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WO2003041848A2 - Appareil melangeur a usage pharmaceutique - Google Patents

Appareil melangeur a usage pharmaceutique Download PDF

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Publication number
WO2003041848A2
WO2003041848A2 PCT/NO2002/000417 NO0200417W WO03041848A2 WO 2003041848 A2 WO2003041848 A2 WO 2003041848A2 NO 0200417 W NO0200417 W NO 0200417W WO 03041848 A2 WO03041848 A2 WO 03041848A2
Authority
WO
WIPO (PCT)
Prior art keywords
mixing
rotor
stator
mixing apparatus
stators
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/NO2002/000417
Other languages
English (en)
Other versions
WO2003041848A3 (fr
Inventor
Tore Omtveit
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GE Healthcare AS
Original Assignee
Amersham Health AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amersham Health AS filed Critical Amersham Health AS
Priority to AU2002339773A priority Critical patent/AU2002339773A1/en
Publication of WO2003041848A2 publication Critical patent/WO2003041848A2/fr
Publication of WO2003041848A3 publication Critical patent/WO2003041848A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/05—Stirrers
    • B01F27/051—Stirrers characterised by their elements, materials or mechanical properties
    • B01F27/053—Stirrers characterised by their elements, materials or mechanical properties characterised by their materials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/27—Mixers with stator-rotor systems, e.g. with intermeshing teeth or cylinders or having orifices
    • B01F27/271—Mixers with stator-rotor systems, e.g. with intermeshing teeth or cylinders or having orifices with means for moving the materials to be mixed radially between the surfaces of the rotor and the stator
    • B01F27/2711—Mixers with stator-rotor systems, e.g. with intermeshing teeth or cylinders or having orifices with means for moving the materials to be mixed radially between the surfaces of the rotor and the stator provided with intermeshing elements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/80—Mixing plants; Combinations of mixers
    • B01F33/81—Combinations of similar mixers, e.g. with rotary stirring devices in two or more receptacles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/80—Mixing plants; Combinations of mixers
    • B01F33/81—Combinations of similar mixers, e.g. with rotary stirring devices in two or more receptacles
    • B01F33/811—Combinations of similar mixers, e.g. with rotary stirring devices in two or more receptacles in two or more consecutive, i.e. successive, mixing receptacles or being consecutively arranged
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
    • B01F2101/22—Mixing of ingredients for pharmaceutical or medical compositions

