U.S.C. xc2xa7371 of PCT/EP98/07321 filed Nov. 10, 1998, which claims priority from EP 97.203.568.7, filed Nov. 17, 1997.
The present invention is concerned with a pharmaceutical composition suitable as a depot formulation for administration via intramuscular or subcutaneous injection, comprising:
(1) as an active ingredient a therapeutically effective amount of a 9-hydroxy-risperidone fatty acid ester or a salt, or a stereoisomer or a stereoisomeric mixture thereof in submicron form and
(2) a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier is water and the active ingredient is suspended therein;
and with a process of preparing such a composition.
The invention further involves such a pharmaceutical composition for use as a medicament in the treatment of psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioural disturbances in mental retardation and autism, Tourette""s syndrome, bipolar mania, depression, anxiety.
Risperidone is generic to 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The preparation and pharmacological activity thereof are described in EP-0,196,132 (corresponding to U.S. Pat. No. 4,804,663). Various conventional pharmaceutical dosage forms, including tablets, capsules, drops, suppositories, oral solutions and injectable solutions are exemplified therein. In practice, risperidone is normally administered as the base in a tablet or in a buffered, oral or intramuscular solution. Particular solutions for oral or intramuscular administration are described in WO-96/01652.
Risperidone is a highly potent drug having a relatively narrow therapeutic index. It may produce undesirable side effects on overdosage, most notably extra pyramidal syndrome (EPS) and to a lesser extent hypotension (due to peripheral alpha-adrenergic activity). For the purpose of producing an antipsychotic effect in a patient the total daily dose of risperidone ranges from about 2 to about 8 mg; for the alleviation of behavioral disturbances associated with neurodegenerative disorders the total daily dose is usually less and typically ranges from about 0.5 to about 2 mg. Inter-individual differences and co-medication may necessitate dose titrating in patients.
It is known that risperidone is metabolized to 9-hydroxyrisperidone which has a pharmacological profile and potency comparable with that of the parent drug risperidone, but which has a longer elimination half-life. Risperidone is distributed to and eliminated from the brain tissues more rapidly than its metabolite 9-hydroxy-risperidone. 9-hydroxyrisperidone, its enantiomeric forms and the C2-20 alkanoic acid esters thereof are described in EP-0,368,388 (corresponding to U.S. Pat. Nos. 5,158,952 and 5,254,556). Said esters are considered to be potentially valuable prodrugs of the active metabolite of risperidone for use in depot formulations.
For a number of reasons, it is desirable to administer risperidone in a sustained or delayed release (depot) formulation which is effective over an extended period of time, preferably about 3 weeks or more, in particular about 1 month.
WO-94/25460 (corresponding to EP-0,697,019) relates to a first such depot formulation and concerns the risperidone pamoate salt, a poorly water-soluble salt form of risperidone, which may be suspended in a pharmaceutically acceptable carrier, such as water or an oil, and may be administered subcutaneously or intramuscularly. This salt, however, has pharmacokinetic properties which are suboptimal. The release of the active ingredient from the formulations appears to be too rapid, which results in relatively high initial plasma levels and an inadequate mean duration of action, both characteristics which should be improved upon in a truly effective depot formulation.
WO-95/13814 concerns sustained release formulations for parenteral administration wherein risperidone is microencapsulated in a biocompatible, biodegradable wall-forming material (e.g. a polymer such as dl-(polylactide-co-glycolide)). The micro-encapsulated formulations have suitable pharmacokinetic properties, but require sophisticated processes of preparation in a purpose-built plant.
PCT/EP97/02504 discloses aqueous suspensions of 9-hydroxyrisperidone fatty acid esters in water wherein the prodrug of the active ingredient is in micronized fonn. Unexpectedly, these formulations prove to be far too longlasting in humans to be therapeutically useful.
Consequently, there is still a need for an effective and readily available depot formulation of risperidone or a risperidone-like compound.
Nanoparticles are well known in the prior art, having been described, for example, in EP-A-0,499,299. These particles consist essentially of a crystalline drug substance having a surface modifier absorbed on the surface of the particles such that the effective average particle size is less than about 400 nm. It is also known that said particles are particularly useful to formulate poorly water soluble active ingredients.
The present invention results from the investigations into the development of an efficient, well-tolerated, sustained or delayed release (depot) formulation of a 9-hydroxyrisperidone alkanoic acid ester which is therapeutically effective for at least three weeks or more, in particular about 1 month. By the expression xe2x80x9ceffective for at least three weeks or morexe2x80x9d, one means that the plasma level of the active ingredient, 9-hydroxyrisperidone (free alcohol liberated by hydrolysis from the alkanoic acid ester), should be above approximately 10 ng/ml. On the other hand, said plasma level should remain at all times below a threshold value of approximately 100 ng/ml in order for one to call the formulation xe2x80x9cefficientxe2x80x9d. The threshold value is the mean plasma level during a considerable period of time, e.g. for more than 15 minutes, above which patients may experience undesirable side effects, or conversely, the value of the plasma level under which the systemic tolerance of the formulation in question is still acceptable. The threshold value does not hold for transient, high plasm levels during a short period of time, e.g. for less than 15 minutes, which are due, for example to unexpected burst-release of the active ingredient.
