The invention relates to the use of variable speed control of the cooling fan on a variable speed oil-injected screw compressor. A screw compressor (11) comprises at least one stage of compression, each with a pair of rotors, variable speed compressor drive means (12), an oil reclaimer (13) from the compressed air and cooling apparatus (17) for cooling the oil extracted from the compressed air. The cooling apparatus comprises a heat exchange device and a fan (18) driven by a motor (19) which can be run at different speeds.

1. Field of the Invention
The invention relates to the use of variable speed control of the cooling fan on a variable speed oil-injected screw compressor.
2. The Prior Art
An oil-injected screw compressor comprising one or more stages of compression can be driven from a variable speed motor. The speed of the motor is controlled automatically to drive the compressor either at one of a series of pre-set speeds or to continuously adjust the speed so that the output volume of the compressor matches the demand.
The oil that is used to cool, lubricate and seal the compressor element is cooled in a radiator that uses ambient air as the cooling medium. A fan is used to pass air over the radiator. The term "oil" as used in this specifically also applies to, and is intended to cover, synthetic oils or other similar coolants.
Conventionally the fan is driven by a fixed speed electric motor, which runs continuously whilst the compressor is running. A thermostatically controlled by-pass valve is generally used as a means of diverting the oil away from the radiator until the oil temperature reaches a certain value. The valve currently used is operated by a self-contained wax capsule. As the oil temperature increases, the wax expands and operates the valve to divert the oil through the radiator.
In a variable speed compressor the quantity of heat rejected to the cooling oil varies with the speed and pressure at which the compressor is running. As the speed or pressure is reduced, less power is required and therefore less heat is rejected to the oil. Whilst running under light load, or in cool conditions, there is a tendency for the oil to overcool causing moisture in the compressed air to condense. Over a period of time, this water accumulates in the oil system. If this is not regularly drained, water will circulate with the oil causing damage to bearings and corroding ferrous surfaces.
It is therefore an object of the present invention to overcome these disadvantages.
The invention therefore comprises a screw compressor comprising at least one stage of compression, each compressor stage comprising a pair of rotors, variable speed compressor drive means for driving at least one of said rotors to effect air compression, an oil reclaimer for extracting oil from the compressed air, cooling apparatus for cooling oil extracted from the compressed air, wherein said cooling apparatus comprises a heat exchange device and a fan driven by a motor which can be run at different speeds to provide cooling air to the heat exchange device, said motor being independent from said variable speed compressor drive means, the speed of the fan motor being controlled by a control unit, the control unit comprising processing means for processing signals generated by a plurality of devices monitoring operating parameters of the compressor, at least one of which monitoring devices monitors the speed of the variable speed compressor drive means, said processing means calculating the input power of the compressor using a combination of the speed measurement and torque of the variable speed compressor drive means, and adjusting the speed of the fan proportionally to the input power to balance the heat rejected to the cooling air with heat rejection to the oil.
Typically each compressor stage of a screw compressor 5 consists of a pair of helically fluted rotors supported at each end in rolling bearings. The following description covers the operation of a single stage compressor, but the invention applies in a similar manner to multi-stage machines. A variable speed motor 12 drives one rotor, which transmits the drive to the counter-rotating rotor. The variable speed motor 12 is used to drive the compressor 5 directly. An electronic control system continuously adjusts the speed of the compressors, within pre-set limits, so that the output flow matches the consumers demand to maintain the designated system pressure.
Air is drawn through an air filter 10 into the compressor by the action of the rotors. In the compression element 11, the air is compressed between the rotors and the casing. During this process oil, at a higher pressure than that of the air, is injected into the air through a port in the compressor casing. The oil cools, lubricates and seals the compressor element 11. The oil/air mixture is further compressed and is then discharged through a delivery port of the compression element 11 into an oil reclaimer 13. The oil is separated from the air in the reclaimer 13. The separated oil from the reclaimer 13 is then returned to the compression element 11 through an oil cooler, and an oil filter 20. The difference in air pressure between the reclaimer 13 and the injection point in the compression element 11 drives the oil through this circuit. The compressed air leaves the reclaimer 13 through a fine filter 14, a non-return valve 15 and, in most cases, an after-cooler 16.
The oil cooler comprises a radiator 17 and fan 18, which is driven by a motor and control unit 19.
The cooling oil is itself cooled in the radiator 17, which uses ambient air as a cooling medium. A fan 18 is used to pass a flow of air over the radiator 17.
A motor and control unit 19, drives the fan 18, which can be controlled to run automatically either at a number of different fixed speeds or the speed can be continuously varied, in response to control signals derived from certain parameters of the operating conditions of the compressor 5. This may be achieved by the use of one of the following alternatives:                i) a pole change (or similar) motor that can be switched to run at two or more speeds;        ii) an induction motor that can be run via an electronic drive at a number of pre-determined speeds or varied continuously in response to a control signal;        iii) a switched reluctance drive motor that can be run via an electronic drive at a number of pre-determined speeds or varied continuously in response to a control signal; or        iv) any other form of electric variable speed drive.
The operating parameters of the compressor 5 are continuously monitored by any appropriate monitoring devices. A monitor M1 monitors speed and torque of the motor of the compressor drive, a monitor M2 monitors the air pressure of the air delivery point of the compressor 5 or at the discharge point of the compressor 5, a monitor M3 monitors oil temperature at the oil cooler outlet, a monitor M4 monitors ambient temperature and a monitor M5 monitors air/oil delivery temperature of the compressor stages, in particular the final stage. Signals are generated by the monitoring devices, which are fed to the electronic controller of the motor and control unit 19 and are processed to enable the controller to adjust the fan speed to modify the heat energy being rejected from the oil to the cooling air. Essentially, by measuring the torque and speed of the compressor drive, the input power to the compressor 5 can be calculated, and the speed of the motor driving the fan 18 is adjusted proportionally to the input power, so that the heat rejected to the cooling air balances the heat rejection to the oil. The input power could, alternatively be measured electrically using a kilowatt transducer. Essentially, by measuring the torque and speed of the compressor drive, the input power to the compressor 5 can be calculated, and the speed of the motor driving the fan 18 is adjusted proportionally to the input power, so that the heat rejected to the cooling air balances the heat rejection to the oil. The input power could, alternatively be measured electrically using a kilowatt transducer.
The oil temperature at the oil cooler outlet, or other measured parameters, is used to further adjust the speed of the fan 18 to compensate for variations n ambient temperature, cooler efficiency and fan performance.
A variable speed drive used on a compressor 5 of this type offers significant efficiency improvements under part load conditions. This is because matching the output of the compressor 5 to the demand by controlling the speed is more efficient than other means of capacity control.
However to have the cooling fan 18 running at full speed (and power) irrespective of the compressor load reduces the overall efficiency improvement. A variable speed fan will mean that the fan 18 only consumes the amount of energy necessary to cool the compressor oil.
A secondary benefit is that reducing the speed of the fan 18 will reduce the noise level of the compressor 5.

Variable speed oil-injected screw compressors


In a process for isomerizing a feed comprising ethylbenzene and a mixture of xylene isomers, the feed is first contacted under xylene isomerization conditions with a first catalyst composition to produce an intermediate product having a higher para-xylene concentration than the feed, and then the intermediate product is contacted under ethylbenzene isomerization conditions with a second catalyst composition. The second catalyst composition comprises a hydrogenation-dehydrogenation component and a molecular sieve having 10-membered ring pores and is effective to selectively isomerize at least part of the ethylbenzene in the intermediate product to para-xylene and thereby produce a further product having a para-xylene concentration greater than the equilibrium concentration of para-xylene at said ethylbenzene isomerization conditions.

