Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
  • B01J2/20—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by expressing the material, e.g. through sieves and fragmenting the extruded length

Definitions

• the subject of the invention is an extruder of the kind which makes it possible to manufacture spheroidal or spheroid particles intended for the pharmaceutical and food industries without the need for recourse to a spheronization step subsequent to the extrusion.
• the spheroidal particles in question are more particularly intended for use in the constitution of tablets, multiparticulate foods, capsules, dry syrups or even oral suspensions, either as such, or after certain modifications such as, for example, place one or more coating layers.
• This comprises the conventional constituent elements of any extruder and comprises, at the outlet of the extrusion die, a rotary tool intended for cutting the wire, rod or extruded profile and equipped with knives whose shape characteristics allow obtain, directly and without an additional spheronization step, particles having an average index of circularity which is good but which remains lower than that of the particles obtained at the end of the conventional spheronization step.
• These knives are in the form of a rectangular blade having first and second flat faces, parallel to each other; this blade which is intended to be fixed on the cutting tool by fixing means provided at one of its ends, is arranged at the other end in the form of a knife proper by means of a recess provided on one on both sides, this recess affecting only part of the face in question so that at one of the long sides of this face remains a narrow rim with a width of less than 2 mm which is parallel to the other long side of the blade, the two sides of which are connected by an inclined surface extending between the non-hollowed side and the narrow edge, the edge of which forms a cutting edge and which constitutes one of the long sides of the blade is used to cut the extruded profile.
• the circularity index which makes it possible to assess the circularity of a particle is constituted by the ratio of the surface of the two-dimensional projection of the particle obtained after cutting, to the surface of the projection d 'a perfect sphere of diameter equivalent to the largest diameter of the particle obtained after cutting; the closer the circularity index is to 1, the closer the overall shape of the particle to that of a sphere.
• the ability of the spheroids of a population of spheroids to receive a coating that is to say the efficiency of the coating operation of such a population of spheroids and the resulting gain in quantity of coating substance deposited is all the more large that the average circularity index is closer to 1.
• the object of the invention is therefore, above all, to produce an extruder of the kind in question which is capable of producing, directly and without an additional spheronization step, spheroids whose average index of circularity is higher than that of the spheroids obtained with the extruders of the kind in question which already exist and which, in any event, is greater than 0.90, preferably 0.95.
• the extruder according to the invention which is equipped with a cutting tool identical or equivalent to that of the extruder according to international application WO 98/44911, is characterized in that it comprises a die d 'tapered extrusion.
• the extruder according to the invention comprises
• a cutting tool equipped with knives which are in the form of a rectangular blade comprising a first and a second plane face and parallel to each other, this blade which is intended to be fixed on the cutting tool by fixing means provided at one of its ends, being arranged at the other end in the form of a knife proper by virtue of a recess provided on one of these two faces , this recess affecting only part of the face in question so that at one of the long sides of this face remain a narrow rim less than 2 mm wide which is parallel to the other long side of the blade, the two faces of which are connected by an inclined surface extending between the non-recessed face and the rim narrow whose edge which forms a cutting edge and which constitutes one of the long sides of the blade, is used to cut the extruded profile and on the other hand, an extrusion die of frustoconical shape.
• the frustoconical extrusion die has an angle of conicity ⁇ r which is from 10 to 45 degrees, preferably from 20 to 30 degrees and more preferably still close to 24 degrees, that is to say between 23.5 and 24.5 degrees, it being understood that the angle of conicity is the angle formed between on the one hand a plane perpendicular to the axis of the die and, d on the other hand, the inclined surface of the conical part thereof.
• FIG. 1 shows in partial schematic axial section an extruder arranged in accordance with the invention
• FIG. 2 is a plan view along II in FIG. 1,
• FIGS. 3a and 3b respectively show in axial section and in end view according to Illb in FIG. 3a, the extrusion die comprised by the extruder and
• the mixture to be extruded is in semi-solid form at room temperature.
• the mixture to be extruded comprises at least one thermoformable or thermoplastic component, that is to say capable of passing into semi-solid form under the action of heat.
• the soft material is extruded by the action of an extrusion screw propelling the mixture through an extrusion die; the latter is constituted by a metal part comprising an orifice through which the semi-solid soft material is expelled. Particle cutting is carried out at the exit of the extrusion die by a cutting tool.
• Figure 1 shows an extruder according to the invention, essentially consisting of a tubular element of axis XY generally designated as T, inside which is housed a worm screw 1 also of axis XY with core conical and with helical rib 2; the worm 1 is supported by a motor M which is capable of driving it in rotation along the arrow F.