Both of the foregoing featuresxe2x80x94plasma levels above a minimal therapeutical concentration but below a side-effect producing threshold valuexe2x80x94are considered to be basic requirements that a contemporary depot formulation should fulfil in order to be acceptable for the intended patients. Limiting the number of drug administrations and the occurrence of undesirable side effects after each administration will undoubtedly improve the patients"" compliance with the therapy. However, beyond these basic requirements, a number of further desiderata can be identified which would further improve patients"" compliance; the two most notable being good local tolerance and ease of administration.
Good local tolerance means minimal irritation and inflammation at the site of injection; ease of administration refers to the size of needle and length of time required to administer a dose of a particular drug formulation. In addition, depot formulations should be stable and have a shelf-life of at least two years under normal conditions.
The investigations into the development of an efficient, well-tolerated, sustained or delayed release (depot) formulation of a 9-hydroxyrisperidone alkanoic acid ester which fulfils the above mentioned requirements, led to the finding that a pharmaceutical composition suitable as a depot formulation for administration by intramuscular or subcutaneous injection should comprise:
a dispersion of particles consisting essentially of a therapeutically effective amount of a crystalline 9-hydroxyrisperidone fatty acid ester having the formula
xe2x80x83or a salt, or a stereoisomer or a stereoisomeric mixture thereof, wherein R represents a straight C9-19alkyl radical; having a surfactant absorbed to the surface thereof in an amount effective in maintaining a specific surface area  greater than 4 m2/g (corresponding to an effective average particle size of less than 2,000 nm), in a pharmaceutically acceptable carrier comprising water.
Surprisingly, it appears that aqueous suspensions of micronized 9-hydroxyrisperidone C10-20 alkanoic acid esters (wherein R represents a straight C9-19 alkyl radical) have an exceptionally longlasting effect in humans, but not in test animals, in particular dogs. This is quite unexpected since the pharmacokinetics of drugs in humans and in dogs are often comparable. The pharmacokinetic properties in humans of the aqueous suspensions of 9-hydroxyrisperidone alkanoic acid esters depend on the particle size to a much larger extent than previously held possible.
C10-20alkanoic acids are selected from the group consisting of decanoic (capric), undecanoic, dodecanoic (lauric), tridecanoic, tetradecanoic (myristic), pentadecanoic, hexadecanoic (palmitic), heptadecanoic, octadecanoic (stearic), nonadecanoic and eicosanoic acid. The ester having a C15 (pentadecyl) chain and the active ingredient corresponding thereto being the 9-hydroxyrisperidone palmitate ester was found to be the superior ester from a pharmacokinetic, as well as from a tolerance point of view.
The nanoparticles of the present invention have a surfactant or surface modifier adsorbed on the surface thereof in an amount sufficient to maintain a specific surface area  greater than 4 m2/g (i.e. corresponding to an average particle size of less than 2,000 nm), preferably the specific surface area  greater than 6 m2/g, and in particular is in the range from 10 to 16 m2/g. Useful surface modifiers are believed to include those which physically adhere to the surface of the active agent but do not chemically bond thereto.
Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. Representative examples of excipients include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene allcyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available Tweens(trademark), polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminate silicate, triethanolamine, polyvinyl alcohol (PVA), poloxamers, tyloxapol and polyvinylpyrrolidone (PVP). Most of these excipients are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986. The surface modifiers are commercially available and/or can be prepared by techniques known in the art. Two or more surface modifiers can be used in combination.
Particularly preferred surface modifiers include polyvinylpyrrolidone; tyloxapol; poloxamers, such as Pluronic(trademark) F68, F108 and F127 which are block copolymers of ethylene oxide and propylene oxide available from BASF; poloxamines, such as Tetronic(trademark) 908 (T908) which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine available from BASF; dextran; lecithin; Aerosol OT(trademark) (AOT) which is a dioctyl ester of sodium sulfosuccinic acid available from Cytec Industries; Duponol(trademark) P which is a sodium lauryl sulfate available from DuPont; Triton(trademark) X-200 which is an alkyl aryl polyether sulfonate available from Rohm and Haas; Tweens(trademark) 20, 40, 60 and 80 which are polyoxyethylene sorbitan fatty acid esters available from ICI Speciality Chemicals; Span(trademark) 20, 40, 60 and 80 which are sorbitan esters of fatty acids; Arlacel(trademark) 20, 40, 60 and 80 which are sorbitan esters of fatty acids available from Hercules, Inc.; Carbowax(trademark) 3550 and 934 which are polyethylene glycols available from Union Carbide; Crodesta(trademark) F110 which is a mixture of sucrose stearate and sucrose distearate available from Croda Inc.; Crodesta(trademark) SL-40 which is available from Croda, Inc.; hexyldecyl trimethyl ammonium chloride (CTAC); bovine serum albumin and SA90HCO which is C18H17CH2(CON(CH3)CH2(CHOH)4CH2OH)2. The surface modifiers which have been found to be particularly useful include tyloxapol and a poloxamer, preferably, Pluronic(trademark) F108 and Pluronic(trademark) F68.
Pluronic(trademark) F108 corresponds to poloxamer 338 and is the polyoxyethylene, polyoxypropylene block copolymer that conforms generally to the formula HO[CH2CH2O]x[CH(CH3)CH2O]y[CH2CH2O]zH in which the average values of x, y and z are respectively 128, 54 and 128. Other commercial names of poloxamer 338 are Hodag Nonionic(trademark) 1108-F available from Hodag, and Synperonic(trademark) PE/F108 available from ICI Americas.