This invention relates to a process for the isomerization of xylenes and the selective conversion of ethylbenzene to para-xylene.
Para-xylene is a valuable chemical feedstock which may be derived from mixtures of C8 aromatics separated from such raw materials as petroleum naphthas, particularly reformates, usually by selective solvent extraction. The C8 aromatic fractions from these sources vary quite widely in composition but will usually be in the range of 10 to 32 wt. % ethylbenzene (EB) with the balance, xylenes, being divided approximately 50 wt. % meta and 25 wt. % each of para and ortho.
Individual isomer products may be separated from the naturally occurring mixtures by appropriate physical methods. Ethylbenzene may be separated by fractional distillation, although this is a costly operation. Orthoxylene may be separated by fractional distillation, and is so produced commercially. Para-xylene may be separated from the mixed isomers by fractional crystallization, selective adsorption, or membrane separation.
As commercial use of para-xylene has increased, combining physical separation with chemical isomerization of the other xylene isomers to increase the yield of the desired para-isomer has become increasingly important. However, since the boiling point of ethylbenzene is very close to those of para-xylene and meta-xylene, complete removal of ethylbenzene from the C8 aromatic feed by distillation is impractical. Hence an important feature of any commercial xylene isomerization process is the ability to convert ethylbenzene in the feed while simultaneously minimizing any conversion of xylenes to other compounds.
One commercially successful xylene isomerization process is described in U.S. Pat. No. 4,899,011 in which a C8 aromatic feed, which has been depleted in its para-xylene content, is contacted with a two component catalyst system. The first catalyst component selectively dealkylates the ethylbenzene to benzene and ethane, while the second component selectively isomerizes the xylenes to increase the para-xylene content to a value at or approaching the thermal equilibrium value. The first catalyst component comprises a Constraint Index 1-12 molecular sieve, such as ZSM-5, which has an ortho-xylene sorption time of greater than 50 minutes based on its capacity to sorb 30% of the equilibrium capacity of ortho-xylene at 120xc2x0 C. and an ortho-xylene partial pressure of 4.5xc2x10.8 mm of mercury, whereas the second component comprises a Constraint Index 1-12 molecular sieve which has an ortho-xylene sorption time of less than 10 minutes under the same conditions. Each catalyst component also contains a hydrogenation component, preferably a platinum group metal.
An improvement over the process of U.S. Pat. No. 4,899,011 is described in U.S. Pat. No. 5,689,027 in which the first catalyst component in the two component system is pre-selectivated by coking, or more preferably by deposition of a surface coating of silica, to increase its ortho-xylene sorption time to greater than 1200 minutes under the same conditions as cited in the ""011 patent. Using such a system it is found that high ethylbenzene dealkylation rates can be achieved with significantly lower xylene losses than obtained with the process of the ""011 patent.
One potential problem of these processes is that the ethylbenzene in the feed is converted via dealkylation to benzene and a C2 fraction. The benzene and C2 fraction must then either be separated from the process stream or converted. Refiners and petrochemical producers are therefore faced with large amounts of benzene by-product which, depending on market conditions, may bring prices below that of the desired xylene product.
Another approach to producing xylenes from a feed stream containing ethylbenzene involves converting the ethylbenzene by isomerization to xylenes. Octafining is one such process where ethylbenzene is converted to xylenes over a catalyst comprising platinum on silica-alumina. In Octafining, ethylbenzene reacts through ethyl cyclohexane to dimethyl cyclohexanes which in turn equilibrate to xylenes. However, competing reactions tend to result in significant losses of C8 aromatics and the amount of para-xylene in the product tends to be at or below equilibrium levels. In addition, catalyst activity tends to decline rapidly especially at high ethylbenzene concentrations in the feed.
U.S. Pat. No. 5,028,573 discloses a dual function composite catalyst for simultaneously isomerizing ethylbenzene and xylenes in a mixed C8 aromatic hydrocarbon feed, wherein the catalyst has an alpha value of 0.005 to 3 and comprises (a) a crystalline aluminosilicate zeolite having a low acid activity as measured by an alpha value of from 0.02 to 11, an average crystal size of not more than 0.4 microns for at least 50% by weight of the crystals, a silica to alumina ratio of at least about 12, a constraint index of about 1 to 12, a xylene sorption capacity greater than 1 gram per 100 grams of zeolite, and an orthoxylene sorption time for 30 percent of said capacity less than 10 minutes, said sorption capacity and sorption time being measured at 120xc2x0 C. and a xylene pressure of 4.5xc2x10.8 mm of mercury, and (b) a supported metal of Group VIII of the Periodic Table having a hydrogenation/dehydrogenation activity sufficient to provide the catalyst with a dehydrogenation activity of at least 10. The zeolite employed in the catalyst disclosed in U.S. Pat. No. 5,028,573 can include ZSM-5, ZSM-11, ZSM-12, ZSM-22, ZSM-23, ZSM-35 and ZSM-48, with ZSM-5 being particularly preferred.
EP-A-0136133 discloses a process for the isomerization of a feed containing an aromatic C8 mixture of ethylbenzene and xylene by which the paraxylene content is enhanced, said process comprising contacting the feed under conversion conditions with a catalyst comprising ZSM-23 zeolite having pores which are substantially unobstructed by silica.
EP-A-0151351 discloses a process for isomerizing ethylbenzene selectively to provide para-xylene comprising passing ethylbenzene and hydrogen under isomerizing conditions over a catalyst comprising: (a) ZSM-22 or ZSM-23 zeolite; and (b) a hydrogenation/dehydrogenation metal, wherein the hydrogenation/dehydrogenation metal is incorporated in the catalyst after any steaming of the catalyst.
U.S. Pat. No. 5,276,236 discloses that platinum-containing Mg/SAPO-31 can be effective in isomerizing ethylbenzene to xylenes in which the para-isomer is in excess of equilibrium concentration but where, as with most commercial feeds, ortho-xylene is also present, the para content in the product is always less than equilibrium.
Thus, while certain prior art processes have been successful in isomerizing ethylbenzene in a mixed C8 aromatic hydrocarbon feed, there remains a need for a process which has improved selectivity to para-xylene, especially in the presence of a feed containing ortho-xylene, and which can be operated with reduced loss of C8 aromatics.
The invention resides in a process for isomerizing a feed comprising ethylbenzene and a mixture of xylene isomers, said process comprising
(a) contacting said feed under xylene isomerization conditions with a first catalyst composition to produce an intermediate product having a higher para-xylene concentration than the feed, and then
(b) contacting at least part of said intermediate product under ethylbenzene isomerization conditions with a second catalyst composition comprising a hydrogenation-dehydrogenation component and a molecular sieve having 10-membered ring pores, said second catalyst composition being effective under said ethylbenzene isomerization conditions to selectively isomerize at least part of the ethylbenzene in said intermediate product to para-xylene and thereby produce a further product having a para-xylene concentration greater than the equilibrium concentration of para-xylene at said ethylbenzene isomerization conditions.
Conveniently, said contacting (a) converts less than 35 wt %, such as less than 20 wt %, of the ethylbenzene in the feed and said contacting (b) converts more than 35 wt %, such as at least 50 wt %, of the ethylbenzene in the intermediate product.
Conveniently, said second catalyst composition has an alpha value of about 0.1 to about 20, such as from about 1 to about 5.
In one embodiment, the second catalyst composition comprises about 0.01 to about 10 wt %, such as about 0.03 to about 3 wt. %, for example about 0.2 to about 1 wt. % of said hydrogenation component. Typically, the hydrogenation component comprises a Group VIII metal, such as platinum.
Conveniently, said molecular sieve is selected from SAPO-11, ZSM-23, ZSM-22, NU-87, ZSM-11, ZSM-50, ZSM-57, SAPO-41, and ZSM-48.
Conveniently, said feed contains about 20 to about 80 wt. %, for example about 25 to about 45 wt. %, of ethylbenzene.
Conveniently, said mixture of xylene isomers comprises less than 90 wt. %, such as less than 60 wt. %, of meta-xylene and conveniently contains about 10 to about 30 wt. % of ortho-xylene.
The present invention provides a two-stage process for isomerizing a feed comprising ethylbenzene and a mixture of xylene isomers, and typically a mixture of xylene isomers depleted in para-xylene. In the first stage of the present process, unlike the two-stage processes of U.S. Pat. Nos. 4,899,011 and 5,689,027, the feed is contacted with a first, xylene isomerization catalyst under xylene isomerization conditions to produce an intermediate product having a higher para-xylene concentration than the feed, preferably with little or no conversion of ethylbenzene in the feed.
In the second stage of the present process, at least part of the intermediate product is contacted with a second, ethylbenzene isomerization catalyst composition under ethylbenzene isomerization conditions so as to selectively isomerize at least part of the ethylbenzene in said intermediate product to para-xylene and thereby produce a further product having a para-xylene concentration greater than the equilibrium concentration of para-xylene at said ethylbenzene isomerization conditions. The second stage of the process is preferably accompanied by little or no isomerization of the xylenes in the intermediate product. The second catalyst composition comprises a hydrogenation-dehydrogenation component and a molecular sieve having 10-membered ring pores.
The present process maximizes the production of para-xylene and minimizes the conversion of C8 aromatics to higher and lower molecular weight products.
In general, the present invention relates to the isomerization of any feed containing ethylbenzene and xylene. In particular, the feed may be any C8 aromatic hydrocarbon feed containing ethylbenzene and a mixture of xylene isomers, such as the C8 fraction derived from catalytic reforming of a petroleum naphtha. Generally, such a feed will have an ethylbenzene content in the range of about 20 to about 80 weight percent, such as about 25 to about 45 weight percent, and the mixture of xylene isomers will contain less than 80 weight percent, such as less than 60 weight percent, of meta-xylene, from about 10 to about 30 orthoxylene and 0 to about 15 weight percent of para-xylene. In addition to the above aromatic C8 mixture, the feed may contain non-aromatic hydrocarbons, e.g., naphthenes and paraffins in an amount up to 30 weight percent.
For example, the feed to the present process may comprise ethylbenzene and a para-depleted mixture of xylenes produced by, for example, subjecting the feed to a para-xylene separation step, such as fractional crystallization.
The first catalyst composition employed in the present process is not critical but should be arranged to maximize the isomerization of ortho- and meta-xylenes in the feed to para-xylene, while minimizing the conversion of ethylbenzene.
Typically, the first catalyst composition will comprise an intermediate pore size molecular sieve having a Constraint Index within the approximate range of 1 to 12 (e.g., having a less pore size than about 7 Angstroms, such as from about 5 to less than about 7 Angstroms). The method by which Constraint Index is determined is described fully in U.S. Pat. No. 4,016,218, incorporated herein by reference for details of the method.
Examples of intermediate pore size molecular sieves useful in the first catalyst composition include ZSM-5 (U.S. Pat. No. 3,702,886 and Re. 29,948), ZSM-11 (U.S. Pat. No. 3,709,979); ZSM-12 (U.S. Pat. No. 3,832,449; ZSM-22 (U.S. Pat. No. 4,556,477); ZSM-23 (U.S. Pat. No. 4,076,842); ZSM-35 (U.S. Pat. No. 4,016,245); ZSM-48 (U.S. Pat. No. 4,397,827); ZSM-57 (U.S. Pat. No. 4,046,685); and ZSM-58 (U.S. Pat. No. 4,417,780). The entire contents of these patents are incorporated by reference herein.
Alternatively, the first catalyst composition may comprise a molecular sieve selected from MCM-22 (described in U.S. Pat. No. 4,954,325), PSH-3 (described in U.S. Pat. No. 4,439,409), SSZ-25 (described in U.S. Pat. No. 4,826,667), MCM-36 (described in U.S. Pat. No. 5,250,277), MCM-49 (described in U.S. Pat. No. 5,236,575) and MCM-56 (described in U.S. Pat. No. 5,362,697), with MCM-49 being particularly preferred. The entire contents of the above references are incorporated by reference herein.
The first catalyst composition may also include a hydrogenationdehydrogenation component, which may be the same material present in the second, ethylbenzene isomerization catalyst. If the same hydrogenationdehydrogenation component is used in both catalysts, typically this component is present in a lower amount in the first catalyst composition than in the second catalyst composition. More preferably, however, to reduce its ethylbenzene conversion activity, the first catalyst composition does not contain a hydrogenation-dehydrogenation component.
