WO2003028698A2 - Procede et dispositif de production de granules comprenant au moins un principe actif pharmaceutique - Google Patents

Procede et dispositif de production de granules comprenant au moins un principe actif pharmaceutique Download PDF

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Publication number
WO2003028698A2
WO2003028698A2 PCT/EP2002/010743 EP0210743W WO03028698A2 WO 2003028698 A2 WO2003028698 A2 WO 2003028698A2 EP 0210743 W EP0210743 W EP 0210743W WO 03028698 A2 WO03028698 A2 WO 03028698A2
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WO
WIPO (PCT)
Prior art keywords
gas
granules
granulating
extruder
granulation
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Application number
PCT/EP2002/010743
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German (de)
English (en)
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WO2003028698A3 (fr
Inventor
Klaus-Jürgen Steffens
Rudolf Schroeder
Original Assignee
Steffens Klaus-Juergen
Rudolf Schroeder
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 Steffens Klaus-Juergen, Rudolf Schroeder filed Critical Steffens Klaus-Juergen
Priority to AU2002342755A priority Critical patent/AU2002342755A1/en
Priority to EP02779415A priority patent/EP1429735A2/fr
Publication of WO2003028698A2 publication Critical patent/WO2003028698A2/fr
Publication of WO2003028698A3 publication Critical patent/WO2003028698A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present invention relates to a method for producing granules comprising at least one active pharmaceutical ingredient, a device for producing such granules, and granules produced by means of these methods and devices.
  • Granulation is the transfer of powder particles into granules, which is important above all for the packaging of pharmaceutical forms in the pharmaceutical industry, but also for the fertilizer industry and the plastics industry.
  • granules are used on the one hand as independent pharmaceutical forms, which are easier to take compared to powder mixtures, and on the other hand as an intermediate product in the filling of drug capsules and tableting, with better flowing bulk goods being obtained by reducing the surface area of the powder mixture, which can be compared Allow to be compressed into powders into mechanically firmer compresses.
  • Granules generally have the advantages of a defined debris and flow behavior, a reduced tendency to segregate and an improved wettability of the active and auxiliary substances.
  • the granulation takes place either on a dry, but mostly on a moist path.
  • moist granules a distinction can be made between crust granules, in which solid bridges form between the powder particles due to crystallization of partially dissolved powder constituents or as a solution of added auxiliaries after evaporation of the granulating liquid, adhesive granules in which binder bridges are formed by moistening with solutions of mostly macromolecular substances and sinter granules, in which solid bridges are formed by melting and then solidifying components of the powder mixture.
  • granules comprising at least one active pharmaceutical ingredient can be produced by means of a process in which, in particular, the homogeneous distribution of substances can be improved by means of an energy input which can be set within a wide range, and in which a specific gas introduction and subsequent expansion the porosity of the granulate particles can be adjusted in a targeted manner.
  • the process according to the invention for the production of granules basically comprises introducing the powder or powder mixture to be granulated into an extruder, adding granulating liquid to form a granulating compound and compacting the granulating compound in the extruder.
  • This process can be followed by further customary process steps, such as sieving, drying, mixing in further constituents and the like.
  • a gas or gas mixture is introduced into the granulating compound in order to impart porosity to the granulating compound.
  • extrusion systems have so far only been used in melting processes, in particular for the processing or processing of fats, waxes or polymers, and in the production of pellets.
  • the masses to be processed in the extruder have completely different physical properties than the granulation masses to be processed according to the present method.
  • the method according to the invention can be carried out using conventional extrusion systems which are modified in such a way that they include a device for metering the powdery starting material to be granulated and, in the case of the wet granulation method according to the invention, a device for metering the liquid required for granulation.
  • a gas is introduced into the granulating compound in order to impart porosity to the granulating compound; in this case the extruder further comprises a corresponding device for introducing the gas and for dosing the gas pressure and the gas quantity.
  • Figure 1 is a schematic representation of an extrusion system according to the invention according to a first embodiment, in which no gas is introduced into the granulating mass;
  • FIG. 2 shows a schematic illustration of an extrusion system according to the invention in accordance with a second embodiment, in which gas is introduced into the granulating compound;
  • Figure 3 is a schematic representation of an extrusion system according to a third embodiment of the invention with rotary locks for powder dosing;
  • FIG. 4 shows an illustration of a two-stage extrusion system according to the invention in accordance with a particularly preferred embodiment, in which gas can be introduced into the granulating compound and