The optimal relative amount of the antipsychotic agent and the surface modifier depends on various parameters. The optimal amount of the surface modifier can depend, for example, upon the particular antipsychotic agent and surface modifier selected, the critical micelle concentration of the surface modifier if it forms micelles, the surface area of the antipsychotic agent, etc. The specific surface modifier preferably is present in an amount of 0.1 to 1 mg per square meter surface area of the antipsychotic agent. In case 9-hydroxyrisperidone palmitate is used as antipsychotic agent and Pluronic(trademark) F108 as a surface modifier, a relative amount (w/w) of both ingredients of approximately 6:1 is preferred.
As used herein, an effective average particle size of less than 2,000 nm means that at least 90% of the particles have a diameter of less than 2,000 nm when measured by art-known conventional techniques, such as sedimentation field flow fractionation, photon correlation spectroscopy or disk centrifugation. With reference to the effective average particle size, it is preferred that at least 95% and, more preferably, at least 99% of the particles have a particle size of less than the effective average particle size, e.g. 2,000 nm. Most preferably, essentially all of the particles have a size of less than 2,000 nm.
The particles of this invention can be prepared by a method comprising the steps of dispersing an antipsychotic agent in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the antipsychotic agent to an effective average particle size of less than 2,000 nm. The particles can be reduced in size in the presence of a surface modifier. Alternatively, the particles can be contacted with a surface modifier after attrition.
A general procedure for preparing the particles of this invention includes
(a) obtaining an antipsychotic agent in micronized form;
(b) adding the micronized antipsychotic agent to a liquid medium to form a premix; and
(c) subjecting the premix to mechanical means in the presence of a grinding medium to reduce the effective average particle size.
The selected antipsychotic agent in micronized form is obtained commercially or prepared using techniques known in the art. It is preferred that the particle size of the micronized antipsychotic agent be less than about 100 xcexcm as determined by sieve analysis. If the particle size of the micronized antipsychotic agent is greater than about 100 xcexcm, then it is preferred that the particles of the antipsychotic agent be reduced in size to less than 100 xcexcm.
The micronized antipsychotic agent can then be added to a liquid medium in which it is essentially insoluble to form a premix. The concentration of the antipsychotic agent in the liquid medium (weight by weight percentage) can vary widely and depends on the selected antipsychotic agent, the selected surface modifer and other factors. Suitable concentrations of antipsychotic agent in compositions vary between 0.1 to 60%, preferably is from 0.5 to 30%, and more preferably, is approximately 7% (w/v).
A more preferred procedure involves the addition of a surface modifier to the premix prior to its subjection to mechanical means to reduce the effective average particle size. The concentration of the surface modifier (weight by weight percentage) can vary from 0.1% to 90%, preferably from 0.5% to 80%, and more preferably is approximately 7% (w/v).
The premix can be used directly by subjecting it to mechanical means to reduce the effective average particle size in the dispersion to less than 2,000 nm. It is preferred that the premix be used directly when a ball mill is used for attrition. Alternatively, the antipsychotic agent and, optionally, the surface modifier, can be dispersed in the liquid medium using suitable agitation such as, for example, a roller mill or a Cowles type mixer, until a homogeneous dispersion is achieved.
The mechanical means applied to reduce the effective average particle size of the antipsychotic conveniently can take the form of a dispersion mill. Suitable dispersion mills include a ball mill, an attritor mill, a vibratory mill, a planetary mill, media millsxe2x80x94such as a sand mill and a bead mill. A media mill is preferred due to the relatively shorter milling time required to provide the desired reduction in particle size. For media milling, the apparant viscosity of the premix preferably is anywhere between 0.1 and 1 Paxc2x7s. For ball milling, the apparant viscosity of the premix preferably is anywhere etween 1 and 100 mPaxc2x7s.
The grinding media for the particle size reduction step can be selected from rigid media preferably spherical or particulate in form having an average size less than 3 mm and, more preferably, less than 1 mm. Such media desirably can provide the particles of the invention with shorter processing times and impart less wear to the milling equipment. The selection of the material for the grinding media is believed not to be critical. However, 95% ZrO stabilized with magnesia, zirconium silicate, and glass grinding media provide particles having levels of contamination which are believed to be acceptable for the preparation of pharmaceutical compositions. Further, other media, such as polymeric beads, stainless steel, titania, alumina and 95% ZrO stabilized with yttrium, are useful. Preferred grinding media have a density greater than 2.5 g/cm3 and include 95% ZrO stabilized with magnesia and polymeric beads.
The attrition time can vary widely and depends primarily upon the particular mechanical means and processing conditions selected. For rolling mills, processing times of up to two days or longer may be required.
The particles must be reduced in size at a temperature which does not significantly degrade the antipsychotic agent. Processing temperatures of less than 30 to 40xc2x0 C. are ordinarily preferred. If desired, the processing equipment may be cooled with conventional cooling equipment. The method is conveniently carried out under conditions of ambient temperature and at processing pressures which are safe and effective for the milling process.
The surface modifier, if it was not present in the premix, must be added to the dispersion after attrition in an amount as described for the premix above. Thereafter, the dispersion can be mixed by, for example, shaking vigorously. Optionally, the dispersion can be subjected to a sonication step using, for example, a ultrasonic power supply.
Aqueous compositions according to the present invention conveniently further comprise a suspending agent and a buffer, and optionally one or more of a preservative and an isotonizing agent. Particular ingredients may function as two or more of these agents simultaneously, e.g. behave like a preservative and a buffer, or behave like a buffer and an isotonizing agent.