In addition, it may be desirable to combine the molecular sieve of the xylene isomerization catalyst with another material resistant to the temperature and other conditions of the process. Such matrix materials include synthetic or naturally occurring substances as well as inorganic materials such as clay, silica, and/or metal oxides. The metal oxides may be naturally occurring or in the form of gelatinous precipitates or gels including mixtures of silica and metal oxides. Naturally occurring clays which can be composited with the molecular sieve include those of the montmorillonite and kaolin families, which families include the subbentonites and the kaolins commonly known as Dixie, McNamee, Georgia and Florida clays or others in which the main mineral constituent is halloysite, kaolinite, dickite, nacrite or anauxite. Such clays can be used in the raw state as originally mined or initially subjected to calcination, acid treatment or chemical modification.
In addition to the foregoing materials, the molecular sieve may be composited with a porous matrix material, such as alumina, silica-alumina, silica-magnesia, silica-zirconia, silica-thoria, silica-berylia, silica-titania, as well as ternary compounds such as silica-alumina-thoria, silica-alumina-zirconia, silicaalumina-magnesia, and silica-magnesia-zirconia. A mixture of these components could also be used. The matrix may be in the form of a cogel. The relative proportions of molecular sieve component and inorganic oxide gel matrix on an anhydrous basis may vary widely with the molecular sieve content ranging from between about 1 to about 99 percent by weight and more usually in the range of about 10 to about 80 percent by weight of the dry composite.
The first catalyst composition typically has an alpha value of about 4 to about 1000, such as from about 5 to about 80, with the preferred value being inversely dependent on reactor temperature. The xe2x80x9calpha valuexe2x80x9d of a catalyst reflects the relative activity of the catalyst with respect to a high activity silicaalumina cracking catalyst. The alpha value test is described in U.S. Pat. No. 3,354,078; in the Journal of Catalysis, Vol. 4, p. 527 (1965); Vol. 6, p. 278 (13966); and Vol. 61, p. 395 (1980), each incorporated herein by reference as to that description. The experimental conditions of the test used herein include a constant temperature of 538xc2x0 C. and a variable flow rate as described in detail in the Journal of Catalysis, Vol. 61, p. 395. The higher alpha values correspond with a more active cracking catalyst.
Alpha values for aluminosilicate and silicoaluminophosphate molecular sieves can be controlled to within the above ranges by suitable selection of the SiO2/A12O3 ratio of the sieve, with higher ratios producing lower alpha values as well known in the art. It is also possible to adjust and in particular reduce the alpha value of a molecular sieve by subjecting the sieve to one or more acidity reducing treatments, such as by steaming, partial exchange with such cations as alkali metals, and like known sodium exchange techniques. Examples of such techniques are described in, for example, U.S. Pat. Nos. 3,899,544, 3,960,978, 3,965,209, 4,105,537 and 4,224,141, the entire contents of which are incorporated herein by reference.
The second catalyst composition is primarily intended to isomerize the ethylbenzene in the feed selectively to para-xylene, while minimizing isomerization of the xylenes in the feed. The second catalyst composition typically comprises a molecular sieve having unidimensional 10-membered ring pores. The phrase xe2x80x9cunidimensional 10-membered ring poresxe2x80x9d means that the pores of the molecular sieve are defined by 10-membered rings of tetrahedrally coordinated atoms which extend essentially in one dimension so that the pores are substantially free from any intersecting pores.
Examples of suitable molecular sieves having unidimensional 10-membered ring pores include SAPO-11, ZSM-23, ZSM-22, NU-87, ZSM-11, ZSM-50, ZSM-57, SAPO-41, and ZSM-48. SAPO-11 and a method of its synthesis are described in U.S Pat. No. 4,440,871. ZSM-23 and a method of its synthesis are described in U.S Pat. No. 4,076,842. ZSM-48 and a method of its synthesis are described in U.S Pat. No. 4,397,827. Each of these patents is incorporated herein by reference.
The molecular sieve of the second catalyst composition typically has an alpha value of about 0.1 to about 20, for example from about 1 to about 5.
The molecular sieve used in the second catalyst composition is associated with a hydrogenation-dehydrogenation component. Examples of such components include the oxide, hydroxide, sulfide, or free metal (i.e., zerovalent) forms of Group VIII metals (i.e., Pt, Pd, Ir, Rh, Os, Ru, Ni, Co and Fe), Group VIB metals (i.e, Cr, Mo, W), Group IVA metals (i.e., Sn and Pb), Group VA metals (i.e., Sb and Bi), and Group VIIB metals (i.e., Mn, Tc and Re). Combinations of catalytic forms of such noble or non-noble metals, such as combinations of Pt with Sn, may be used. The metal is preferably in a reduced valence state. The reduced valence state of the metal may be attained, in situ, during the course of the reaction, when a reducing agent, such as hydrogen, is included in the feed to the reaction. Treatments such as coking or sulfiding may also be employed, especially at the start of a run with fresh catalyst, to modify the catalytic performance of the metal.
In one practical embodiment, the hydrogenation-dehydrogenation component is a noble metal (i.e., Pt, Pd, Ir, Rh, Os and Ru) and particularly is platinum.
The hydrogenation/dehydrogenation component may be incorporated into the catalyst by methods known in the art, such as ion exchange, impregnation or physical admixture. For example, solutions of appropriate metal salts may be contacted with the remaining catalyst components, either before or after selectivation of the catalyst, under conditions sufficient to combine the respective components. The metal containing salt is conveniently water-soluble. Examples of such salts include chloroplatinic acid, tetraamineplatinum complexes, platinum chloride, tin sulfate and tin chloride. The metal may be incorporated in the form of a cationic, anionic or neutral complex such as Pt(NH3)42+and cationic complexes of this type will be found convenient for exchanging metals onto the molecular sieve. For example, a platinum modified catalyst can be prepared by first adding the catalyst to a solution of ammonium nitrate in order to convert the catalyst to the ammonium form. The catalyst is subsequently contacted with an aqueous solution of tetraamine platinum(II) nitrate or tetraamine platinum(II) chloride. Anionic complexes such as the metatungstate, permanganate or perrhenate ions are also useful for impregnating metals onto the molecular sieves. After incorporation of the metal, the catalyst can then be filtered, washed with water and calcined at temperatures of from about 250 to about 500xc2x0 C.
The amount of the hydrogenation-dehydrogenation component is suitably from about 0.001 to about 10 percent by weight, e.g, from about 0.03 to about 3 percent by weight, such as from about 0.2 to about 1 percent by weight of the total catalyst although this will, of course, vary with the nature of the component, with less of the highly active noble metals, particularly platinum, being required than of the less active base metals.
The second catalyst composition may also include a binder and/or matrix material which may be the same as, or different from, any binder and/or matrix material contained by the first catalyst composition. In particular, the binder in the second catalyst composition may be a zeolitic material such that the second catalyst composition comprises a so-called xe2x80x9czeolite-bound zeolitexe2x80x9d as described in, for example, U.S. Pat. No. 6,517,807, the entire contents of which are incorporated herein by reference. Thus, the second catalyst composition may comprise a core zeolite having unidimensional 10-membered ring pores, such as ZSM-48, bound with a high silica binder which is at least partly converted to a high silica zeolite (such as ZSM-5 or ZSM-48) which at least partly covers the surface of the core zeolite. By ensuring that the zeolitic binder has a higher silica to alumina molar ratio than the core zeolite, the binder can lower the surface activity of the core zeolite and hence reduce any unwanted xylene isomerization which would otherwise occur at the surface of the core zeolite.
In general, the second catalyst composition is different from the first catalyst composition, for example by containing a different molecular sieve, having a lower alpha value and/or by containing more or a more active hydrogenation/dehydrogenation component. Process Conditions
The conditions employed in the xylene isomerization stage of the present process are not narrowly defined but generally include a temperature of from 250 to about 600xc2x0 C., a pressure of from about 0 to about 500 psig (100 to 3550 kPa), a weight hourly space velocity (WHSV) of between about 0.05 and about 50 hrxe2x88x921, and a hydrogen, H2, to hydrocarbon, HC, molar ratio of between about 0.05 and about 20. Typically, the xylene isomerization step is conducted in the liquid phase under conditions including a temperature of from about 250 to about 400xc2x0 C., a pressure of from about 50 to about 400 psig psig (445 to 2870 kPa), a WHSV of between about 1 and about 10 hrxe2x88x921, and a H2 to HC molar ratio of between about 1 and about 10. In general, the conditions employed in the xylene isomerization stage are such as to convert less than 35 wt. %, and more typically less than 20 wt. %, of the ethylbenzene in the feed and to produce a para approach to equilibrium (PATE) greater than 80% (preferably greater than 95%). PATE defined as:
(PXPRODUCTxe2x88x92PXFEED/PXEQUILIBRIUMxe2x88x92PXFEED)xc3x97100
where PXPRODLJCT is the percent para-xylene in the isomerization product by weight of the total xylenes in the product;
where PXFEED is the percent para-xylene in the isomerization feed by weight of the total xylenes in the feed; and
PXEQUILIBRIUM is the percent para-xylene by weight of the total xylenes in an equilibrium mixture of xylenes at the reactor temperature.
The conditions used in the ethylbenzene isomerization stage are also not narrowly defined, but generally include a temperature of from about 250 to about 600xc2x0 C., a pressure of from about 0 to about 500 psig (100 to 3550 kPa), a weight hourly space velocity (WHSV) of between about 0.01 and about 20 hrxe2x88x921, and a hydrogen, H2, to hydrocarbon, HC, molar ratio of between about 0.05 and about 20. Typically, the conditions include a temperature of from about 400 to about 500xc2x0 C., a pressure of from about 50 to about 400 psig (445 to 2870 kPa), a WHSV of between about 1 and about 10 hrxe2x88x921, and a H2 to HC molar ratio of between about 1 and about 10. In general, the conditions are selected so that the ethylbenzene conversion per pass is greater than 35% and typically greater than 45%.
In general, the xylene isomerization step and the ethylbenzene isomerization step of the present process are carried out in fixed bed reaction zones containing the catalyst compositions described above. The reaction zones may be in sequential beds in a single reactor, with the ethylbenzene isomerization catalyst being located downstream of the xylene isomerization catalyst and with the feed being cascaded from the first to the second bed without intervening separation of light gases. As an alternative, the ethylbenzene isomerization catalyst and the xylene isomerization catalyst can be disposed in separate reactors which, if desired, can be operated at different process conditions, in particular with the temperature of the ethylbenzene isomerization reactor being higher than that of the xylene isomerization reactor.
In a further embodiment, the process can comprise three or more stages, with a first xylene isomerization stage using the first catalyst composition described above, a final ethylbenzene isomerization stage using the second catalyst composition described above and at least one intermediate stage using a mixture of the first and second catalyst compositions.
The isomerization product can be treated to isolate para-xylene and/or other desirable xylene(s). Thus, for example, the isomerized product can be fed to a variety of para-xylene recovery units, such as a crystallizer, a membrane separation unit, or a selective adsorption unit, and thus the para-xylene may be isolated and recovered. The residual isomerizate can be stripped of products lighter than C8. Products heavier than C8 in the residual isomerizate can be further processed or may be fractionated out. C8 fractions from which para-xylene has been removed can be recycled to the process. Napthenes are typically recycled to extinction in the process of the invention.
Using the process of this invention, it is found that the ethylbenzene in a feed containing a mixture of xylenes in which the meta-xylene content is less than 90% can be selectively converted to para-xylene such that the para approach to equilibrium (PATE) is in excess of 105%. In addition, the amount of conversion of ethylbenzene to benzene and light products is minimized and typically is less than 20 weight percent, such as less than 10 weight percent.
The invention will now be more particularly described with reference to the accompanying Examples.