  • FIG. 5 shows an illustration of a single-stage extrusion system according to the invention in accordance with a particularly preferred embodiment in which gas is not introduced into the granulating composition.
  • the device for carrying out the method according to the invention basically comprises an extruder (D), a device for metering solids (A) and optionally a device for metering the granulating liquid (B) and a device for metering gas (C).
  • (E) means downstream process steps, that is to say those process steps which usually follow the granulation, such as, for example, sieving, drying and admixing further constituents.
  • the type and scope of these downstream process steps depend on the requirements and the further use of the granulate. For example, granules of an essentially uniform desired size can be obtained by press sieves.
  • the device for solids metering marked with (A) in the figures can be a gravimetric metering screw or another suitable apparatus which enables a defined addition of the powdered starting materials of the granulate.
  • the outlet of the dosing unit opens onto the feed screw of an extruder or, if available, into its hopper.
  • a cellular wheel sluice is used instead of the hopper which is usually used for powder application.
  • the device for liquid metering (B) is used to introduce the liquid required for granulation, possibly also an adhesive solution, into the process via a suitable injection device.
  • the feed point is preferably directly behind the feed screw in the front area of the extrusion unit. It should advantageously enable the quantity processed to be recorded.
  • the structure and type of the dosing unit depend essentially on the pressure conditions within the extruder at this point and the properties of the granulating liquid such as viscosity, stickiness etc.
  • the added components are processed into an adhesive granulate or another processable mass.
  • the extruder must transfer a minimum amount of shear forces to the mixture in order to achieve sufficient dispersing performance.
  • certain pressure conditions must also prevail within the extruder, especially in the embodiment in which a gas is additionally introduced into the granulating composition in order to impart porosity to the granulating composition.
  • the pressure conditions in the extruder are indicated by the wedges below the figures. Between the points marked with (1) and (2) (see FIG.
  • a gas preferably nitrogen
  • a device for gas metering (C) is required, by means of which the gas is introduced into the process.
  • Both the gas pressure and the gas quantities can advantageously be regulated using suitable equipment such as pressure reducers or volume flow meters.
  • the maximum gas pressure required depends on the mass pressure of the mixture inside the extruder at the point at which the gas is introduced and immediately before and at the nozzle of the extruder.
  • the measuring range of the volumetric flow meter depends on the throughput of the extruder and the desired porosity.
  • Nitrogen is a suitable gas, but any other gas is conceivable that does not have a negative impact on the quality of the product and is justifiable for other, non-process-related reasons, especially with regard to environmental compatibility.
  • FIGS. 1 and 3 can also be used.
  • FIG. 1 A single-stage extrusion system is shown schematically in FIG. 1, in which work is carried out without introducing gas and in the pressure gradients mentioned above. This configuration is advantageous for very pressure / shear sensitive mixtures, the granulation of which leads to a product with sufficient properties even without gas dispersion.
  • FIG. 3 A device is schematically shown in FIG. 3, in which a cellular wheel sluice is used instead of the hopper which is usually used for powder application. Fumigation of the granulation mass can then take place despite the one-stage construction between the rotary valve and the screw feeder of the extruder.
  • a nozzle In order to prevent nitrogen escaping from the product side of the extruder, either a nozzle can be used which prevents the gas from escaping by means of a suitable seal, or if a nozzle is to be dispensed with, an additional rotary valve can be integrated instead , Depending on the material properties and the requirements, when using a nozzle and a second rotary valve, pressure must be equalized between the area of the auger and the area immediately behind the nozzle.
  • the granules according to the invention are produced by introducing the powder or powder mixture to be granulated into the extruder via the metering unit (A).
  • the extruder is a planetary roller extruder.
  • a granulating mass is then produced in the extruder, either by introducing a suitable granulating liquid such as water, ethanol, isopropanol or the like or mixtures thereof, or by introducing a solution of suitable adhesives such as polyvidone, gelatin, cellulose derivatives and the like.
  • suitable granulating liquid such as water, ethanol, isopropanol or the like or mixtures thereof
  • suitable adhesives such as polyvidone, gelatin, cellulose derivatives and the like.
  • the aforementioned granulating liquids and adhesives are only examples of a large number of other substances which are known to the person skilled in the art.
  • the granulation mass After optional gassing of the granulation mass, it emerges from the extruder as a mass with cake-like consistency and can then be further processed; for example, it can be sieved, dried and / or mixed with other constituents.
  • the granules thus produced can then be used directly as the final pharmaceutical form or they can be filled into capsules or compressed into tablets.