Suitable suspending agents for use in the aqueous suspensions according to the present invention are cellulose derivatives, e.g. methyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl methyl cellulose, polyvinylpyrrolidone, alginates, chitosan, dextrans, gelatin, polyethylene glycols, polyoxyethylene- and polyoxy-propylene ethers. Preferably sodium carboxymethyl cellulose is used in a concentration of 0.5 to 2%, most preferably 1% (w/v). Suitable wetting agents for use in the aqueous suspensions according to the present invention are polyoxyethylene derivatives of sorbitan esters, e.g. polysorbate 20 and polysorbate 80, lecithin, polyoxyethylene- and polyoxypropylene ethers, sodium deoxycholate. Preferably polysorbate 20 is used in a concentration of 0.5 to 3%, more preferably 0.5 to 2%, most preferably 1.1% (w/v).
Suitable buffering agents are salt of weak acids and should be used in amount sufficient to render the dispersion neutral to very slightly basic (up to pH 8.5), preferably in the pH range of 7 to 7.5. Particularly preferred is the use of a mixture of disodium hydrogen phosphate (anhydrous) (typically about 0.9% (w/v)) and sodium dihydrogen phosphate monohydrate (typically about 0.6% (w/v)). This buffer also renders the dispersion isotonic and, in addition, less prone to flocculation of the ester suspended therein.
Preservatives are antimicrobials and anti-oxidants which can be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, a gallate, a hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-xcex3-piccolinium chloride, phenylmercuric acetate and thimerosal. In particular, it is benzyl alcohol which can be used in a concentration up to 2% (w/v), preferably up to 1.5% (w/v).
Isotonizing agents are, for example, sodium chloride, dextrose, mannitol, sorbitol, lactose, sodium sulfate. The suspensions conveniently comprise from 0 to 10% (w/v) isotonizing agent. Mannitol may be used in a concentration from 0 to 7% More preferably, however, from about 1 to about 3% (w/v), especially from about 1.5 to about 2% (w/v) of one or more electrolytes are used to render the suspension isotonic, apparently because ions help to prevent flocculation of the suspended ester. In particular electrolytes of the buffer serve as isotonizing agent.
A particularly desirable feature for an injectable depot formulation relates to the ease with which it can be administered. In particular such an injection should be feasible using a needle as fine as possible in a span of time which is as short as possible. This can be accomplished with the aqueous suspensions of the present invention by keeping the viscosity below about 75 mPaxc2x7s, preferably below 60 mPaxc2x7s. Aqueous suspensions of such viscosity or lower can both easily be taken up in a syringe (e.g. from a vial), and injected through a fine needle (e.g a 21 G 1xc2xd, 22 G 2 or 22 G 1xc2xc needle).
Ideally, aqueous suspensions according to the present invention will comprise as much prodrug as can be tolerated so as to keep the injected volume to a minimum, and as little of the other ingredients as possible. In particular, such a composition will comprise by weight based on the total volume of the composition:
(a) from 3 to 20% (w/v) of the prodrug;
(b) from 0.5 to 2% (w/v) of a wetting agent;
(c) one or more buffering agents sufficient to render the composition neutral to very slightly basic (pH 8.5);
(d) from 0.5 to 2% (w/v) of a suspending agent;
(e) up to 2% (w/v) preservatives; and
(f) water q.s. ad 100%.
In view of the usefulness of 9-hydroxyrisperidone in the treatment of a number of disorders, the present invention also concerns a pharmaceutical composition as described hereinbefore for use as a medicament in the treatment of psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioural disturbances in mental retardation and autism, Tourette""s syndrome, bipolar mania, depression, anxiety.
In addition, the present invention concerns the use of a composition as described hereinbefore for the preparation of a medicament for treating psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioural disturbances in mental retardation and autism, Tourette""s syndrome, bipolar mania, depression, anxiety.
The present invention further concerns a method of treating warm-blooded animals, in particular humans suffering from psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioural disturbances in mental retardation and autism, Tourette""s syndrome, bipolar mania, depression, anxiety, said method comprising the administration of a therapeutically effective amount of an, aqueous suspension as described hereinbefore. Typically, said formulation will be administered approximately every three weeks or even at longer intervals where possible. The dosage should range from about 2 to 4 mg/kg body weight.

Aqueous suspensions of submicron 9-hydroxyrisperidone fatty acid esters

Abstract: (2) a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier is water and the active ingredient is suspended therein:

Abstract: The invention further concerns such a pharmaceutical composition for use as a medicament in the treatment of psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioural disturbances in mental retardation and autism, Tourette""s syndrome, bipolar mania, depression, anxiety.


A mechanism is provided for presenting contextually relevant patient data in relation to other patients in a graphical user interface. Using a medical condition associated with a patient and a current treatment being followed by the patient, a cohort of similar patients with the same medical condition are identified. For each of the patients in the cohort, a set of next treatments are identified for those patients that stopped the current treatment and followed a next treatment. For each next treatment followed by a patent in the cohort of similar patients, a determination is made as to whether the next treatment controlled or failed to control the same medical condition for the patient. Then a presentation is provided indicating the set of next treatments, a number of patients following each next treatment, whether each treatment controlled or failed to control the same medical condition, and a statistical significance.

The present application relates generally to an improved data processing apparatus and method and more specifically to mechanisms for presenting contextually relevant patient data in relation to other patients to a medical professional.