Definitions

  • This invention relates to improvements in and relating to mixing apparatus used for production of pharmaceutical compositions, e.g. emulsions, suspensions or dispersions, and to the process for preparation of such compositions.
  • the invention relates to apparatus for mixing of components, and to a process of mixing such components, wherein at least one of the components to be mixed has a low boiling point temperature.
  • the invention provides a solution to the problem associated with heat being generated during a mixing process and especially to how compositions with a high vapour pressure may be prepared using a mixing apparatus.
  • Much of the large-scale apparatus used in pharmaceutical production is made of stainless steel because of its chemical inertness, corrosion resistance, ease of production and simplicity of sterilisation.
  • An important group of apparatus used in the pharmaceutical industry is the conventional group of mixing apparatus, e.g. homogenizers, atomizers, sonicators, cap mixers, shakers, paddle mixers, blade mixers, static mixers, expansion nozzles, extruders and rotor stator mixers.
  • Such mixers may for instance be used in the preparation of emulsions, suspensions or dispersions.
  • Gas containing vesicles may readily be produced by shaking or sonicating a liquid containing a membrane- forming material in the presence of a suitable gas or gas-mixture.
  • a gas-precursor which is gaseous at body temperature, e.g. at 37 °C.
  • gas containing vesicles advantageously may be produced by passing a mixture of gas, liquid and vesicle membrane material through zones of a rotor stator apparatus in which the mixture is subjected to shear forces.
  • Rotor stator mixers are commonly used to produce emulsions from a mixture of immiscible liquids and/or gases.
  • the present invention provides important modifications and improvements to the mixing apparatus, especially to rotor stators, described in the WO 99/08782 document.
  • the vesicle yield can be improved if vesicle production is effected using a rotor-stator mixer, i.e. a mixer in which the starting mixture is passed through one or several zones in which shear forces are exerted upon it by relative rotation of two surfaces, one on an element referred to as a rotor and the other on an element referred to as a stator.
  • a rotor-stator mixer i.e. a mixer in which the starting mixture is passed through one or several zones in which shear forces are exerted upon it by relative rotation of two surfaces, one on an element referred to as a rotor and the other on an element referred to as a stator.
  • the yield was found to be improved if the relative speed of the rotor and stator surfaces exceeded 20 m s.
  • the stators and rotors had axially extending interlocking ridges and groves provided with radially extending fluid transmit means to define a plurality of shear force zones for fluid passing radially between the rotor and stator.
  • mixing apparatus such as rotor stators can generate a noticeable heating effect on components to be mixed, such as gas, gas-precursor, liquid and membrane forming material, and as vesicle size and stability may be affected by temperature
  • the apparatus was provided with temperature control means. It was further described that temperature control means may comprise thermostate-controlled heating or cooling means such as a cooling jacket surrounding the mixing chamber or alternatively a cooling element within or in thermal connection with the stator or the rotor.
  • a cooling element within or in thermal connection with the rotor drive shaft or the mechanical seal surrounding the rotor drive shaft could be included.
  • Such cooling elements could for example take the form of coolant coils surrounding or embedded in the component to be cooled or coolant fluid conduits or channels disposed in or in thermal connection with such components, e.g. within a drive shaft, on the side of a stator remote from its corresponding rotor, about the periphery of a stator, etc.
  • the temperature of the mixture could be monitored at the outlet of each mixing chamber or at the rim of the rotor and this may be used to control such temperature control means.
  • the rotors and stators were preferably made of stainless steel and optionally coated. A gold- coating of the rotors and/or stators to further improve the vesicle yield has been disclosed in WO 00/10697 of Nycomed Imaging AS.
  • a mixing apparatus can generate a noticeable heating effect during the mixing, and the heat from the apparatus will be transferred to the components being mixed in the apparatus.
  • components may start to boil and hence evaporate during the mixing process.
  • the boiling of the components will depend on both temperature and pressure in the system, hence it is important to control both these parameters during the mixing process.
  • the following invention provides a solution to the problem associated with heat generated during a mixing process and especially to how heating and evaporation of the components being mixed during a mixing process may be avoided.
  • stainless steel In conventional mixing apparatus for preparation of pharmaceutical compositions stainless steel has traditionally been used as the apparatus material. Steel is a metal composed of iron alloyed with various small percentages of carbon. Steel may be alloyed with other metals, as nickel, chromium, manganese, molybdenum etc., to produce specific properties, as hardness, corrosion resistance etc. Especially the content of carbon is varied to change the hardness of the alloy. Hence, an extensive list of different steel types is available. Reasons for using stainless steel in pharmaceutical mixing apparatus are its high strength, high stability, its inertness and its corrosion resistance. In addition it is relatively cheap and easily available.
  • a mixing apparatus for mixing of a composition comprising at least one volatile component
  • water is often used as a cooling media in pharmaceutical apparatus.