Isomerization of ethylbenzene and xylenes


A gamma-melanocyte stimulating hormone (γ-MSH) derivative having improved stability, selectivity and bioavailabilty. The γ-MSH derivative is selective for the melanocortin-1 receptor (MC1 R) and is deliverable to skin cells via topical or transdermal delivery. The γ-MSH derivative is made up of naturally occurring amino acids for stimulating melanin from within for photoprotection of human skin against ultraviolet radiation damage.

There is a critical medical need for prevention of skin damage and development of melanoma and other cancer cells in the human skin caused by ultraviolet (UV) chemical damage to DNA in the cell. Skin cancer is the most commonly diagnosed cancer in the US, and an estimated 76,380 new cases of melanoma will be diagnosed in the US in 2016. Current efforts to prevent UV damage to human skin, which in many cases leads to melanoma and other skin cancers, is primarily limited to using lotions containing organic compounds that absorb light in the UV absorption regions of the electromagnetic spectrum (200-800 nM). Although this approach has some success, the use of lotions is an overall failure due to the inadequacies of the lotions or the improper or inadequate use of these lotions. It has been observed that when dark- and light-skinned persons both spend significant time in the sun, dark-skinned persons have a much lower risk of developing melanoma. Internally simulated photo-protection of human skin would provide a more effective path to sun protection and cancer prevention than currently available via sunscreen lotions.
Melanocyte stimulation hormones (MSH), also known as melanotropins, are products of the natural precursor protein, propiomelanocortin (POMC), which is found in all terrestrial animal life and is responsible for both skin and hair color in animal life. MSH consists of α-melanocyte-stimulating hormone (α-MSH), β-melanocyte-stimulating hormone (β-MSH), and γ-melanocyte-stimulating hormone (γ-MSH). The melanocortin 1 receptor (MC1R), also known as a melanocyte-stimulating hormone receptor, a melanin-activating peptide receptor, or a melanotropin receptor, is a protein that can bind to MSH, and is known to regulate pigmentation for the skin. When MC1R is activated, it can trigger melanocytes to produce eumelanin, which is a type of melanin that can protect the skin from damage caused by UV radiation in sunlight. The γ-MSH is one of a family of naturally occurring peptide hormones that are released by skin cells in response to the damaging rays of UVR. Because γ-MSH has higher affinity for MC1R, while showing less affinity for MC3R, MC4R, and MC5R receptors, it almost exclusively induces melanin production. As it is more selective for MC1R, γ-MSH can have less negative side effects than the other family members, α-MSH and β-MSH.
The present invention features organic peptides related to the melanocyte stimulation hormone. These compounds are the most selective for the relevant hMC1R. The target peptide γ-MSH is modified to improve its properties as a cancer preventive to make γ-MSH more stable, more MCR1 selective, and more readily bioavailable for topical or transdermal delivery.
Studies have shown that "skin tanning (pigmentation)" by the native hormone α-MSH and especially by a more stable analogue [Nle4, D-Phe7] α-MSH (NDP-α-MSH) protects against UV damage to the skin of normal humans, including those who do not pigment well in response to UV radiation (UVR). Hence, the present invention provides an innovative approach to promote the natural pigmentation of skin without exposure to sunlight with a peptide ligand that is selective for the hMC1R and therefore will have no side effects (toxicities). Moreover, because the present invention internally stimulates photo-protection of human skin, it provides a more effective path to UVR protection and cancer prevention than the protection currently available from commercial chemical sunscreens (lotions, sprays, etc.) and it does not rely on multi or daily reapplications.
Any feature or combination of features described herein are included within the scope of the present invention provided that the features included in any such combination are not mutually inconsistent as will be apparent from the context, this specification, and the knowledge of one of ordinary skill in the art. Additional advantages and aspects of the present invention are apparent in the following detailed description and claims.

Enhanced melanoma cancer prevention by novel melanotropins

ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIVERSITY OF ARIZONA


The instant invention is directed toward a process for the production of a sterile, stabilized nanodispersion or loaded micelle comprising a polymer and a biologically active composition; particularly to nanodispersions produced by rehydration of a freeze-dried cake produced via the direct lyophilization of a stabilized solution comprising a polymer, such as an amphiphilic block copolymer or a small molecular weight surfactant, a biologically active agent, an optional additive, and a suitable solvent.