An electronic health record (EHR) or electronic medical record (EMR) is the systematized collection of patient and population electronically-stored health information in a digital format. These records can be shared across different health care settings. Records are shared through network-connected, enterprise-wide information systems or other information networks and exchanges. EMRs may include a range of data, including demographics, medical history, medication and allergies, immunization status, laboratory test results, radiology images, vital signs, personal statistics like age and weight, and billing information.
EMR systems are designed to store data accurately and to capture the state of a patient across time. It eliminates the need to track down a patient's previous paper medical records and assists in ensuring data is accurate and legible. It can reduce risk of data replication as there is only one modifiable file, which means the file is more likely up to date, and decreases risk of lost paperwork. Due to the digital information being searchable and in a single file, EMRs are more effective when extracting medical data for the examination of possible trends and long term changes in a patient. Population-based studies of medical records may also be facilitated by the widespread adoption of EMRs.

Presenting contextually relevant patient data in relation to other patients to a medical professional

International Business Machines Corporation


The transfer assembly for a dispensing cabinet for dispensing wound sheet material, such as paper toweling, from a primary roll and a reserve roll includes a transfer arm having a pair of dispensing fingers under which the leading end of the sheet material from the reserve roll is disposed and a sensing arm including a sensing surface over which sheet material from the primary roll being fed into the nip between a drive roller and a pressure roller rides. The transfer arm and sensing arm are mounted for common movement between a non-transfer position wherein the sheet material riding over the sensing surface of the sensing arm, in cooperation with the pulling force being applied thereon by the drive roller, holds the transfer finger away from the nip and a transfer position wherein, in response to the tail end of the sheet material being detached from the primary roll, the transfer arm moves toward the nip and the transfer fingers push sheet material from the reserve roll into the nip. Subsequent rotation of the drive roller causes the sheet material from the reserve to be fed through the nip and dispensed from the cabinet.

This invention relates to dispensers for multiple rolls of sheet material and, in one aspect, to dispensers for two rolls of paper towel.
Dispenser for rolls of flexible sheet material, such as paper towel rolls, are well known. Paper towel dispensers are widely used in public lavatories to dispense paper toweling for users to dry their hands. Such dispensers typically include either a crank or lever which the user operates to drive a feed mechanism for dispensing the paper toweling. The feed mechanism typically includes a drive roller rotated by a crank or lever or an idler or pressure roller, the paper toweling is fed through a nip between these two rollers and the pressure roller is spring loaded to provide sufficient friction for rotation of the drive roller to unwind the paper toweling off a roll core.
Some paper towel dispensing devices are capable of sequentially dispensing two rolls of paper toweling. This type dispenser includes a transfer mechanism arranged so that, when all the paper toweling from a primary roll has been dispensed, toweling from the reserve roll is introduced into the feed mechanism. One type transfer mechanisms includes a number of rollers which are arranged to provide tension between the paper toweling being unwound from the primary on the feed mechanism and, in response to loss of this tension, effect a transfer of paper toweling from the reserve roll into the feed mechanism. This loss of tension usually occurs when the tail end of the paper toweling has been completely unwound and detached from the primary roll core. However, a loss of tension occasionally can occur during normal use even though there is still paper on the primary roll. For example, if the primary roll core binds and the user is required to use additional force to operate the crank or lever, the primary roll can over run after the bind is broken loose. This can cause a slack condition which is the same as the loss tension to the transfer mechanism and it makes a false transfer, causing paper toweling from the reserve roll to be introduced into the feed mechanism. When this occurs, the feed mechanism can become jammed and no longer capable of dispensing paper toweling or simultaneously dispense paper toweling from both the primary and reserve rolls.
In another type multiple roll dispenser, the transfer assembly is a one-piece unit and includes a transfer arm having a pair of axially spaced transfer fingers and a sensing arm having a sensing surface. The transfer assembly is mounted for common pivotal movement and the sensing surface engages the outer surface of the toweling on the primary roll. The transfer assembly is arranged so that, by the time the sensing surface engages the primary roll core, the transfer arm has pivoted to a position where the transfer fingers push the leading end of the toweling from the reserve roll into the feed mechanism.

Dispenser for multiple rolls of sheet material


A process for preparing 1-chloro-1,1,3,3,3-pentafluoropropane, CF3CH2CF2Cl, comprising contacting in a reaction zone in the substantial absence of oxygen, reactants comprising chlorine and 1,1,1,3,3-pentafluoropropane, CF3CH2CHF2 (also referred to as HFC-245fa), and subjecting the reactants to actinic radiation, such as UV light at about 2,000 to 4,000 Angstroms, wherein: (1) inert gas is present at a concentration equal to or less than about 5 wt. % of the total weight of reactants; (2) the molar ratio of chlorine to CF3CH2CHF2 is from about 0.2:1 to about 1.5:1; and (3) the concentration of chlorinated product produced having greater than one chlorine present in the molecule is less than or equal to about 10 wt. %.

This invention relates to a process for producing hydrochlorofluorocarbons (i.e., compounds that contain only hydrogen, fluorine, chlorine and carbon atoms, HCFCs) that are useful for producing fluorine-containing olefins, which are themselves useful as intermediates for making industrial chemicals, including polymers. HCFCs can also be used in place of chlorofluorocarbons, (i.e., compounds that contain only carbon, chlorine and fluorine atoms, CFCs) since the latter have been implicated in the depletion of stratospheric ozone and HCFCs are believed to contribute less to such depletion. More particularly, the present invention relates to a process for producing 1-chloro-1,1,3,3,3-pentafluoropropane or CF3CH2CF2Cl (also designated xe2x80x9cHCFC-235faxe2x80x9d), by photochlorinating 1,1,1,3,3-pentafluoropropane, or CF3CH2CHF2, (also designated xe2x80x9cHFC-245faxe2x80x9d).
