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WO2018138569A1 - Nouvelle conception pour un sécheur mélangeur à double cône utilisé pour produire des granules pharmaceutiques prêtes à la compression - Google Patents

Nouvelle conception pour un sécheur mélangeur à double cône utilisé pour produire des granules pharmaceutiques prêtes à la compression Download PDF

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Publication number
WO2018138569A1
WO2018138569A1 PCT/IB2017/058401 IB2017058401W WO2018138569A1 WO 2018138569 A1 WO2018138569 A1 WO 2018138569A1 IB 2017058401 W IB2017058401 W IB 2017058401W WO 2018138569 A1 WO2018138569 A1 WO 2018138569A1
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WO
WIPO (PCT)
Prior art keywords
granules
bdg
production
solvent
air
Prior art date
Application number
PCT/IB2017/058401
Other languages
English (en)
Inventor
Khashayar Karimian
Ahmad YARI
Original Assignee
Khashayar Karimian
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 Khashayar Karimian filed Critical Khashayar Karimian
Publication of WO2018138569A1 publication Critical patent/WO2018138569A1/fr

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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
    • B01J2/16—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by suspending the powder material in a gas, e.g. in fluidised beds or as a falling curtain
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B08—CLEANING
    • B08B—CLEANING IN GENERAL; PREVENTION OF FOULING IN GENERAL
    • B08B9/00—Cleaning hollow articles by methods or apparatus specially adapted thereto
    • B08B9/08—Cleaning containers, e.g. tanks
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to a novel design of a blender, dryer and granulator (BDG) which is used to produce granules used in various industries. This includes ready-to-press granules used in the pharmaceutical industry for the production of tablets and capsules.
  • BDG blender, dryer and granulator
  • Granulation is the process of agglomeration of a dry powder mixture with a suitable binder whereby small particles are gathered to form larger, permanent aggregates in which the original particles can still be identified and retains its chemical and physical properties. Enlargement of particles through the granulation process is necessary for manufacturing solids that must be further processed. Numerous patents have been issues for apparatus of various designs to achieve granulation of different material or mixtures of material (see for example US Patent 4655701, European Patent Application 0330207 Al, US Patent Application 2008/0299305 Al, US Patent 4,591,324, US Patent 6,499,984 B l).
  • US Patent Application 2008/0299305 Al describes the process of granulation using fluid bed granulator in which a "growth liquid" must be used to increase the size of granules by spraying the said liquid on the mixture of powders preferably in atomized form.
  • US Patent No. 4,591,324 describes a granulating apparatus for continuously producing granules which comprises a binder solution-feeding means which is set inside of the granulation chamber to spray a binder solution on the raw powder.
  • the granulating apparatus is also equipped with a granule-discharging means to transfer the granules through the outlet port of the granulator to the dryer.
  • US Patent No. 6,499,984 B l describes an apparatus for producing pharmaceutical granules which comprises a twin screw wet granulator-chopper (TSWGC), to which active ingredient(s) and solid and liquid additives are fed, which mixes, granulates, and wet mills the said components to form a granulation product.
  • TSWGC twin screw wet granulator-chopper
  • the wet granules are then dried using a dielectric energy source, such as radio frequency (RF), microwave energy, or both.
  • RF radio frequency
  • Fluid bed granulators are the most frequently used apparatus for the production of ready- to-press granules in which granules are formed by spraying a fluid bed of homogeneous mixture of powders and drying the wet granules by spraying them with a growth liquid.
  • Size of the granules are controlled by changing the process parameters such as air flow rate, air temperature and rate of spraying which can be controlled manually or automatically using a general algorithm and introducing appropriate parameters for a specific process (Handbook of Pharmaceutical Granulation Technology, Informa Healthcare USA, Inc., 3rd edition, 2010: 164-165).
  • ready-to-press granules which contain an Active Pharmaceutical Ingredient (API) and various diluents (excipients) facilitate and expedites the production of various dosage forms of drugs such as tablets and capsules (see for example Granulation techniques and technologies, Bioimpacts, 2015; 5(1): 55-63).