  • water, as a circulating cooling medium should have a temperature not below 4 °C, and at least not lower than 0 °C. If the cooling media has a lower temperature than 0 °C problems with freezing of apparatus parts or components to be mixed may be seen.
  • the composition to be prepared was preferably an emulsion with a high vapour pressure, and it was important to avoid evaporation of the emulsion, or components of this, during the mixing process. Insufficient cooling was experienced.
  • Several attempts to optimise the cooling system failed. It was acknowledged that steel is a too poor thermal conducting metal, and hence inefficient in heat transfer. The use of a mixing apparatus of stainless steel for mixing of volatile components does no enable a sufficient cooling of the apparatus and the components to be mixed.
  • composition comprising at least one volatile component
  • pharmaceutical apparatus for mixing of a composition comprising at least one volatile component could be prepared from a material having a substantially higher thermal conductivity than steel. It has been found that better cooling of the components to be mixed, and the product being prepared, can be achieved by increasing the thermal conductivity of the material constituting at least part of the mixing apparatus.
  • An aspect of the invention is hence a mixing apparatus for production of a pharmaceutical composition wherein the apparatus at least partly comprises a material that is hard, has high strength and a high thermal conductivity as defined below.
  • the invention provides a mixing apparatus at least partly comprising a material having the following properties at 100 °C:
  • the hardness of the material is given in HB, Brinell (-1/3 x Yield Strength MPa). More preferably the material has the following properties:
  • the material has the following properties: Thermal conductivity: 150-450 W ⁇ 'K "1 and Tensile strength: 400-600 MPa and Hardness: 120-180 HB
  • 316 stainless steel has the following properties at 100 °C: Thermal conductivity: 16.3 W/m-K, Tensile strength: 550 MPa, Hardness: 80 HB
  • stainless steel has a much lower thermal conductivity than requested, and hence does not fulfil the requirements to a material used in an apparatus for mixing of volatile components.
  • the apparatus material preferably comprises a metal, and more preferably it is an alloy.
  • composites i.e. certain polymers and ceramics, may have properties as requested in the invention. It has for instance been found that certain carbon fibres and pyrolytic graphite have extremely high thermal conductivity and tensile strength.
  • Noble metals such as gold and silver have high thermal conductivity properties.
  • Silver for instance, has a thermal conductivity of about 420 W ⁇ f'K "1 , the tensile strength is 325 MPa and the hardness is 90-100 HB.
  • a mixing apparatus at least partly made of silver or another noble metal forms a further aspect of the invention.
  • a noble metal, or the noble metals is modified with other metals.
  • Preferred additives are copper, titanium and nickel. It has been found that an alloy of gold, silver and copper may have properties making the alloy suitable to be used in a mixing apparatus.
  • An alloy of about 60 % gold modified with a mixture of silver and copper gives a tensile strength of typically 400-650 MPa, hardness of 200-220 HB and thermal conductivity of 300-350 Wm " 'K ' '.
  • a mixing apparatus at least partly comprising such alloy forms a further aspect of the invention.
  • a mixing apparatus according to the invention preferably partly comprises a silver/copper alloy. It has been found that a mixing apparatus at least partly made of a silver/copper alloy has higher heat conducting properties than a mixing apparatus made of steel, at the same time as the tensile strength and hardness have been retained.
  • the mixing apparatus preferably at least partly comprises an alloy wherein the ratio of the two metals in the alloy is 70-95 % silver and 5-30 % copper. More preferably the ratio is 75-90 % silver and 10-25 % copper, and most preferably the ratio is 80-86 % silver and 14-20 % copper.
  • an alloy of 83 % silver and 17 % copper has a thermal conductivity of 400 W/m-K, a tensile strength of 450 MPa and a hardness of 140 HB.
  • a mixing apparatus at least partly comprising an alloy consisting of 83 % silver and 17 % copper is an especially preferred aspect of the invention. Both silver and copper are relatively soft metals. It has however been found that an alloy of copper and silver has a higher strength than the two metals alone. This fact has been used to produce a material that have properties as requested and that sustain machining in order to give apparatus parts to be used in a mixing apparatus.
  • compositions comprising at least one component having a vapour pressure above the vapour pressure of water may be prepared using an apparatus of the invention.
  • a composition comprising at least one volatile component having a vapour pressure above 0.04 Bar at 25 °C may be prepared when using a mixing apparatus according to the invention, with minimal or no evaporation of the component during mixing. More preferably the component(s) have a vapour pressure above 0.1 Bar, and most preferably above 0.3 Bar at 25 °C.
  • the volatile component is preferably one of the main components in the composition. It is known that when water is included in the composition, traces of some gases (such as N 2 and O 2 ) may be present in the water. Such contamination is not regarded as the volatile component in the aspect of the invention.
  • the apparatus should in addition be made of a material, and must be constructed in such a way, that there is minimal risk of contamination of the components to be mixed and the product being prepared.
  • the material in the mixing apparatus is inert. Any minor contamination from the mixing apparatus material may be washed away during a sterilisation process prior to the mixing.
  • the mixing apparatus is steam sterilised before using it in a mixing process.
  • parts of the mixing apparatus material may be coated with an inert material, such as gold.