U.S. Pat. No. 6,187,976 B1 describes the preparation of 1-chloro-1,1,3,3,3-pentafluoropropane by reacting, in the liquid or vapor phase, CCl3CH2CCl3 with hydrogen fluoride in the presence of a fluorination catalyst.
The production of CF3CH2CF2Cl occurs as an intermediate during the production of CF3CH2CHF2, as described in U.S. Pat. No. 5,728,904, incorporated herein by reference to the extent permitted. That method involves conversion of CCl3CH2CCl3 to CF3CH2CF2Cl by reaction with HF in the presence of a fluorination catalyst, selected from TiCl4, SnCl4 or mixtures thereof.
The UV catalyzed reaction of CF3CH2CHF2 and chlorine to produce CF3CH2CF2Cl is described by J. Chen et al., J. Phys. Chem. A, 1997, 101, 2648-2653, 2649. The reaction was carried out in the absence of oxygen and using a mixture of CF3CH2CF2H at a concentration range of 0.4-0.7 Torr and Cl2 at a concentration range of 3-4 Torr; the overall system diluted in 700 Torr of helium. The corresponding molar ratio of chlorine to CF3CH2CHF2 for this system ranged from 4.3 to 10:1. In this highly dilute, inert environment (at most, the reactants represented only 0.7% of the overall composition), it is said that the primary reaction products were CF3CH2CF2Cl and HCl. The conditions and process described, while suitable for academic research, are not amenable to scale-up and industrial use.
While the photochlorination of fluorine-containing hydrocarbons is described in the patent literature, it is in connection with the purification of 1,1,1,3,3-pentafluoropropane, HFC-245fa, by chlorinating olefinic impurities, U.S. Pat. Nos. 6,077,982 and 5,951,830; and the production of HCFCs (and HFCs), wherein the HCFC compounds contained more than one chlorine atom, U.S. Pat. Nos. 5,421,971 and 4,060,469. In particular, U.S. Pat. No. 6,077,982 discloses that the amount of chlorine added relative to the unsaturated impurity present can range from about 1 to 1.5 times the concentration of the unsaturated impurity (col. 3, lines 4-6) and the concentration of the unsaturated species is from about 300-20,000 wt. ppm (col. 2, lines 55-56). Based on these values, the maximum ratio of chlorine to HFC-245fa disclosed in this patent is about 0.1. While the patent discloses that increasing the amount of chlorine relative to the amount of impurity improves its chlorination and ultimate removal, the increase is within the scope of the range disclosed and there is no recognition that further increases run the risk of chlorinating or over-chlorinating the primary product, HFC-245fa. In fact, chlorination of HFC-245fa is contrary to the objectives of this patent.
There is a continuing need for the production of HFC-235fa, a useful industrial chemical, using a controlled process that produces little or no undesirable by-products.
A process for preparing 1-chloro-1,1,3,3,3-pentafluoropropane, CF3CH2CF2Cl, comprising contacting in a reaction zone in the substantial absence of oxygen reactants comprising chlorine and 1,1,1,3,3-pentafluoropropane, CF3CH2CHF2, and subjecting the reactants to actinic radiation, wherein: (A) inert gas is present at a concentration equal to or less than 5 wt. % of the total weight of said reactants; and (B) the concentration of chlorinated product produced having greater than one chlorine present in the molecule is less than or equal to about 10 wt. %.
As used herein, xe2x80x9cactinic radiationxe2x80x9d means light irradiation of sufficient intensity and at appropriate wavelengths, including ultraviolet and visible light, but preferably wavelengths shorter than those of visible light, such that the radiation causes photochemical effects, especially including chemical reaction between chlorine and 1,1,1,3,3-pentafluoropropane.
Various methods for producing 1,1,1,3,3-pentafluoropropane or HFC-245fa are described in U.S. Pat. Nos. 5,710,352; 5,969,198; and 6,023,004. Another method, described in U.S. Pat. No. 5,728,904, is said to be economical, amenable to large scale application and uses readily available raw materials. The process of that patent uses three steps, as follows: 1) formation of CCl3CH2CCl3 by the reaction of CCl4 with vinylidene chloride; 2) conversion of CCl3CH2CCl3 to CF3CH2CF2Cl by reaction with HF in the presence of a fluorination catalyst, selected from TiCl4, SnCl4 or mixtures thereof; and 3) reduction of CF3CH2CF2Cl to CF3CH2CF2H. The disclosures of each of these four patents are incorporated herein to the extent permitted. Commercial quantities of CF3CH2CHF2, or HFC-245fa, also are available from Honeywell International Inc., Morristown, N.J. for use as a reactant in the present process.
The preferred reaction of the present process between HFC-245fa and chlorine in the presence of actinic radiation causes substitution of a covalently bonded hydrogen atom in the substrate molecule by chlorine, as represented by the following equation:
CF3CH2CHF2+Cl2xe2x86x92CF3CH2CF2Cl+HCl
Undesirable multichlorinated byproducts include, for example, 1,1,1,3,3-pentafluoro-2,2,3-trichloropropane, CF3CCl2CF2Cl, and CF3CHClCF2Cl.