This application relates to sterile, stabilized nanodispersions or micelles comprising a polymer and a biologically active composition; particularly to nanodispersions or micelles produced by rehydration of a freeze-dried cake produced via the direct lyophilization of a solution comprising a dispersing agent such as an amphiphilic block copolymer, or a small molecular weight surfactant, a biologically active composition, a suitable solvent, and optionally, an additive.
Many important biologically active agents, such as drugs, are hydrophobic and have limited solubilities in water. In order to attain the expected therapeutic effect of such agents, it is usually required that a solubilized form or nanodispersed form of the agent be administered to a patient.
Thus, a number of methods have been developed which are based on the use of auxiliary solvents; surfactants; soluble forms of the drug, e.g., salts and solvates; chemically modified forms of the drug, e.g., prodrugs; soluble polymer-drug complexes; special drug carriers such as liposomes; and others. Indeed, the use of amphiphilic block copolymer micelles has attracted a great deal of interest as a potentially effective drug carrier which is capable of solubilizing a hydrophobic drug in an aqueous environment.
Each of the above methods is hampered by one or more particular problems, e.g., the method based on the use of surfactant micelles to solubilize hydrophobic drugs has problems in that some of the surfactants are relatively toxic and that precipitation of hydrophobic drugs occurs when subjected to dilution.
A variety of methods and procedures have been described in the prior art for preparing nanodispersions of hydrophobic compounds, particularly pharmaceutical preparations. It is known to incorporate hydrophobic biologically active agents having limited solubility in an aqueous or hydrophilic environment into block copolymers which form micelles capable of acting as carriers for the biologically active agents.
A variety of methods have been utilized, either alone or in combination, in order to incorporate or solubilize one or more biologically active agents, within polymer carriers. Included among these prior art methods are:
(1) Stirring
This method consists in adding the drug to a polymeric micelle solution and permitting the drug to dissolve in the micellar core. Such a procedure yields generally poor entrapment efficiency mainly because of the poor affinity of the drug for the aqueous medium. The water solution can then be freeze dried;
(2) Heating
A drug and a block copolymer are dissolved in an organic solvent and the solvent is evaporated off at an elevated temperature (from about 40xc2x0 C. to about 80xc2x0 C. under a nitrogen atmosphere or by rotary evaporator under vacuum). The resulting mixture is kept at a temperature of 20xc2x0 C. to about 80xc2x0 C., preferably at about 40-70xc2x0 C., for 2 hours. Then, warm water (about 40xc2x0 C. to about 70xc2x0 C.) is added thereto, and the mixture is stirred until a polymeric micelle containing drug is formed.
(3) Ultrasonic Treatment
A mixture of a drug and an aqueous solution of a block copolymer is subjected to ultrasonic treatment for a period ranging from about 1 second to 1 hour and then stirred at room temperature to obtain micelles containing the drug.
(4) Solvent Evaporation
A drug is dissolved in a water-immiscible organic solvent, for example, dichloromethane, chloroform and the like, and then added to an aqueous solution of a block copolymer. Subsequently, the organic solvent is slowly evaporated off, e.g. at 25-40xc2x0 C. while stirring, optionally under vacuum, and then filtered to remove undissolved drug.
(5) Dialysis
A drug and a block copolymer are dissolved in a water-miscible organic solvent. The solution is dialyzed against a buffer solution and then against water.
In the dialysis method, suitable water-miscible organic solvents for dissolving drugs may include members selected from the group comprising acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, dimethylacetamide (DMAC) and the like.
The unloaded drug can diffuse with the organic solvent and/or precipitate in the dialysis bag. The precipitated drug can be removed by filtration. The colloidal dispersion is then generally freeze-dried.
(6) Emulsification-Evaporation/Salting Out Procedure
The drug and polymer are dissolved in a water-immiscible organic solvent which is emulsified in water. The aqueous phase may or may not contain stabilizers. The organic solvent is then removed by evaporation or other methods. If needed, the nanodispersion can be further purified to remove the stabilizers. Then, the colloidal dispersion can be freeze-dried.
(7) Spray-Drying
The drug is dissolved in an organic solvent which is then nebulized so as to obtain drug loaded nanoparticles. Such a process may not be adapted for temperature-sensitive drugs and is not optimal to produce particles of less than 1 xcexcm.
(8) Micronization/Controlled Precipitation/High Pressure Homogenization
These methods are aimed at producing nanoscaled drug dispersions. Such techniques can be applied to almost any kinds of hydrophobic drugs. All require specific specialized equipment and/or are difficult to control.
Each of the above procedures are associated with certain drawbacks. For example, with some of the procedures the stabilizers need to be removed. Others yield poor entrapment efficiencies (e.g. equilibration), relatively large particle sizes (e.g. spray drying) or are time-consuming (e.g. dialysis).
Many studies, literature articles and patents have been directed toward the use of amphiphilic block copolymers having surfactant-like properties, particularly regarding their use as carriers for hydrophobic drugs.
For example, EP No.0397307A2 discloses polymeric micelles of an AB type amphiphilic diblock copolymer which contains poly(ethylene oxide) as the hydrophilic component and poly(amino acid derivatives) as the hydrophobic component, wherein therapeutically active agents are chemically bonded to the hydrophobic component of the polymer.
EP No. 0583955A2, on the other hand, discloses a method for physically incorporating hydrophobic drugs into amphiphilic diblock copolymer micelles described in EP No. 0397307A2. This method, thus, solves the above disadvantage of the chemical bond type polymeric micelle drug
U.S. Pat. No. 4,745,160 discloses a pharmaceutically or veterinary acceptable amphiphilic, non-cross linked linear, branched or graft block copolymer having polyethylene glycol as the hydrophilic component and poly(D-, L- and DL-lactic acids) as the hydrophobic components. In the preparation process, a water-miscible and lyophilizable organic solvent is used. When a mixture of the polymer, drug and organic solvent is mixed with water, precipitates are formed and then the mixture is directly lyophilized to form particles. Thereafter, when this particle is dispersed in water, it forms a colloidal suspension containing fine particles wherein hydrophilic components and hydrophobic components are mixed.
In contrast to that which is disclosed in the prior art, the present invention forms a clear solution that can be sterilized by filtration (220 nm pore size filter) prior to freeze-drying, and yields a storable powder which is readily reconstituted. What is particularly unique, is that the micelle or nanodispersion is produced directly and spontaneously upon addition of an aqueous medium. This is in direct contrast to prior art processes which must first produce a nanodispersion which is subsequently lyophilized and then reconstituted. Furthermore, the instant process suffers no loss of drug during the loading procedure.
U.S. Pat. No. 6,322,805 discloses a biodegradable polymeric drug carrier micelle composition capable of solubilizing a hydrophobic drug in a hydrophilic environment. The patent discloses a biodegradable polymeric drug carrier micelle and a hydrophobic drug wherein the drug is physically trapped within and not covalently bonded to the polymeric drug carrier micelle. The drug carrying micelle is capable of dissolving in water to form a solution thereof, and the drug carrier comprises an amphiphilic block copolymer having a hydrophilic poly(alkylene oxide) component, and a biodegradable hydrophobic polymer component selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(xcex5-caprolactone), a derivative thereof and a mixture thereof. The disclosed micelle is characterized as a solubilizing agent for a hydrophobic drug. The drug solution thus obtained may be freeze-dried for long-term storage, and the lyophilized biodegradable polymeric micelle-type drug composition may be restored to its original solution by using water or an isotonic solution. This patent also fails to disclose or suggest a process wherein a sterile nanodispersion is spontaneously created upon reconstitution of a lyophilized cake.
U.S. Pat. No. 5,543,158 discloses nanoparticles or microparticles formed of a block copolymer consisting essentially of poly(alkylene glycol) and a biodegradable polymer, poly(lactic acid). In the nanoparticle or microparticle, the biodegradable moieties of the copolymer are in the core of the nanoparticle or microparticle and the poly(alkylene glycol) moieties are on the surface of the nanoparticle or microparticle in an amount effective to decrease uptake of the nanoparticle or microparticle by the reticuloendothelial system. In this patent, the molecular weight of the block copolymer is too high to be soluble in water, and a nanoparticle can only be prepared by first dissolving the block copolymer and a drug in an organic solvent, forming an o/w emulsion by sonication or stirring, and then collecting the precipitated nanoparticles containing the drug. The patent fails to provide the concept of solubilization of hydrophobic drugs, nor does it teach or suggest the formation of a clear, sterilizable solution containing the polymer/drug blend and subsequent lyophilization thereof, resulting in a readily dispersible nanodispersion, formed upon reconstitution.
EP 0520888 A1 discloses a nanoparticle made of a poly(lactic acid) and poly(alkylene oxide) block copolymer. A high molecular weight poly(lactic acid) is used and a surfactant is employed in preparing a colloidal suspension of the nanoparticles. In this patent, nanoparticles are prepared by dissolving the block copolymer and a drug in an organic solvent, emulsifying the organic solution in water, and evaporating the organic solvent to precipitate the nanoparticles containing the drug. The resulting nanoparticles are fine particles having both hydrophilic and hydrophobic components and they are not soluble in water.
U.S. Pat. Nos. 4,370,349 and 4,311,712 disclose a process for preparing a freeze-dried, potential liposome, mixture which comprises either (a) dissolving at least one liposome-forming amphiphilic lipid, at least one biologically-active compound, and optionally one or more adjuvants, in a suitable solvent, and then freeze-drying the solution, or (b) preparing by any known method an aqueous liposome composition containing at least one biologically-active compound, and then freeze-drying the said aqueous liposome composition. The patents are particularly directed toward a process for preparing an aqueous liposome composition which comprises dispersing said freeze-dried, potential liposome, mixture, obtained by procedure (a) or (b), in a suitable aqueous medium. The process of the instant invention is not directed toward liposome production.
The patents fail to disclose the formation of a clear solution that can be sterilized by filtration (e.g. by use of a filter media having a pore size of about 220 nm) prior to freeze-drying, yields a storable powder which is readily reconstituted, and suffers no loss of drug during the loading procedure. Furthermore, the patents fail to teach a method for producing a sterile drug formulation which, upon the addition of water, produces drug-loaded micelles or drug nanodispersions stabilized by an amphiphilic biodegradable polymer.
In order to overcome the problems encountered by the prior art, the instantly disclosed invention relies on the lyophilization of an organic solvent or mixture thereof, or a mixture of water and organic solvent in which the biologically active agent, e.g. a drug, the dispersing agent, e.g. a polymer, copolymer, small molecular weight surfactant, or the like, and optionally an additive, non-limiting examples of which include a bulk forming additive, a cryoprotectant, and a lyoprotectant, is dissolved. Such a solution can be sterilized by filtration before lyophilization and subsequently freeze-dried, forming a powder or cake. The resulting freeze-dried material can be stored and then redispersed prior to use by the addition of an aqueous solution. The organic solvent can be collected on the condenser and recycled for future use.
The instant process illustrates a simple and elegant procedure for directly obtaining nanodispersions upon reconstitution, thereby resulting in the formation of drug-loaded micelles or drug nanodispersions which are stabilized by a suitable dispersing agent, e.g. an amphiphilic biodegradable polymer or copolymer, or alternatively a small molecular weight surfactant. There is no loss of the drug during the loading procedure.
Examples of suitable dispersing agents include, but are not limited to amphiphilic polymers such as linear, branched or star-shaped block amphiphilic copolymers where the hydrophilic part may include at least one member selected from a group consisting of poly(ethylene oxide), poly(N-vinylpyrrolidone), poly(N-2-hydroxypropylmethacrylamide), poly(2-ethyl-2-oxazoline), poly(glycidol), poly(2-hydroxyethylmethacrylate), poly(vinylalcohol), polymethacrylic acid derivatives, poly(vinylpyridinium), poly((ammoniumalkyl)methacrylate), poly((aminoalkyl)methacrylate) and combinations and derivatives thereof;
and wherein the hydrophobic segment may include at least one member which is selected from a group consisting of a poly(ester), poly(ortho ester), poly(amide), poly(ester-amide), poly(anhydride), poly(propylene oxide), poly(tetrahydrofuran) and combinations thereof.
The poly(ester) may be at least one member selected from a group consisting of poly(xcex5-caprolactone), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), poly(hydroxy alkanoates) (e.g. poly (xcex3-hydroxybutyrate), poly(xcex4-hydroxy valerate)), poly (xcex2-malic acid), and derivatives thereof.
Non-limiting illustrative examples of low molecular weight surfactants may include at least one member selected from the group consisting of sodium lauryl sulfate, hexadecyl pyridinium chloride, polysorbates, sorbitans, poly(oxy ethylene) alkyl ethers, poly(oxyethylene) alkyl esters and the like, including various combinations thereof.
Without limiting the scope of the present invention, suitable biologically active agents for incorporation in a nanodispersion produced in accordance with the teachings of the instant invention may include agents such as anti-cancer drugs, antiphlogistic anodynes, immuno-suppressants, hepatism remedies, hormone compositions, chemotherapeutics, metabolic pharmaceuticals, digestive disease remedies, respiratory disease remedies, anti-allergic pharmaceuticals, central nervous system disease remedies, peripheral disease remedies, and circulatory disease remedies. In their broadest sense, the xe2x80x9cbiologically active agentsxe2x80x9d of the present invention will include both human and veterinary medicaments, hormones, marker compounds, and the like.
The instant invention is most suitable for the manufacture of formulations containing biologically active agents which are sensitive or which may be degraded by exposure to adverse pH, temperature, and certain types of solvent environments.
Hydrophobic drugs which are of particular interest for incorporation in the present invention may include, but are not limited to members selected from the group comprising paclitaxel, doxorubicin, melphalan, docetaxel, teniposide, etoposide, daunomycin, vinblastine, indomethacin, ibuprofen, cyclosporine, tacrolimus, ketoconazole, amphotericin B, fenobibrate and biphenyl dimethyl dicarboxylate(DDB).
Suitable solvents or mixtures thereof will have the ability to dissolve appropriate amounts of the drug, without denaturation or degradation thereof. Preferred solvents (or mixtures of solvents) should remain solid during the freeze-drying process and should be relatively inert with regard to rubber seals. The solvent should also be easily removed under reduced pressure. While numerous solvents are capable of functioning in accordance with the process of the instant invention, non-limiting illustrative examples of such solvents include t-butanol, n-butanol, dioxane, pyridine, pyrimidine, and piperidine ,which are useful either alone or in combination, and may be further admixed, e.g. with water, to form a binary mixture. It is known that the latter 4 solvents may pose potential toxicity problems.
Other solvents may be added in small amounts ( less than 10%) to facilitate the dissolution of the drug.
Accordingly, it is a principle objective of the instant invention to provide a process for the formation of a sterile, loaded micelle or nanodispersion comprising an amphiphilic biodegradable polymer.
It is a further objective of the instant invention to provide a process whereby a clear solution of the biologically active agent, polymer and optionally an additive (e.g. a bulk forming agent, a cryoprotectant, a lyoprotectant) and/or stabilizer is initially formed with a suitable solvent prior to lyophilization.
It is a further objective of the instant invention to provide a process whereby the solvent used in forming the clear solution is recyclable.
It is a still further objective of the invention to produce a stable freeze-dried cake which is readily dispersible to form a stabilized drug nanodispersion.
Other objectives and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying drawings wherein are set forth, by way of illustration and example, certain embodiments of this invention. The drawings constitute a part of this specification and include exemplary embodiments of the present invention and illustrate various objectives and features thereof.