  • a gold coating may prevent components of the high thermal material, such as copper, from being in direct contact with the product and will therefore reduce the possibility for reactions between copper and the product.
  • An apparatus as earlier described at least partly coated with gold forms a further aspect of the invention.
  • the actual mixing parts of the apparatus are coated with an inert material, such as gold.
  • the mixing apparatus of or used according to the invention may be any of the conventional types of mixing apparatus, e.g. homogenizers, atomizers, sonicators, cap mixers, shakers, paddle mixers, blade mixers, static mixers, expansion nozzles, extruders and rotor stators.
  • the apparatus is preferably one in which the material being mixed is subjected to high shear forces, e.g. high shear homogenizers and sonicators and in particular rotor stator mixers.
  • the mixing apparatus is a rotor stator mixer. Independent of what kind of mixing apparatus is chosen, it is preferred that at least one of the actual mixing parts of the apparatus is made of the high thermal conductivity material.
  • the parts of the apparatus wherein the generation of heat is greatest should be made of the high thermal conducting material.
  • the parts of the apparatus wherein heat is generated and which are difficult to cool by conventional cooling systems should preferably be substituted with parts made of the high conducting material.
  • the mixing apparatus is a rotor stator this may comprise one or several sets of rotors and stators. Both rotors and stators in each set may be made of a material having the requested properties, and preferably at least the stators is made of such material. Most preferably at least the first stator is made of such material.
  • the rotors and/or stators may in addition be coated with gold.
  • the invention provides a process for the preparation of a pharmaceutical composition in which the process comprises introducing the composition components into the mixing apparatus and mixing the components in the mixing apparatus that at least partly comprises a high conductive material as described.
  • the composition prepared is an emulsion comprising at least one component with a high vapour pressure.
  • the material such as an alloy
  • care is taken during the machining of the material to manufacture the apparatus parts as wanted.
  • a cooling fluid should be used during the machining to avoid the softening of the material.
  • the material is slowly heated during machining, keeping a high temperature for some while, and then to let it cool to room temperature. This is in order to reduce tensions in the material.
  • the material may for instance be heated to about 300 °C for 15-20 minutes, before it is cooled to room temperature.
  • cavitation is meant a local evaporation due to a local reduced pressure. Even though the measured system temperature is below the boiling point temperature of the substances at the system pressure, there may be local points with a lower pressure where formation and collapse of vapour bubbles may occur. A way of overcoming the problem of cavitation in the mixing apparatus has been sought.
  • Fluid transit means are provided by radially spaced, axially extending slots (e.g. cuts) in the cylindrical extensions, as given in figure 2. It has now further been found that these fluid transit means are superfluous and that an improved control of the pressure in the system may be achieved by removing these slots. It is likely that the pressure in the slots will be lower than in the rest of the aperture giving possibilities for cavitation, i.e. local evaporation, of volatile components in the slots. This is highly unwanted.
  • a further embodiment of the invention is hence to reduce the risk of boiling and evaporation of volatile components by using a mixing apparatus wherein a substantially constant pressure is found throughout the aperture.
  • this can be achieved by having substantially even cylindrical extensions in the rotors and stators, hence that they have no slots.
  • the cylindrical extensions (flanges) have an even surface comprising substantially continuous annulus running protrusions, as given in figure 3.
  • the slots are traditionally there most likely because rotor stator equipment has mostly been used in the food industry for homogenising for example fibrous slurries. It makes sense to have a kind of scissoring effect, which the "teeth" of the cylindrical extensions with the slots will provide, in that specific use.
  • emulsions and dispersion it has surprisingly been found that it is the high shear forces in the fluid in the lamellaes between the rotor and stator that tear the drops or bubbles apart and not the slots in the cylindrical extensions.
  • an improved control of the size distribution is achieved.
  • an improved control of the size distribution of the vesicles may be achieved by using a rotor stator wherein the slots in the cylindrical extensions are removed.
  • the size distribution of the vesicles reflects the residence time of the fluid in the high shear sones. It is thereby an advantage to ensure that there are no gaps in the cylindrical extension such that all the fluid elements are forced to take the same route through the aperture. The possibility of fluid elements to by-pass the shear zones by passing through the slots is hence not present, giving an improved control of the emulsion droplet size distribution, and hence a more narrow size distribution.
  • a further aspect of the inventions is a rotor stator mixer wherein the rotors and stators in the rotor stator mixer comprise substantially continuous annulus running interlocking protrusions.
  • Such rotors and stators without slots can more easily be manufactured by machining than the rotors and stators having radially spaced, axially extending slots.
  • apparatus parts may be prepared from the high thermal conducting material described. Using such apparatus the invention accordingly encompasses a process for preparation of pharmaceutical compositions providing a highly controlled vesicle size distribution.