The apparatus used for photochlorination can be any suitable reactor capable of containing the reactants at the temperature and pressure during the photochlorination reaction and also containing an appropriate actinic radiation source or sufficiently transparent to actinic radiation in the desired wavelength range. For example, the reactor can be constructed of suitably corrosion-resistant metal, metal lined with glass or plastic, or glass, in other words a material suitably resistant to the corrosive effects of chlorine, and include a well, for example a quartz well, in which a light source is located. Alternatively, the reactor can be constructed of glass and the light source can be external to the reaction zone, but irradiating the reaction zone or focused thereon. Preferably, the reactor includes means to mix or stir reactants in the liquid and/or vapor phase and at least one condenser or cold trap in order to control the reactants and reaction products. The apparatus preferably includes at least one inlet for the reactants and at least one outlet for the reaction by-products. For example, multiple inlets are provided, one for HFC-245fa and one for chlorine. A suitable reactor consists of a glass reactor, of appropriate size for producing the quantities of product desired, equipped with a condenser or cold trap, a magnetic stirrer, and fitted with a water cooled, quartz immersion well for placement of a 450 watt, quartz, medium pressure, mercury vapor lamp, e.g., providing radiation at about 200-400 nm, and having an inlet for the introduction of chlorine and an outlet for gaseous products. Such an apparatus, having a capacity of 1 liter, is available from Ace Glass Co., Vineland, N.J. In addition, the Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 17, pages 545-555 (3d ed. 1982) contains a general description of the types of light sources and reactors that may be used; this portion of the reference is incorporated herein to the extent permitted.
Desirably the reaction zone is maintained at a temperature of from about xe2x88x925xc2x0 C. to about +10xc2x0 C.; preferably is maintained from about xe2x88x923xc2x0 C. to about +5xc2x0 C.; more preferably from about xe2x88x920xc2x0 C. to about +2xc2x0 C. Typically the reaction zone is maintained at a temperature such that HFC-245fa is present in both the liquid and vapor phase during the course of the reaction.
When it is introduced as a separate feed stream, chlorine is typically introduced into the reactor as a gas. The flow rate of the chlorine gas should be carefully regulated and controlled so that the molar ratio of chlorine relative to HFC-245fa in the reaction zone typically does not exceed about 1.5:1; preferably it does not exceed about 1.3:1; more preferably it does not exceed about 1.2:1; most preferably it does not exceed about 1.1:1. As for the minimum amount of chlorine required for the reaction, the ratio of chlorine to HFC-245fa is typically about 0.2:1; preferably about 0.3:1; more preferably, about 0.5:1; most preferably about 0.75:1; for example, about 0.9:1. Each of the expressed lower and upper concentrations can be combined to construct suitable ranges for the ratio of chlorine to HFC-245fa; for example, from about 0.2 to about 1.5; from about 0.2 to about 1.1; from about 0.5 to about 1.1; etc. The most preferred ratio is from about 1.0: to about 1.2:1. If the feed rate or amount of chlorine relative to the amount of HFC-245fa is too low, the process can be economically unattractive, e.g., the amount of chlorinated product produced is unacceptably low. Conversely, if the ratio of chlorine to HFC-245fa is too high, an excessive amount of by-products containing more than one chlorine on the hydrochlorofluorocarbon (a xe2x80x9cmultichlorinatedxe2x80x9d product) is obtained. For convenience, particularly when a batch or titration-type process is practiced (see below for a description of the latter), the molar ratio of chlorine to HFC-245fa can be calculated based on the total amount of each reactant used during the course of the process; in such event, the ratios expressed above should be maintained in order to achieve the benefits of the present invention.
Typically the product of the process will contain less than about 10 wt. % multichlorinated product; preferably less than about 6 wt. %; more preferably less than about 4 wt. %. It is particularly preferred that no such multichlorinated products be produced, but a trace level of multichlorinated product may be expected, for example from greater than about zero to less than about 1 wt. %; preferably less than about 0.5 wt. %; more preferably less than about 0.1 wt. %; still more preferably less than about 0.05 wt. %; for example from greater than zero to less than about 0.025 wt. %.
Chlorine can be fed to the reactor in several ways. It can be introduced to the reactor by way of a feed line and enter the reactor preferably by way of a sintered glass sparger, for example, submerged under liquid HFC-245fa already present in the reactor; it can be added to the vapor phase of the reactor; it can be premixed with HFC-245fa, for example, if the latter is to be fed continuously, at a distance upstream from the reactor in order to partially or thoroughly saturate the HFC-245fa before the mixture enters the reactor; it can be premixed with HFC-245fa as described and also be present in excess in the premixed stream. Preferably chlorine is fed to the reactor as a gas through a sparger under HFC-245fa that is present in the reactor as a liquid phase; and wherein chlorine and/or HFC-245fa can also be present in the vapor phase at the temperature and pressure conditions of the reactor. In this manner the chlorine can be introduced for a period of time so as to partially or fully saturate the HFC-245fa liquid prior to initiating the photochlorination reaction by providing actinic radiation.
The process of the present invention can be carried out as a batch reaction, a semi-continuous reaction or as a continuous reaction. By a semi-continuous reaction is meant where effectively all of the HFC-245fa is fed to the reaction zone and thereafter chlorine gas is introduced into the reactor, preferably sparged into the HFC-245fa at a controlled rate. During the course of the reaction chlorine gas is introduced in a controlled manner to maintain the ratio of chlorine to HFC-245fa at a suitable level, until most of the HFC-245fa is consumed. Additional HFC-245fa can be added to maintain the ratio of reactants at the desired level, as described above. Such a process can also be considered to be a titration-type process, since the titrating agent, chlorine, is added to HFC-245fa in a substantially continuous manner until the desired end-point is reached, e.g., until the HFC-245fa is sufficiently consumed that the reaction is terminated. Suitable analytical monitoring means, e.g., gas chromatography, can be employed to ascertain the concentrations of HFC-245fa and/or HCFC-235fa so as to avoid an excessively high ratio of chlorine to HFC-245fa.