• the tubular element T At the end lb of the conical core la by which it is mounted on the motor M and supported by the latter, the tubular element T comprises an orifice 3 surmounted by a hopper 4 through which the interior of the tubular element can be supplied with material, for example thermoplastic, not shown, intended to be extruded.
• the tubular element comprises a frustoconical extrusion die according to the invention generally designated at E; this comprises an orifice 8 of axis XY, through which the wet or thermoformable material is extruded filling, inside the tubular element T, the space between said tubular element and the endless screw with conical core the rotation of which propels the wet or thermoformable mixture towards the extrusion die which is thus subjected to an increasingly high pressure as it is transported towards the extrusion die due to the increasingly restricted space which is allocated to it as a result of the conicity of the core of the worm.
• E frustoconical extrusion die according to the invention generally designated at E; this comprises an orifice 8 of axis XY, through which the wet or thermoformable material is extruded filling, inside the tubular element T, the space between said tubular element and the endless screw with conical core the rotation of which propels the wet or thermoformable mixture towards the extrusion die which is thus subjected to
• Means 9 for regulating the temperature which may be constituted by heating collars, are arranged on the external surface of the tubular element so such that it becomes possible to impose a predetermined temperature on the mixture to be extruded at each point of its path inside the tubular element T.
• a rotary cutting tool with four knives 10, fixed on a plate 13, is arranged at the outlet of the extrusion die and ensures the cutting into successive particles of the wire, rod or profile leaving the die.
• the distance between the outlet orifice of the die and the plane in which the knives 10 move is less than 5 mm, preferably between 0.01 and 1.5 mm and, more preferably still, close to 0.1 mm.
• FIG. 2 shows an embodiment thereof with four knives 10, these knives being mounted by screws 11 and 12 on a rotary plate 13 of axis ZZ 'parallel to the XY axis of the extruder of which only the orifice 8 of the extrusion die E is shown.
• the plate 13 is rotated along the arrow F2 by motor means not shown.
• one extruder, of which only the orifice 8 of the die E is shown is disposed above the plane in which the plate 13 is disposed; the extruded profile to be cut therefore arrives from above relative to the plane containing the plate 13.
• the extrusion die E is shown in more detail • in FIGS. 3a and 3b.
• the value of d1 is 0.1 to 2 mm, preferably between 0.6 and 0.9 mm and, more preferably still, close to 0.75 mm.
• the value of d2 is 2.5 to 10 mm and preferably close to 5 mm.
• the knife 10 which is in the form of a blade with two plane faces Pi and P2, parallel to each other, is of generally rectangular shape, the two long sides of which are designated by ml and m2, the two short sides being designated by ni and n2.
• This knife includes:
• a part C2 comprising on the face P2 a recess K arranged from the large side m2 in the direction of the large side ml which comprises a cutting or cutting part 20 of the knife up to a distance d relative to this side ml, d being less than 2 mm, so that the surface of the knife, which is represented by the face P2 of the part Cl, is extended, at the level of the part C2, along the side ml by a narrow rim B of width d.
• the knife 10 strikes the wire (not shown leaving the die not shown) by the cutting edge 20 and thus causes the cutting of the wire into successive particles.
• d is determined as a function of the diameter of the die hole and the speed with which the extruded wire leaves the latter, the relationship between these quantities being determined on a case-by-case basis.
• the value of the angle ⁇ , visible in FIG. 4c and formed between the surface Pi of the plane part of C2 and the inclined part I, also called cutting angle, is from 30 to 65 degrees, preferably between 45 and 50 degrees.
• One of the advantages of the invention lies in the fact that it is possible to easily adapt it to the devices conventionally used in the field of extrusion. Indeed, the essential characteristics of the invention lie in the use of a frustoconical die and knives of geometry hollowed out above described with which it is easy to equip any already existing extruder.
• the mixture to be extruded can comprise a plurality of excipients and active ingredients; it must be in a semi-solid form, that is to say plastically moldable at the time of its passage through the extrusion die.
• the extruder according to the invention can be used both in the context of the so-called “hot extrusion” method and in that of the so-called “wet” extrusion method in which the heat action is not necessary to give the mixture to be extruded the required plastic qualities.
• the mixture to be extruded which comprises a thermoformable constituent
• the mixture to be extruded is heated to a temperature close to the glass transition temperature of the thermoformable constituent and is conveyed in a semi-solid form to the die.
• the means in question can for example comprise one or more thermocouples suitable for measuring the temperature of the mixture throughout its progression along the extrusion screw.
• the mixture can be heated, for example, by means of one or more heating collars arranged around the tubular element T or sheath surrounding the extrusion screw.