  • the pelletizing unit of the particularly preferred planetary roller extruder consists of a helically toothed central spindle (4), which is the only part of the process that is directly connected to the drive and is only supported at the drive point.
  • To the central 3 to 7 planetary spindles (5) are arranged around the spindle, which have opposing toothing and overlap to a high degree with the toothing of the central spindle.
  • the planet spindles are supported on the outside in the toothing of the casing (6). Viewed from the front, this system is therefore very similar to a planetary gear.
  • the constituents are dispersed by constant rolling between the planetary spindles and central spindle on the one hand and by planetary spindles and jacket on the other hand. These surfaces can preferably be temperature-controlled, so that the process heat that occurs is dissipated directly at the point at which they arise, which permits excellent temperature control.
  • the entire structure of the granulating unit can be seen in FIG. 4.
  • the granulation system shown in Figure 4 has a two-stage structure, i.e. there are two more or less independent process steps of the structure described above, which are only connected to one another by a gap a few millimeters wide, formed by a thrust ring and the central spindle.
  • the continuous mode of operation requires a close interlinking of powder or liquid metering and the pelletizing unit, whereas the subsequent process steps can take place spatially but also separately from each other.
  • the pelletizing unit consisted of a specially modified planetary roller extruder (L-WE 50, Entex Rust + Mitschke GmbH, Bochum, Germany) with a one- or two-stage structure and a length / diameter ratio (LD) of 8 or 16.
  • the powder mixture entered the extrusion or pelletizing area via a feed screw of length 4D, where the pelletizing liquid was added via an injection channel.
  • a feed screw of length 4D where the pelletizing liquid was added via an injection channel.
  • the two-stage design it was also possible to introduce gas into the system after 8D using a special thrust ring.
  • the ring also prevented the gas from flowing in against the direction of extrusion.
  • the exit opening of the extruder resulted in a tubular strand with a wall thickness of 1.5 mm and a diameter of about 30 mm.
  • the powder was dosed using a single-screw dosing device (Brabender, Duisburg, Germany), the granulating liquid was pumped using a peristaltic pump (Ismatec, Zurich, Switzerland). Nitrogen was used as the gas in the two-stage construction. The entire granulating unit was cooled with water.
  • the granulated material was dried in a vacuum drying cabinet at 30 ° C. However, a continuously operating microwave-based dryer can also be used. seven
  • the porosity of the granulate strands was determined using the ratio of true volume to apparent volume.
  • the true volume was measured in the gas pycnometer.
  • the granulation was done only with water.
  • the parameters of the pelletizing unit approximately 50% of the maximum permissible powder input was determined when the water input was greatly increased, and then the amount of water was limited to a level determined by the product temperature and power consumption.
  • the product temperature should not exceed 60 ° C and the power consumption should not exceed 80% of the permissible maximum limit.
  • the speed of the pelletizer was 150 or 200 revolutions per minute set. The product was then dried to a residual moisture of about 2.5%.
  • the granules were additionally characterized by flow rate, density of debris and tamping and Hausner factor.
  • the flow rate was measured using a round discharge funnel with an opening width of 11 mm and debris and tamping density according to Ph.Eur. certainly.
  • the granules were mixed in the Turbula mixer (T2C, Willy A. Bachofen, Basel, Switzerland) at 90 revolutions per minute with the addition of disintegration accelerator and flow regulating agent or lubricant for 10 or 2 minutes.
  • the granulate mass was 400 g, the volume of the mixing vessel was 1250 ml.
  • the final mixture was pressed on an instrumented eccentric press with a biconcave die set, the nominal mass was 400 - 430 mg.
  • a tensile strength profile was created for press forces in the range of 6 - 18 kN.
  • the tablets were also tested for disintegration time and drug release. This was done with tablets with a breaking strength of 100 N, regardless of the pressing force used.
  • Caffeine is relatively uncritical in granulation because it is stable up to quite high temperatures. In this respect, granulation was possible from a water volume of 8%. The granulation was carried out with 12% water addition and a resulting product temperature of 51 ° C.
  • the disintegration time was very short at 8 minutes directly after tabletting, the release profile of these tablets is shown in FIG. 7.
  • the tablets tended extremely Post-curing.
  • the release time increased about 60 times, the disintegration time increased to 56 minutes. Therefore, a way had to be found to prevent or at least reduce this post-hardening.
  • This problem was solved by adding 5% cellulose. This caused a disturbance in the granulate structure, which reliably prevented post-curing.
  • the tableting and release behavior was almost identical to that already determined. The technological stability could be confirmed analytically up to a storage period of six months. A review after this period was no longer carried out.
  • ibuprofen has a relatively low melting point of 75 - 78 ° C, so that a maximum permissible product temperature of 40 ° C has been set.