  • Granulation process converts fine powders into free-flowing granules that are easy to compress.
  • granulation poses various challenges due to high quality requirement of the formed granules in terms of content uniformity and physicochemical properties such as granule size, bulk density, disintegration time, hardness, moisture content, compressibility, etc., together with physical and chemical stability of the drug.
  • granulation begins after initial dry mixing of the necessary powder ingredients along with the active pharmaceutical ingredient (API), so that a uniform distribution of each ingredient throughout the powder mixture is achieved.
  • Blend of powders containing pharmaceutical excipients and API can be compressed into tablets either by direct compression (see Granulation techniques and technologies, Bioimpacts, 2015; 5(1): 55-63; Handbook of Pharmaceutical Granulation Technology, Informa Healthcare USA, Inc., 3 edition, 2010: 164-165) or after making granules by agglomeration or granulation techniques.
  • Granulation process can be broadly classified into two types. First, wet granulation in which a liquid, that may contain binders, is added as a solution or a suspension form to afford a mixable paste. The paste is then dried, usually in tray driers and milled to the appropriate particle size distribution.
  • Dry compaction techniques such as roller compaction
  • Dry compaction are used extensively in various industries. In the pharmaceutical industry, many drug substances are moisture sensitive, ruling out wet granulation. Dry compaction is achieved either by roller compaction or by slugging (production of large tablets). Roller compaction is preferred to slugging because it offers greater capacity and ease of process control. It also offers a higher manufacturing efficiency per hour and, unlike slugging which is a batch process, is a continuous process. In dry compaction, the procedure is shorter because preparation of binder solution and drying are not required. It simply involves powder blending, roller compaction and milling, requiring fewer number of equipment, less time and energy and easier cleaning and validation of equipment.
  • roller compaction is a phenomenon called 'loss of re-workability' . Tablets made by roller compaction sometimes show inferior tensile strength compared to tablets prepared by wet granulation or direct compaction (slugging).
  • a second disadvantage of roller compaction is the production of non-compacted powder. Because no liquid binder is used, high quantities of fine powders remain and a lower product yield is obtained. It is therefore very important that these shortcomings are addressed by proper choice of excipients as well as the process parameters of dry compaction (see Handbook of Pharmaceutical Granulation Technology, Informa Healthcare USA, Inc., 3 edition, 2010: 170; Roller Compaction of Theophylline, H. Leuenberger, 2008).
  • wet granulation involves the addition of a liquid solution to the powder mixture and the massing of the mixture to produce granules.
  • the fluid contains a solvent that must be evaporated by drying.
  • direct compression is not applicable to mixture of powders containing certain APIs and wet granulation of the said mixture affords better re-workability.
  • wet granulation is very cumbersome, time-consuming and highly energy-extensive and affords final drug products of lower stability (vide supra).
  • a good alternative for those cases is ready-to-press granules using fluid bed granulators or similar apparatus.
  • Fluid-bed processors have been used in the pharmaceutical industry for the last 35 years. Initially, their use was limited to drying. However, fluid-bed processors are now used as multiprocessors for granulation, drying, pelletizing, and coating particles.
  • Fluidized bed granulation is a process by which granules are produced in a single piece of equipment by spraying a binder solution on to a fluidized powder bed. During the fluid-bed granulation process, the liquid feed is atomized at the top of the tower in a concurrent mode. After the liquid is evaporated, the subsequently formed particles leave the drying chamber together with the exhaust air.
  • Granules are produced for further processing in various industries.
  • ready-to-press granules are used for the production of various solid forms of drug products.
  • ready-to-press granules are obtained using a modified double cone blender dryer which, because of the said modification, can be utilized for granulation and is therefore a Blender Dryer Granulator (BDG).
  • BDG Blender Dryer Granulator
  • the BDG can be utilized for the production of pharmaceutical granules used in the production of solid dosage forms such as tablets and capsules.