• the largest dimension of the spheroidal particles obtained using the extruder according to the invention is generally 0.1 to 2 mm.
• This dimension is a function of the speed of rotation of the shaft of the extrusion screw, and also, in the case of a "hot" extrusion, of the temperature gradient prevailing in the extrusion zone, the temperature and dimensions of the die.
• the speed of rotation of the worm screw is preferably from 1 to 90 revolutions per minute.
• the temperature gradient in the extrusion zone and the temperature of the die are preferably located, in a range from 10 to 200 ° C.
• the speed of rotation of the cutting tool is fixed as a function of the speed at which the extrudate leaves the orifice of the die; preferably, it is 40 to 6000 revolutions per minute.
• thermoformable excipient which is solid at room temperature, passes by heating in a semi-solid form.
• substances belonging to the family of methacrylic polymers can be used, such as, for example, the excipients sold under the brand Eudragit® defined in more detail below.
• Eudragit RD100 which is a mixture of sodium carboxymethylcellulose, poly (ethyl acrylate), and sodium chloride.
• Eudragit RS100 which is a mixture of poly (ethyl) acrylate, methylmethacrylate and trimethylammonioethylmethacrylate chloride in the proportions of 1: 2: 0.1.
• thermoformable excipients certain cellulose derivatives such as ethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose or hydroxymethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate, cellulose acetate phthalate or else microcrystalline cellulose.
• thermoformable excipients vinyl derivatives of the type of vinyl polymers such as polyvinyrolidone or PVP, crospovidone or alternatively compounds belonging to the family of polyethylene glycols, in particular PEG 6000 or PEG 8000.
• the sodium diclofenac and the ethylcellulose are sieved beforehand over a 1 mm sieve in order to remove the agglomerates.
• the stearyl alcohol is ground using a knife mill of the IKA brand type M20 for 10 seconds and then sieved through 1mm mesh.
• Sodium diclofenac, ethylcellulose and stearyl alcohol are introduced into the tank of a CONTESSO brand coulter mixer and mixed for 5 min at 20 revolutions.min -1 .
• the triethyl citrate is gradually incorporated into the mixture while the latter is still subjected to the same agitation, the speed of the peristaltic pump being kept constant at 10 revolutions.min -1 .
• the mixture tends to soften under the action of the temperature and pressure imposed by the extrusion process.
• the conventional or so-called "flat" die used in experiments a and b has a circular outlet orifice, the diameter of which is 750 ⁇ m.
• the frustoconical form of the invention (experiments c and d) has the following characteristics:
• the diameter of the outlet orifice is 750 ⁇ m
• the diameter of the flat part of the truncated cone is 5 mm and the angle (X characteristic of the conicity of the die is 24 degrees.
• the conventional knives used in experiments a and c differ from the knives used in accordance with the invention in experiments b and d by the fact that they do not have a recessed area; more particularly, the knives used in accordance with the invention in experiments b and d have the shape resulting from FIGS. 4a, 4b and 4c.
• the shape of the particles obtained in these four experiments was determined by visual observation and classified according to 4 categories: chip, cylinder, ovoid and spheroid.
• the circularity index and the average particle diameter were measured using an OLYMPUS microscope using the "Ellix” software marketed by the company MICROVISION on a population of 50 particles, considered to be representative.
• Fenofibrate-based spheroids are prepared.
• the composition of the fenofibrate-based extruded mixture is shown in Table 5.
• the Fenofibrate and the Eudragit RD 100 are introduced into a container, then mixed using a horizontal multi-axis mixer of revolution of the TURBULA brand, for 10 minutes at 30 revolutions.min -1 .
• the mixture thus obtained is introduced manually or using an endless screw into the feed zone of the extruder, used in Example 1 which includes the die and the knives used in experiment d.
• the result is excellent, the particles obtained being almost spherical.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Processing And Handling Of Plastics And Other Materials For Molding In General (AREA)
• Extrusion Moulding Of Plastics Or The Like (AREA)

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• 2003
  • 2003-02-14 FR FR0301814A patent/FR2851178B1/fr not_active Expired - Fee Related
• 2004
  • 2004-02-09 WO PCT/FR2004/000291 patent/WO2004073860A2/fr not_active Application Discontinuation
  • 2004-02-09 CA CA002515809A patent/CA2515809A1/fr not_active Abandoned
  • 2004-02-09 EP EP04709255A patent/EP1592502A2/de not_active Withdrawn
  • 2004-02-09 US US10/544,900 patent/US20060182836A1/en not_active Abandoned

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