Preparation of sterile stabilized nanodispersions


A novel tricyclodecanyl (meth)acrylate compound and a method of producing the same are provided. The compound is 8-alkyl-8-tricyclodecanyl (meth)acrylate represented by formula (1):

1. Field of the Invention
The present invention relates to a novel tricyclodecanyl (meth)acrylate compound and a method of producing the same, and more particularly, to 8-alkyl-8-tricyclodecanyl (meth)acrylates and a method of producing the same.
2. Description of the Related Art
Acrylates or methacrylates are useful monomers which are polymerized solely or copolymerized with other monomers to provide various kinds of polymers exhibiting excellent performance. The thus-produced polymers generally have excellent weather resistance and transparency. Also, according to the kinds of ester substituents, polymers of various performance levels can be produced. Specifically, in the case where the ester substituent is a bulky alicyclic compound which has low chemical reactivity, the polymers can be commercially used as various flame retardants and much attention is being paid to the production thereof.
However, conventional (meth) acrylate compounds having a bulky alicyclic substituent are cumbersome in view of reaction conditions, resulting in poor yield, and the purification thereof is difficult. Thus, it is quite difficult to produce the conventional (meth)acrylate compounds on a commercial scale.
To solve the above problems, it is an object of the present invention to provide an acrylate compound having a bulky substituent which can be produced and purified by a simplified process to be suitable for commercial-scale production.
It is another object of the present invention to provide a method for producing the acrylate compound.
Accordingly, to achieve the first object, there is provided 8-alkyl-8-tricyclodecanyl (meth)acrylate represented by formula (1):
wherein R1 is methyl or ethyl and R2 is hydrogen or methyl.
To achieve the second object, there is provided a method of producing the compound including the steps of a) synthesizing 8-alkyl-8-tricyclodecanol by reacting tricyclodecan-8-one with either an alkyl Grignard reagent or an alkyl lithium reagent, and b) synthesizing 8-ethyl-8-tricyclodecanyl acrylate by reacting the 8-alkyl-8-tricyclodecanol synthesized in the step a) with (meth)acryloyl chloride.
Preferably, the Grignard reagent is either alkyl magnesium bromide or alkyl magnesium chloride.
More preferably, if the alkyl is ethyl, ethyl magnesium bromide or ethyl magnesium chloride is used as the Grignard reagent.
In the production method of the acrylate compound according to the present invention, a separation process may be performed after each step is completed. However, the separation process may be performed after all steps are performed in situ.

8-alkyl-8-tricyclodecanyl (meth)acrylate and method of producing the same


A process is disclosed for the continuous transesterification of alkoxysilanes wherein an alkoxysilane is transformed to a different alkoxysilane in the presence of a catalyst and at least one alcohol that provides the different alkoxy group.

1. Field of the Invention
The present invention relates to a continuous transesterification process. More particularly, the present invention relates to a continuous transesterification process for the conversion of alkoxysilanes to different alkoxysilanes.
2. Description of Related Art
The major portion of the chemical industry involved in the production of organofunctional silicon compounds has been working on processes and products that do not involve the handling of hazardous chlorositanes as raw materials. The direct preparation of hydroalkoxysilanes from alcohols and silicon metal (see for example, U.S. Pat. No. 4,762,939) as shown in Reaction (I) avoids the preparation of chlorosilanes as was done in the older, two-step, process shown in Reactions (IIa) and (IIb), involving the preparation of trichlorosilane from hydrogen chloride and silicon metal followed by its esterification to the corresponding hydroalkoxysilane.
Hydroalkoxysilanes are useful in a variety of hydrosilation reactions, of the kind shown in Reaction (III), known to and practiced by those skilled in the art to provide commercially useful organofunctional silicon compounds:
where, for example, R is a hydrocarbon group or a substituted hydrocarbon group, Rxe2x80x2 is R, Rxe2x80x3 is H or R, and X is a functional group, including Cl, NH2, NHR, O2CCMexe2x95x90CH2, an epoxy-group containing moiety, and the like, and x is 1, 2, or 3.
Recent advances in the technology of hydrosilation reactions of hydroalkoxysilanes have provided such organofunctional silicon compounds in economically attractive yields (see, for example, U.S. Pat. Nos. 4,709,067, 5,041,595, and 5,559,264), overcoming earlier, well-recognized deficiencies, particularly for the hydrosilation of allyl chloride (U.S. Pat. No. 5,559,264).
Nevertheless, a problem remains in that the production efficiencies are highest when R is a methyl group, such that the ROH above is methanol, and the (RO)3SiH is trimethoxysilane, but various applications of organofunctional silicon compounds require other R groups derived from other alcohols for reasons of reactivity, stability, toxicity, volatility, solubility, and flammability, among others. Other R groups that are useful in products include ethyl, propyl, isopropyl, butyl, 2-methoxyethyl, and the like. Thus, there is a need in the industry for a highly efficient process for transforming lower alkoxy groups attached to silicon, such as methoxy groups, to higher alkoxy groups, such as ethoxy groups, to provide a variety of organofunctional silicon compounds as may be required for a particular use. There is also, on occasion, a separate need for the reverse process, i.e., the transformation of higher alkoxy groups to lower alkoxy groups. For reasons of high reaction rates, high efficiencies, and lower capital investments, such a process, heretofore known in the art only in batch or non-continuous modes, should be of a continuous nature. While continuous processes exist for the conversion of chlorosilanes to alkoxysilanes, e.g., esterification (Reaction (IIb) see, for example, U.S. Pat. Nos. 4,298,753 and 4,924,022), continuous technology does not appear to have been applied to transesterification, i.e., the replacement of one alkoxy group with another, even by organizations knowledgeable in continuous esterification technology (see U.S. Pat. No. 6,005,132 wherein the continuous removal of lower alcohol is disclosed, but the process itself is not continuous, i.e., all the higher alcohol is fed at once at the start). Batch transesterification is well known in the art, but is prone to long reaction times or lower efficiencies relating to the use of excess alcohol to provide the desired alkoxy group in a reasonable reaction time.
There is also a need to perform such continuous transesterification processes in giving consideration to minimized economics, including the minimized generation of hazardous wastes. This can be accomplished by the use of recycled raw materials and/or materials of lower purity, or through the performance of more than one process step concurrently, as by combining the neutralization of a feed stream with transesterification of the bulk of that stream, or by transesterification of more than one alkoxysilane concurrently, with later separation of the products, as by simple distillation.
The present invention provides a process for the conversion of alkoxysilanes to different alkoxysilanes, i.e., transesterification, that is efficient and continuous and can be practiced in commercially available equipment designed for continuous operation. The process comprises the reaction of an alkoxyorganosilicon compound containing at least one alkoxy group with one or more alcohols that provide different alkoxy groups on silicon according to Equation (IV).
wherein R and Rxe2x80x2 are independently selected from the group consisting of unsubstituted and substituted hydrocarbon moieties and are different from one another. The other three bonds on the silicon in Reaction (IV) can be to the same or other alkoxy groups, hydrocarbon groups, functionalized hydrocarbon groups (as in the products of Reaction (III), silicon-containing moieties, and even halogen groups (esterification of Si-halogen groups may occur concurrently with transesterification of alkoxy groups on silicon).
More particularly, the present invention is directed to a method for the continuous transesterification of alkoxysilanes comprising reacting at least one alkoxyorganosilicon compound containing at least one alkoxy group with at least one alcohol that provides at least one different alkoxy group on the silicon in the presence of an effective amount of an acidic or basic transesterification catalyst at an elevated temperature with continuous separation of product streams.
The process of the present invention is not narrowly limited and is thus applicable to a very large variety of alkoxyorganosilicon compounds, including monomeric silanes having one to four alkoxy groups, silanes containing more than one silicon atom, including oligomers and polymers, alkoxysiloxanes, and alkoxypolysiloxanes, as well as blends or mixtures thereof
The process of the present invention is a continuous process for the interconversion of alkoxysilanes, i.e., transesterification, according to the general Equation IV above. More specifically, when the alkoxysilane is a monomeric silane, said transesterification is expressed by Equation V, wherein R and Rxe2x80x2 are as defined above and R2 is the same as or different from R or Rxe2x80x2.
with the added proviso that R and Rxe2x80x2 contain no functional group that will not remain largely intact during the transesterification, and x is as defined above.
The process of the present invention can be performed in a variety of commercially available continuous units, including those typically used for continuous esterification, such as those described in U.S. Pat. No. 4,924,022, or in custom-designed commercial or laboratory scale units. Continuous stirred tank reactors, alone or in series, can be used, as can units designed for continuous countercurrent reactive distillation. Said units can be operated at or near atmospheric pressure, under vacuum, or under positive pressure; the choice being determined by the boiling points of the reactants and the desired operating temperature. The operating temperature will typically be an elevated temperature to maximize reaction rates and boiling point differences between reactants and products. Preferably, the elevated temperature is at least the boiling point of the lowest boiling alcohol at reaction pressure.
The catalysts operable in the present invention include those typically used for batch esterifications and transesterifications, i.e., acids and bases. The catalyst selection is determined in part by the alkoxysilane being transesterified. For example, an aminoalkylalkoxysilane would normally be transesterified with a basic catalyst, such as the corresponding sodium alkoxide, while a silane containing non-functional or base-sensitive alkyl or alkoxy groups would be transesterified with an acid catalyst, such as toluenesulfonic acid. When the concurrent neutralization or removal of halosilane groups is practiced, either an acid catalyst is used or sufficient base catalyst is employed to account for losses to reactions with halosilanes. The catalysts can be heterogeneous, in the form of pellets or beads, depending on equipment design, or homogeneous, i.e., completely soluble in the reaction medium. The concentration of the transesterification catalyst is not narrowly critical, and can be in the range of from about 0.001 to about 1.0% by weight relative to the alkoxyorganosilicon compound. Preferably, the transesterification catalyst is soluble in the reaction medium at a level of 0.001 to 1.0 % by weight of the alkoxyorganosilicon compound.
The alcohols used in the present invention include a wide range of hydroxyl-functional hydrocarbons, including methanol, ethanol, propanol, isopropanol, isomers of butanol, allyl alcohol, 2-methoxyethanol, benzyl alcohol, diols, and the like with the provisos that the alcohol must be stable under transesterification conditions and must not be so sterically hindered as to prevent reaction. When the lower and higher alcohols have boiling points that are relatively close, such as methanol and ethanol, the ethanol fed to the reactor can, if desired, contain some methanol, e.g., it may be a recycle stream or impure stream from some other process that is fed to the continuous reactor at a point where the reaction in progress contains both methanol and ethanol. Thus, the total feed of higher alcohol need not be high in purity to make pure products. The relative purities of the lower and higher alcohols may, as a practical matter, be determined by the purity needs of the products, and whether or not they are to be further purified, as by distillation. Typically, an excess of the transesterifying alcohol is used, and the excess can be up to 100% or more on a molar basis relative to the alkoxy groups being transesterified. This necessitates at least a partial purification of the continuously separated alcohol stream for purposes of recycling.
The alkoxysilane raw materials, as well as the alkoxysilane products, can be monomeric silicon compounds, dimers, trimers, oligomers, or polymers, and when not monomers, can contain the same or different siloxane units. Thus, any alkoxyorganosilicon compound known in the art can be considered to be within the contemplated application of the method of the instant invention, with the provisos that the compound should not contain functional groups that will not largely survive the transesterification reaction conditions, and the alkoxy group being transesterified must not be so sterically hindered so as to avoid reaction. Specifically included are the organofunctional trialkoxysilanes, the organofunctional alkyldialkoxysilanes, and the organofunctional dialkylalkoxysilanes.
The alkoxysilane raw materials can also be blends or mixtures and can contain impurities. For example, the alkoxysilane raw material can be the product stream from a different process, such as the product stream from the hydrosilation of allyl chloride with trimethoxysilane. This stream (see U.S. Pat. Nos. 5,559,264 and 6,015,920) is known to contain low levels of chlorosilyl groups and tetramethoxysilane in addition to product, 3-chloropropyltrimethoxysilane. When this stream is transesterified with ethanol, chlorosilyl groups are concurrently converted to ethoxysilyl groups and the resultant product becomes largely a mixture of tetraethoxysilane and 3-chloropropyltriethoxysilane, which can be purified as needed, as by distillation.
In a similar vein, tetramethoxysilane may be introduced, as a by-product from the direct reaction of methanol with silicon metal, with 3-chloropropyltrimethoxysilane to yield the same mixture of products. Alternatively, chlorosilyl groups may be present as an added raw material, such that reaction of a mixture of 3-chloropropyltrimethoxysilane and 3-chloropropyltrichlorosilane with ethanol to yield 3-chloropropyltriethoxysilane is within the scope of the instant invention.
In one aspect of the present invention, the alkoxyorganosilicon compound comprises a minor proportion of a halosilane group or a minor proportion of a halosilane compound.
In a preferred aspect of the present invention, the alkoxyorganosilicon compound is selected from the group consisting of sulfur-containing silanes and amino-group containing silanes.
It is recognized that for most functional silane products, the content of transesterified alkoxy groups may not be 100% of theory, and that there may be some low percentage of non-transesterified alkoxy groups. The allowable level will be determined by the performance requirements of a particular product.
While the process of the present invention does not inherently require a solvent, a solvent can present, and can assist the process as by forming lower boiling azeotropes with one or more of the reactants or products.
Those skilled in the art will recognize the very wide ranges of equipment, reactants, catalysts, and reaction conditions under which the process of the present invention can be practiced. It is also recognized that the transesterification reactions performed by the practice of the present invention need not be quantitative, and that products may contain minor amounts of the starting alkoxy groups. Owing to the continuous nature of the process of the present invention, product of lower purity can be reintroduced to the reactor to drive the transesterification more toward the desired product. Similarly, the mixed alcohol streams taken overhead can be separated by well-known methods to the extent desired and reused, further increasing process efficiency.