  • the granulation required 14% water and was completely stable over a test period of 4 hours.
  • the good flowability of the granules was confirmed, as was the ease of tabletting.
  • the residual moisture in the granules before the final mixture was prepared was 1.4%.
  • the release profile could be confirmed as well as the stability of the drug form over 6 months.
  • the disintegration time was 1.7 minutes, which is not surprising because of the poor solubility of the active ingredient in water.
  • mefenamic acid was granulated with the addition of the identical auxiliaries.
  • Mefenamic acid is an almost non-wettable active ingredient. Nevertheless, an almost complete encapsulation of the active ingredient was recognized in the same way as recipe II. Due to the poorer wettability, the granulation required considerably more water. With a water addition of 22%, product temperatures of 75 ° C were measured, but this does not pose a risk for mefenamic acid.
  • the granules were overall finer than in recipe II: the drying resulted in fine gaps between the active ingredient and the binder, so that the mefenamic acid crystals were loosely embedded in the binder structure and the extrudate was therefore also much more fragile. Nevertheless, after drying to a residual moisture content of 1.1%, tabletting was possible without any problems.
  • Table 1 shows the recipes that were granulated with nitrogen injection.
  • the components of the outer phase are percentages of the granulate mass. All figures in% (m / m)
  • the total porosity of the mixture appears to be very low in comparison to existing literature data for granules, however, it should be borne in mind that this is the porosity of a strand of granules and this is also determined differently here than the porosity of a pile, which usually results from the ratio of true density to tamped density and thus encloses the interparticle cavities. In the case of the present strands of granules, however, this only results from the sieving.
  • the porosity of the mixture increases with the gas pressure, since the pressure difference between the gas pressure and the mass pressure of the mixture decreases immediately before the outlet opening of the granulating unit, thus facilitating transport of the disperse system through the outlet channel.
  • the drop in porosity at a gas pressure of 10 bar can be explained by the fact that the gas escapes more or less in an uncontrolled manner and is therefore no longer available for increasing the porosity.
  • the upper gas retention limit of the system is reached, which results from the mass pressure and the "tightness" of the granulate mixture and the cross-sectional area of the outlet opening. Since the cross-sectional area of the granulation unit to be passed immediately before the gassing duct is lower than at the outlet opening, a gas is hereby - Avoiding penetration against the direction of extrusion
  • the residual water content of the granulate strands immediately after granulation is around 10%, the product temperature decreases with increasing gas pressure (from 56 to 50 ° C). As expected, the product temperature correlates primarily with the amount of water used.
  • the adjustable porosity influenced the breaking strength. This is shown in Figure 9, the pressing force is 5, 10 and 15 k ⁇ . Clearly is an increase in breaking strength, which, however, does not increase with increasing porosity, as would be expected, but decreases again at a gas pressure of 4 - 6 bar. An explanation for this may be that the number of cavities generated by nitrogen within the granules increases with increasing gas pressure. Within these, almost non-wetted powder fractions can be seen in the electron microscope, which can then be responsible for the deteriorating tabletting properties.
  • the disintegration time of the tablets was 10-12 minutes for a breaking strength of 100 N, the value being quite independent of the gas pressure used and correlating primarily with the breaking strength.
  • Recipe VI showed significantly shorter disintegration times of 6.5 minutes, which was to be expected due to the high cellulose content of 15%. However, this mixture required about twice the amount of water compared to the IN formula. A change in the amount of powder used while the water supply remained the same resulted in an solution of the pressing force - breaking strength profile and - as expected - the product temperature. The decay time remained almost unaffected.
  • recipe VII provided granules with satisfactory tableting and disintegrating properties as well as sufficient gas holding capacity.
  • Recipes VIII and IX illustrate the use of other fillers and binders. However, this showed a different effect than with the previous recipes.
  • recipe VIII the tablet hardness initially showed a decrease in gas pressure, but increased again at 6 bar.
  • Active substance particles should have been coated with a binder.
  • the ibuprofen used here was a strongly lipophilic substance, which could therefore interact more with the non-polar gas than with the hydrophilic binder, which enabled the nitrogen to displace the HPMC used from the active ingredient.
  • the process according to the invention enables intimate mixing of the substances to be granulated, which results in a particularly homogeneous distribution of the ingredients in the resulting granulate.
  • gas By introducing gas into the pelletizing mass provided according to the invention, it can be given a desired porosity, so that the process according to the invention makes it possible to influence the release of active pharmaceutical ingredients contained in the pellets from the final pharmaceutical forms, for example tablets ,