Preferably the reaction is carried out in a substantially oxygen-free environment. This can be accomplished by, for example, flushing the reactor with an inert gas such as nitrogen, helium, argon, etc., prior to carrying out the reaction; nitrogen is preferred. It is expected that such an inert gas is itself substantially free of oxygen. Suitable commercial nitrogen is available that contains from about 100 ppm to about 2 wt. % oxygen and at levels in between including 0.1, 0.2, 0.5 and 1 wt. % oxygen. Nitrogen containing the lowest oxygen level commensurate with good economics should be used for the process. If nitrogen is used to flush the system, the nitrogen is preferably flushed from the reactor, e.g., with chlorine and/or HFC-245fa, before the reactants are introduced and the actinic radiation is activated. Alternatively, the use of nitrogen or an inert gas can be avoided and the reactor can be flushed with chlorine and/or HFC-245fa prior to carrying out the reaction. In any event, it is preferred that the reactor be substantially free of inert gas at the start of the reaction. In this context, substantially free means that the reactor contains less than about 10 weight % inert gas; more preferably less than about 5%; still more preferably less than about 3%; for example from less than about 1% to about 2%. In the preferred method of carrying out the process of the present invention, the reaction is carried out in the substantial absence of an inert gas such as nitrogen or helium; in other words, only the reactants and products of the reaction are present in the reaction zone except for the possible presence of trace levels of an inert gas diluent, e.g., less than about 1 wt. % of such a material.
The pressure in the reaction zone is not a critical variable for the process of the present invention. For example, the pressure can vary from slightly less than ambient pressure of one atmosphere (about 101 kPa) to a pressure somewhat greater than one atmosphere; generally the process can be carried out under pressures of from about one atmosphere up to about 3.5 atmospheres (about 354 kPa). Suitable account should be taken of the fact that the reactants, the desired product CF3CH2CF2Cl, or HCFC-235fa, and by-product HCl can have significant vapor pressure. In particular, if the process is carried out in a closed system as a batch process, the changing amounts of reactants and reaction products should be taken into account to avoid excessive pressure build-up.
The source of irradiation for the photochlorination is not critical and it may be provided by any conventional source such as sun lamps, mercury vapor lamps (high, medium and low pressure types), bright incandescent and fluorescent lamps. Although any type of irradiation may be suitable, including visible light and ultraviolet light, ultraviolet light is preferred. The wavelength of the light can be from about 2000 to about 14500 Angstroms; for example from about 2500 to about 14000 Angstroms. The light source preferably radiates at from about 2700 Angstroms to about 5000 Angstroms; more preferably from about 2000 Angstroms to about 5000 Angstroms; most preferably from about 3000 Angstroms to about 4000 Angstroms. No advantage accrues from using radiation having wavelengths above about 5000 Angstroms.
As described above, the photochlorination reaction produces HCl in addition to the desired product. In one embodiment, following reaction or contact of the reactants in the presence of actinic radiation, the reactants and reaction products, including HCl, HCFC-235fa and possible multichlorinated products are contacted with an aqueous solution selected from the group consisting of a metal bisulfite, carbonate and hydroxide wherein the metal is selected from the group consisting of Group 1 and Group 2 according to the New Notation of the Periodic Table of the Elements. In particular, HCl can be removed from the product stream using conventional means such as absorption by a water or caustic scrubber, or distillation. The desired reaction product, HCFC-235fa can be separated from the overall reaction product stream or composition, which may include multichlorinated product, by using conventional means such as fractionation, distillation or liquid-liquid extraction. Unreacted HFC-245fa can be recycled back to the photochlorination reaction provided that it is treated to avoid undesirable impurities that may be present as a result of the separation processes, e.g., water. The effluent from the reactor also includes unreacted chlorine gas that can first be separated and purified by conventional methods and recycled.
All references herein to elements or metals belonging to a certain Group refer to the Periodic Table of the Elements as it appears in Hawley""s Condensed Chemical Dictionary, 13th Edition. Also, any references to the Group or Groups shall be to the Group or Groups as reflected in this Periodic Table of Elements using the xe2x80x9cNew Notationxe2x80x9d system for numbering groups.
The following examples are given as specific illustrations of the invention. It should be understood, however, that the invention is not limited to the specific details set forth in the examples. All parts and percentages in the examples, as well as in the remainder of the specification, are by weight unless otherwise specified.
Further, any range of numbers recited in the specification or paragraphs hereinafter describing or claiming various aspects of the invention, such as that representing a particular set of properties, units of measure, conditions, physical states or percentages, is intended to literally incorporate expressly herein by reference or otherwise, any number falling within such range, including any subset of numbers or ranges subsumed within any range so recited. The term xe2x80x9caboutxe2x80x9d when used as a modifier for, or in conjunction with, a variable, is intended to convey that the numbers and ranges disclosed herein are flexible and that practice of the present invention by those skilled in the art using temperatures, concentrations, amounts, contents, carbon numbers, and properties that are outside of the range or different from a single value, will achieve the desired result, namely, photochlorination process for the preparation of chlorinated HFC-245fa, or HCFC-235fa.