Continuous transesterification process for alkoxyorganosilicon compounds


A pharmaceutical composition for oral adminstration comprising a film-coated solid dosage form including 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide or a pharmaceutically acceptable salt or solvate thereof as active ingredient.

The present invention relates to a pharmaceutical composition containing as active ingredient 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide, in particular a composition for oral administration.
3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide, which may be represented by the formula (I)
and its physiologically acceptable salts and solvates are disclosed in UK Patent Specification No. 2162522. The compound of formula (I) exhibits selective vasoconstrictor activity and is useful in the treatment of migraine.
Oral administration constitutes the generally preferred route for administration of pharmaceuticals since this route is particularly convenient and acceptable to patients. Unfortunately oral compositions may be associated with certain disadvantages in the treatment of conditions associated with cephalic pain. For example, such conditions, particularly migraine are associated with gastrointestinal dysfunction in the form of delayed gastric emptying. This leads to both a delay and an impairment of drug absorption and it is generally accepted that oral formulations of drugs for the treatment of such conditions should be administered in the form of a liquid preparation.
Numerous clinical studies have demonstrated the effectiveness of the compound of formula (I) in migraineurs. Hitherto, the drug has always been administered either by parenteral injection or in the form of a dispersible tablet which is dispersed in drinking water prior to oral administration This mode of oral administration was believed to minimise the potential problems associated with gastrointestinal dysfunction in migraineurs.
However, it has been found that the compound of formula (I) has a particularly unpleasant taste. When the compound of formula (I) is administered orally this unpleasant taste may exacerbate the nausea and vomiting associated with migraine.
The present invention provides a particularly advantageous formulation suitable for oral administration of the compound of formula (I).
There is thus provided according to the invention a pharmaceutical composition for oral administration comprising a film-coated solid dosage form including 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide or a pharmaceutically acceptable salt or solvate thereof as active ingredient.
As used herein the term xe2x80x9cfilm-coated solid dosage formxe2x80x9d means a solid core comprising the active ingredient, which solid core is substantially covered with a film coating.
The compositions of the invention may comprise, for example, granules, tablets or capsules. Preferably the compositions of the invention will comprise tablets, most preferably compressed tablets.
There is provided in a preferred aspect of the invention a film coated tablet comprising a tablet core containing an effective amount of 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide or a pharmaceutically acceptable salt or solvate thereof as active ingredient and a film coat on the tablet core.
We have found that the unpleasant taste associated with oral administration of the compound of formula (I) is substantially eliminated by the formulations of the present invention. The film coating also makes the formulations easier to handle and reduces potentially hazardous dust formation occurring during the packaging or administration of the drug. Surprisingly these advantages are attained without any significant loss in the bioavailability of the compound of formula (I) when compared to aqueous solutions or dispersible tablet formulations for oral administration to migraineurs. Film-coated tablets according to the invention are therefore surprisingly effective in the treatment of migraine.
It is preferred that 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide should be employed in the compositions of the invention in the form of a physiologically acceptable salt. Such salts include salts of inorganic or organic acids such as hydrochloride, hydrobromide, sulphate, nitrate, phosphate, formate, mesylate, citrate, benzoate, fumarate, maleate, tartrate and succinate salts. Most preferably 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide will be employed in the compositions of the invention in the form of its succinate (1:1) salt.
The film coating comprises a polymer. Suitable polymers include cellulose ethers, for example, hydroxypropyl methylcellulose, hydroxypropyl cellulose or methylcellulose, and copolymers of methacrylic acid and methyl methacrylate.
Preferably the film coating will comprise hydroxypropylmethyl cellulose.
The total film coating solids are generally applied to the solid dosage form, for example the tablet core, in an amount of from 2 to 5% w/w, preferably from 3 to 4% w/w, based on the weight of the solid dosage form.
The film coating may additionally comprise any pharmaceutically acceptable colourants or opacifiers including water soluble dyes, aluminium lakes of water soluble dyes and inorganic pigments such as titanium dioxide and iron oxide. Suitable colourants or opacifiers may comprise from 5% to 65% w/w, preferably from 25 to 50% w/w, based on the dry weight of film coating.
The film coating may also contain one or more plasticizing agents conventionally used in polymeric film coatings, for example polyethylene glycol, propylene glycol, dibutyl sebecate, mineral oil, sesame oil, diethyl phthalate and triacetin. Suitable plasticizing agents may comprise 1 to 40% preferably 5 to 20% w/w based on the dry weight of the film coating.
In addition to the compound of formula (I) or a physiologically acceptable salt or solvate thereof, compositions of the invention will preferably comprise pharmaceutically acceptable carriers and excipients, such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, sucrose, mannitol, maize starch, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. stearic acid, polyethylene glycol, magnesium stearate, talc or silica); disintegrants (e.g. potato starch, sodium starch glycollate or croscarmellose sodium); or wetting agents (e.g. sodium lauryl sulphate).
For the preparation of compositions according to the invention 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide or a physiologically acceptable salt or solvate thereof may be blended with suitable excipients and, if desired, granulated. Preferably 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide will be granulated with a filler before admixture with the other excipients. Most preferably the filler employed will be lactose. Tablets in uncoated form may be prepared, for example, by compression of the powder blend or granulate, using a lubricant as an aid to tabletting. Compressed tablets are preferred.
The solid dosage form is then film-coated using a suspension comprising a suitable polymer in a suitable solvent. The preferred solvent for the film coating components is purified water but various classes of organic solvents commonly used in this art such as alcohols, ketones, ethers and chlorinated hydrocarbons, for example ethanol, acetone, methylene chloride and the like, may also be used. The solvent does not appear in the final product. The amount of solvent may be varied according to the equipment and coating conditions used to produce an aesthetically coated tablet.
The amount of 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide, preferably in the form of a physiologically acceptable salt, employed in the compositions of the invention will preferably be in the range of about 25 mg to about 200 mg, most preferably about 50 mg or 100 mg, expressed as the weight of free base.
A further aspect of the invention provides a method of treating a mammal, including man, suffering from or susceptible to conditions associated with cephalic pain such as cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders headache associated with substances or their withdrawal (for example drug withdrawal), tension headache and in particular migraine which comprises oral administration of a pharmaceutical composition comprising a film-coated solid dosage form of 3-[2-dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide or a pharmaceutically acceptable salt or solvate thereof as active ingredient. It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
It will be appreciated that the precise therapeutic dose of the active ingredient will depend on the age and condition of the patient and the nature of the condition to be treated and will be at the ultimate discretion of the attendant physician.
However, in general effective doses for the treatment of conditions associated with cephalic pain, for example acute treatment of migraine, will lie in the range of 10 to 500 mg, preferably 20 to 300 mg, most preferably 25 to 200 mg, for example 50 mg or 100 mg of the active ingredient per unit dose which could be administered in single or divided doses, for example, 1 to 4 times per day.