  • a further embodiment of the invention is hence a process for the preparation of a pharmaceutical composition in which the process comprises mixing the composition materials in a rotor stator assembly, wherein the rotors and stators comprise substantially continuous annulus running interlocking protrusions.
  • the materials being mixed using the process of the invention are preferably fluids, i.e. liquids, gases or gas-precursors, whereby an emulsion or dispersion is produced on mixing.
  • Suspensions may also be prepared.
  • the composition produced on mixing is preferably a sterile pharmaceutical composition wherein at least one component of the composition has a high vapour pressure.
  • the composition prepared is an emulsion.
  • An emulsion prepared may form a component in a diagnostic imaging contrast media or a therapeutic composition.
  • a contrast agent would preferable be an ultrasound, X-ray or MR contrast media, and most preferably an ultrasound contrast agent.
  • a product obtained by a process using an apparatus according to the invention hence forms a further aspect of the invention.
  • the use of an apparatus at least partly comprising a material having the properties as described, in the preparation of a pharmaceutical composition forms yet another aspect of the invention.
  • Figure 1 is a cross-sectional drawing of a rotor stator mixer wherein the rotors and/or stators may comprise a high thermal conductive material as described.
  • Figure 2 is a perspective view of the rotor and stator stage in the apparatus of WO 99/08782. The figure shows how known rotors and stators have cylindrical extensions provided with radially spaced, axially extending slots.
  • Figure 3 is a perspective view of the rotor and stator stage in the rotor stator mixer given in figure 1, showing rotors and stators without slots.
  • Figure 4 and figure 5 are photos of gold-coated stators from figure 2 and 3, i.e. with and without slots, respectively.
  • a rotor stator mixer there is shown a rotor stator mixer.
  • the components to be mixed are introduced through inlets 5 and 6 into premixing chamber 7, the walls of which are defined by a concave section of housing 8, first stator element 9, and the tip 10 of rotor drive shaft 11.
  • Tip 10 of rotor drive shaft 11 carries a flange 12 (seen side-on) which serves to mix the components in pre-mix chamber 7.
  • the housing provides a cylindrical chamber and has a cup-shaped portion 8 and an end cap 13 with rotor drive shaft 11 entering through the base of portion 8 and sealed by a double mechanical seal 14.
  • Drive shaft 11 is rotated for example at speeds of up to 8000 rpm by externally positioned motor 15 and rotates first rotor 16 and second rotor 17 which are in interlocking engagement with first stator 18 and second stator 19.
  • the rotors and/or stators are made of a high thermal conducting alloy according to the invention and are optionally gold plated to a thickness of 2 to 30 ⁇ m and have an external diameter of about 110 mm.
  • at least stator 18 is made of the material according to the invention. Remaining parts may be made of other materials, such as stainless steel.
  • Premix chamber 7 communicates with first mixing chamber 20 which is defined by surfaces of housing 8, first stator 18, and second stator 19 and which has an outlet 21 which corresponds to the inlet to second mixing chamber 22.
  • Second mixing chamber 22 is defined by surfaces of second stator 19 and housing 8.
  • first mixing chamber 20 material from premixing chamber 7 passes radially outward through shear force zones 23a,b,c etc. between cylindrical extensions 24,25 of first stator 18 and first rotor 16.
  • each rotor stator assembly defines about 12 to 14 such shear force zones and the radial clearance between the cylindrical extensions is conveniently about 250 ⁇ m.
  • the material being mixed is forced through the shear forces towards the periphery of the mixing chamber before it is passed radially inward to pass from first mixing chamber to second mixing chamber through outlet 21.
  • the mixture passes radially outward between second rotor and second stator before leaving through outlet 28 as a prepared pharmaceutical composition, such as an emulsion.
  • First and second mixing chambers 20 and 22 are provided with drainage ports 29 and 30 along their lower boundary. These drainage ports may be connected to a steam trap and drain, e.g. as is conventional in pharmaceutical manufacturing apparatus.
  • steam generally superheated steam
  • Liquid media may likewise be introduced through inlet 5; however in this instance inlet 5 is desirably provided with a valve (not shown) which provides a larger inlet diameter (e.g. 3 to 8 mm) when liquid is to be introduced than the diameter (e.g. 0.2 to 2 mm, preferably 0.5 mm) used when gas is introduced.
  • Liquid inlet 6 likewise conveniently has a diameter of 3 to 8 mm.
  • first and second mixing chambers are provided with annular temperature control means, e.g. water cooling jackets, 31 and 32, temperature controlled by monitors 33,34 and control means 35,36.
  • Further cooling means e.g. coolant ducts, may be provided to cool the stators, the rotor drive shaft and the mechanical seal.
  • the stators 18 and 19 may comprise cooling channels at the side of the stator remote from its corresponding rotor.
  • drive shaft 11 is rotated at 8000 m or such a rate as to cause outer shear force zone 23 to have a relative rotor stator speed of at least 32 m/s, e.g. 46 m/s.
  • the rotors and stators according to the invention have cylindrical extensions (flanges) 24, 25 having even surfaces providing substantially continuous annulus running protrusions.
  • the stator has cylindrical extensions provided with radially spaced, axially extending slots.
  • FIG. 5 a photo of a gold-coated stator according to the invention having cylindrical extensions comprising continuous annulus running protrusions (no slots) is shown.
  • the stator is made of a high thermal conducting material, an alloy, according to the invention, and in addition coated with gold.