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Abstract

La présente invention concerne un procédé de production de granules comprenant au moins un principe actif pharmaceutique. Selon ledit procédé, la poudre à mettre sous forme de granules est introduite dans une extrudeuse, réduite à l'état de masse de granulation par adjonction d'un liquide de granulation, ladite masse étant compactée grâce à l'application de forces de cisaillement. Un gaz ou un mélange gazeux peut éventuellement être introduit dans la masse de granulation compactée, afin de conférer de la porosité à la masse de granulation.
PCT/EP2002/010743 2001-09-26 2002-09-25 Procede et dispositif de production de granules comprenant au moins un principe actif pharmaceutique WO2003028698A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002342755A AU2002342755A1 (en) 2001-09-26 2002-09-25 Method and device for producing granulates that comprise at least one pharmaceutical active substance
EP02779415A EP1429735A2 (fr) 2001-09-26 2002-09-25 Procede et dispositif de production de granules comprenant au moins un principe actif pharmaceutique

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DE10147414.8 2001-09-26
DE10147414 2001-09-26

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WO2003028698A2 true WO2003028698A2 (fr) 2003-04-10
WO2003028698A3 WO2003028698A3 (fr) 2003-10-23

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WO2005023215A2 (fr) * 2003-09-10 2005-03-17 Janssen Pharmaceutica N.V. Particules en forme de lamelles
US8114383B2 (en) 2003-08-06 2012-02-14 Gruenenthal Gmbh Abuse-proofed dosage form
US8114384B2 (en) 2004-07-01 2012-02-14 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US9486413B2 (en) 2006-08-25 2016-11-08 Purdue Pharma L.P. Tamper resistant dosage forms
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
WO2018054577A1 (fr) * 2016-09-21 2018-03-29 Robert Bosch Gmbh Module de production et procédé pour la fabrication de formes médicamenteuses solides
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US11529313B2 (en) * 2016-04-22 2022-12-20 R.P. Scherer Technologies, Llc Twin-screw dry granulation for producing solid formulations

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SI2273983T1 (sl) 2008-05-09 2016-11-30 Gruenenthal Gmbh Postopek za pripravo intermediatne praškaste formulacije in končne trdne odmerne oblike z uporabo stopnje strjevanja z razprševanjem
WO2015173195A1 (fr) 2014-05-12 2015-11-19 Grünenthal GmbH Formulation pour capsule à libération immédiate résistant aux manipulations illicites comprenant du tapentadol

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US10369109B2 (en) 2002-06-17 2019-08-06 Grünenthal GmbH Abuse-proofed dosage form
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US8114383B2 (en) 2003-08-06 2012-02-14 Gruenenthal Gmbh Abuse-proofed dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
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