Abstract: The film-coated solid dosage forms are of use in the treatment of conditions associated with cephalic pain, in particular migraine.


An optical head for performing optical data operations relative to a medium includes a slider body and at least one lens. Positioned between the slider body and the lens is an aperture stop for blocking the transmittance of light. The aperture stop includes an opaque layer that circumscribes a transparent region.

The present invention relates to optical heads. In particular, the present invention relates to flying optical heads.
Optical data storage systems access data by focusing a laser beam or other light source onto a data surface of a medium and analyzing the light reflected from or transmitted through the medium. In general, data is stored in optical storage systems in the form of marks carried on the surface of the medium which are detected using a reflected laser light.
Compact discs, which are widely used to store computer programs, music and video, are one type of optical data storage system. Typically, compact discs are permanently recorded during manufacture by etching the surface of the compact disc. Another type of optical system is a write once read many (WORM) system in which a user may permanently write information onto a blank disc. Other types of systems are erasable, such as phase change and magneto-optic (M-O) systems. Phase change systems detect data by sensing a change in reflectivity. M-O systems read data by measuring the rotation of the incident light polarization due to the magnetic state of the storage medium.
The above systems require a beam of light to be focused on to a data surface of a disc. Storage density is determined not only by the size of the markings on the data surface, but also by the size of the beam focused on the surface (i.e., resolution). In general, the optics used to focus the beam on the surface can be divided into two groups: those with flying heads and those without flying heads. In those systems that do not use a flying head, a portion of the optics system typically moves radially over the disc to follow tracks on the disc. The moving portion of the optics is supported by a physical structure that extends over the disc. In systems with flying heads, the optics within the head are actually supported by a thin layer of fluid, typically air, that rotates with the disc. By flying on this thin layer of fluid, the optics of the head are positioned extremely close to the surface.
In both systems an objective lens is used to focus the light into a spot on the disc. In a system with a flying head, the objective lens is used in conjunction with a solid-immersion-lens or SIL. The objective lens focuses the beam into the SIL and the SIL reduces the beam spot size by virtue of wavelength reduction which occurs when light passes through optically dense media. Because it is on a flying head, the SIL is positioned very close to the data surface so that light from the SIL couples to the disc surface via evanescent waves.
In both optical systems, as light passes through the objective lens a portion of the light forms fringe fields around the perimeter of the otherwise focused beam. In systems where the objective lens and SIL do not fly over the medium, such as most compact discs, the objective lens is large enough that these fringe fields can be eliminated by coating the outer perimeter of the objective lens with a material that reflects or absorbs light. Alternatively, a separate piece may be inserted above the objective lens to block this extraneous light.
The coating method described above cannot be used with flying optical heads because the objective lens used in flying heads is too small and its hemispherical shape makes it difficult to properly align a mask for depositing material on the lens. Similarly, a separate piece cannot be added to the flying head to block the extraneous light because such a piece would add too much weight to the head.
An optical head for performing optical data operations relative to a medium includes a slider body and at least one lens. Positioned between the slider body and the lens is an aperture stop for blocking the transmittance of light. The aperture stop includes an opaque layer that circumscribes a transparent region.
In preferred embodiments, the aperture stop is deposited directly on the slider body through photolithography methods. The clear slider body allows the aperture stop to be aligned with a feature formed on the opposite side of the slider body.


A lane divider for fitting to a shelf having front and rear rails, including at least one elongated loop having front and rear ends and a member affixed to each of the front and rear ends of the elongated loop, the member including a face for engaging the front and rear rails, respectively, of the shelf, whereby when the elongated loop is dimensioned to be positioned with the faces of the members respectively engaging the rails.

1. Field of the Invention
This invention relates to commercial display refrigerators having glass doors for allowing viewing of merchandise contained within the refrigerator. More particularly, this invention relates to shelving that is employed within commercial display refrigerators on which the merchandise is placed for viewing by the consumers.
2. Description of the Background Art
Presently, display refrigerators are commonly used in retail stores such as grocery and convenience stores, for refrigerating merchandise such as beverages placed on shelving behind the glass doors allowing the discriminating shopper to view the merchandise while shopping. Once the selection is made, the shopper may then open the glass door and remove the product from the refrigerator.
There exists many different types of shelving. Shelving that is most commonly used for beverages, is tilted forwardly from the back to the front of the refrigerator. Further, such shelving is typically divided into lanes by means of lane dividers, the distances between which are dimensioned so as to accommodate beverages bottled in various type of containers. For example, one lane my be dimensioned for 12 ounce carbonated beverage cans of a particular brand and an adjacent lane for 16 ounce sports drink bottle.
As may be appreciated, as the consumer removes one of the beverages from a particular lane, the remaining beverages slide forwardly by gravity to the front of the shelf. Hence, all of the lanes remain xe2x80x9cfrontedxe2x80x9d with their respective beverages, thereby presenting an attractive presentation to the consumer.
Some lane dividers are formed of a rigid solid material that is injection molded or theretofore with pre-dimensioned lanes for standard sizes of beverages. These rigid lane dividers are then placed on top of the shelf or are integrally formed with the shelf itself. Unfortunately, most of these rigid lane dividers are not adjustable to accommodate different kinds of beverages and therefore are too restrictive to changes in merchandising plans that may occur from time to time. Others include divider plates that can be repositioned to a degree to form lanes. Representative rigid lane dividers are disclosed in U.S. Pat. Nos. 5,531,336, 5,197610, 5,417,333, 5,097,962, 5,050,748, 5,022,535, 4,801,025, 4,785,943, 4,785,945, 4,690,287, 4,454,948, 4,423,818, 5,088,607, 4,416,380 4,565,725, 4,454,949, 5,295,591 and 5,645,176, the disclosures of which are hereby incorporated by reference herein.
More contemporary lane dividers comprise wire-formed lane dividers that attach to the shelf by various means. Some attachments are fixedly-attached whereas others are adjustable. A representative wire lane divider is disclosed in U.S. Pat. No. 4,890,746, the disclosure of which is hereby incorporated by reference herein.
Wire lane dividers are often employed with a ridged xe2x80x9cslick sheetxe2x80x9d, typically composed of rigid plastic materials with friction-reducing compounds embedded in it, that is placed on the shelf. The beverages are then placed on top of the slick sheet in the desired lanes. The slick sheet more readily assures that the beverages are gravity-fed to slide down their respective lanes to the front of their shelf without sticking.
Unfortunately, wire lane dividers, particularly those that are adjustably-mounted, have a tendency to slide sideways, thereby squeezing the beverages in an adjacent lane and precluding them from sliding forward. Hence, there exists a need in the industry for wire lane dividers that are adjustable to various lane widths yet preclude sideways movement during use.
Therefore, it is an object of this invention to provide an improvement which overcomes the aforementioned inadequacies of the prior art devices and provides an improvement which is a significant contribution to the advancement of the shelving art in the field of commercial display refrigerators.
Another object of this invention is to provide a lane divider that may that be utilized in connection with various types of commercial display refrigerators.
Another object of this invention is to provide a lane divider that is adjustable to define differently-sized lanes so as to accommodate the shelving display of differently-sized beverages that are lined-up in their respective lanes on the shelf and are gravity-fed forwardly toward the front of the refrigerator display.
The foregoing has outlined some of the pertinent objects of the invention. These objects should be construed to be merely illustrative of some of the more prominent features and applications of the intended invention. Many other beneficial results can be attained by applying the disclosed invention in a different manner or modifying the invention within the scope of the disclosure. Accordingly, other objects and a fuller understanding of the invention may be had by referring to the summary of the invention and the detailed description of the preferred embodiment in addition to the scope of the invention defined by the claims taken in conjunction with the accompanying drawings.
For the purpose of summarizing this invention, this invention comprises a wire-formed lane divider for commercial display refrigerators. The lane divider of the invention is designed for adjustable use with conventional wire shelving including those employing slick sheets. Thus, the lane divider may be easily installed in conventional wire shelving at different lane widths so as to accommodate differently-sized beverages as may be desired for various merchandising plans. Further, the design of the lane divider of the invention precludes sideways shifting, thereby obviating the squeezing of the beverages in an adjacent lane that would otherwise occur upon such sideways shifting of the lane divider.
The lane divider of the invention, being formed by wire technology, is inexpensive to manufacture due to low tooling and material costs. Moreover, the employment of wire in the design permits the removal of the slick sheet for cleaning and to otherwise allow debris to fall through the shelving to the floor where it can be more easily cleaned up.
The foregoing has outlined rather broadly the more pertinent and important features of the present invention in order that the detailed description of the invention that follows may be better understood so that the present contribution to the art can be more fully appreciated. Additional features of the invention will be described hereinafter which form the subject of the claims of the invention. It should be appreciated by those skilled in the art that the conception and the specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims.

Lane dividers for commercial display refrigerators

Commercial Refrigerator Door Company, Inc.