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Colloid Chemistry (AREA)

Abstract

L'invention concerne des perfectionnements apportés à un appareil mélangeur utilisé pour la production d'une composition pharmaceutique, par exemple, une émulsion, suspension ou dispersion, ainsi qu'au procédé de préparation d'une telle composition. L'invention concerne en particulier un appareil destiné au mélange de composants, et à un procédé de mélange de ces composants, au moins l'un des composants à mélanger étant volatil. L'invention apporte une solution au problème associé à la chaleur générée lors du mélange et, en particulier, sur la façon dont l'évaporation des composants à haute tension de vapeur peut être évitée lors d'un tel processus de mélange. Cette solution consiste, conformément à l'invention, à utiliser un appareil mélangeur comprenant un matériau à haute conductivité thermique, ainsi qu'à haute résistance et haute dureté.
PCT/NO2002/000417 2001-11-12 2002-11-11 Appareil melangeur a usage pharmaceutique Ceased WO2003041848A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002339773A AU2002339773A1 (en) 2001-11-12 2002-11-11 Construction material for a pharmaceutical mixing apparatus

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NO20015534 2001-11-12
NO20015534A NO20015534D0 (no) 2001-11-12 2001-11-12 Farmasöytisk blandeapparat

Publications (2)

Publication Number Publication Date
WO2003041848A2 true WO2003041848A2 (fr) 2003-05-22
WO2003041848A3 WO2003041848A3 (fr) 2003-08-14

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PCT/NO2002/000417 Ceased WO2003041848A2 (fr) 2001-11-12 2002-11-11 Appareil melangeur a usage pharmaceutique

Country Status (3)

Country Link
AU (1) AU2002339773A1 (fr)
NO (1) NO20015534D0 (fr)
WO (1) WO2003041848A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1844849A1 (fr) * 2006-03-29 2007-10-17 Vakumix Rühr- und Homogenisiertechnik Aktiengesellschaft Dispositif pour homogénéiser, mélanger ou disperser de matières fluides
EP2114173A4 (fr) * 2007-06-27 2012-10-31 H R D Corp Système et procédé de production d'amidon
EP2152406A4 (fr) * 2007-06-27 2014-03-05 H R D Corp Système et processus pour la production d'un produit liquide à partir d'un gaz léger
EP2152378A4 (fr) * 2007-06-27 2014-03-12 H R D Corp Procédé à cisaillement élevé de production d'aspirine
US9592484B2 (en) 2007-06-27 2017-03-14 Hrd Corporation Gasification of carbonaceous materials and gas to liquid processes

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3743252A (en) * 1972-03-16 1973-07-03 Gloucester Eng Co Inc Air cooled extruder
EP0700513B1 (fr) * 1993-05-28 1997-07-30 FISONS plc Appareil d'analyse
DE19511588C2 (de) * 1995-03-29 1997-02-06 Janke & Kunkel Kg Magnetrührer mit einem blockförmigen Gefäßhalter
US6054103A (en) * 1997-06-25 2000-04-25 Ferro Corporation Mixing system for processes using supercritical fluids
GB9818021D0 (en) * 1998-08-18 1998-10-14 Nycomed Imaging As Apparatus

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1844849A1 (fr) * 2006-03-29 2007-10-17 Vakumix Rühr- und Homogenisiertechnik Aktiengesellschaft Dispositif pour homogénéiser, mélanger ou disperser de matières fluides
EP2114173A4 (fr) * 2007-06-27 2012-10-31 H R D Corp Système et procédé de production d'amidon
US8518186B2 (en) 2007-06-27 2013-08-27 H R D Corporation System and process for starch production
EP2152406A4 (fr) * 2007-06-27 2014-03-05 H R D Corp Système et processus pour la production d'un produit liquide à partir d'un gaz léger
EP2152378A4 (fr) * 2007-06-27 2014-03-12 H R D Corp Procédé à cisaillement élevé de production d'aspirine
US9192896B2 (en) 2007-06-27 2015-11-24 H R D Corporation System and process for production of liquid product from light gas
US9592484B2 (en) 2007-06-27 2017-03-14 Hrd Corporation Gasification of carbonaceous materials and gas to liquid processes

Also Published As

Publication number Publication date
WO2003041848A3 (fr) 2003-08-14
NO20015534D0 (no) 2001-11-12
AU2002339773A1 (en) 2003-05-26

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