  • the process of preparing granules with BDG involves blending the active ingredient with diluent(s) and binding agent to obtain homogeneous powder.
  • the binding solvent (growth solvent) is sprayed on the powder with concomitant mixing and heating to form granules.
  • Mixing, spraying and heating are adjusted and follow a specific regime depending on desired specifications of the granules. Heating the mixture can be achieved with pre -heated filtered air or through jacketed BDG or both.
  • the equipment can be subjected to vacuum to facilitate solvent removal.
  • the content of the BDG is sifted through the suitable mesh sieve.
  • the process may further include incorporating a flow enhancer, disintegrant, wetting agent or lubricant or a mixture thereof.
  • the blender dryer granulator (BDG) reported in this invention can be used for the production of ready-to-press granules in the pharmaceutical industry used in the manufacturing of solid dosage forms such as tablets and capsules. It is a further object of the present invention to provide a convenient and expedited process for the production of pharmaceutical granules with simple and quick cleaning of the granulation equipment.
  • the BDG which is used as a granulator has functions of blending, drying, fluidization and granulation as well. It is fabricated in stainless steel and is electro-polished.
  • the BDG basically consists of two conical portions and a center cylindrical midsection.
  • the powdery materials is charged into the BDG through the loading end of the apparatus via an intake valve, processed and discharged through butterfly valve at the unloading end of the double cone.
  • the manhole lid in addition to the intake valve (attached to auto-feed), is equipped with a sight glass and held to the apparatus by quick release clamps (air-sealed) for easy filling and inspection of the mixture.
  • the apparatus rests on two hollow drive shafts and is rotated around the axis of the hollow drive shafts used a gear box for controlling the rpm.
  • an internal spray systems through a hollow drive shaft for spraying the binding liquid (growth liquid) in atomized form.
  • the hollow drive shafts also serve as pre-heated filter air inlet and air exit.
  • the contents of the BDG are blended, sprayed and dried forming granules.
  • the spray nozzle disperses the liquid material into tiny liquid droplets to cover the surface of the ingredients in the powder mix. Heating the mixture is achieved by pre-heated filtered air that is guided by a stainless steel tube through one drive shaft and into the mixing chamber and sucked out through the other drive shaft using a suction fan.
  • the BDG can be jacketed and heated using hot water circulation.
  • the mixing chamber may be put under reduced pressure to expedite the removal of the spray solvent.
  • the final granules are discharged from the unloading end of the BDG through a butterfly valve and milled into the appropriate bin or container. The entire process is a closed system and the apparatus can be used for the production of ready to press granules of hazardous drugs category III-V (vide infra).
  • the process of manufacturing granules with BDG comprises first transferring powdery material, including the active ingredient, diluent(s) and binding agent, through the intake valve on manhole lid via an auto-feed. The content of the BDG is then blended to obtain a homogeneous mixture.
  • the BDG rests on two horizontal hollow shafts that serve as rotation shafts.
  • a horizontal tube located inside the entry shaft provides filtered hot air to the chamber and another horizontal pipe attached to spray nozzles provides the spray mixture.
  • Hot air maybe provided using a tube condenser (as shown above) or a simple explosion proof electric heating unit. Damp air is removed from the chamber using an exhaust fan attached to the exit hollow rotation shaft.
  • the exhaust air is filtered using change-in-place HEPA filter system and finally treated with neutralizing solution in a scrubber.
  • Sodium hypochlorite is used in the scrubber to decompose the trace quantities of sub-micronized solids that may escape the exit HEPA filters.
  • Spraying the mixture in the chamber is achieved by pumping the spray solution through a horizontal pipe located in the entry shaft and attached to spray nuzzles inside the chamber.
  • the spray solvent may contain a binder which may be dissolved or may be applied to the powder mixture as a suspension.
  • An ordinary spray system routinely used in the pharmaceutical industry is utilized to convert the liquid into tiny droplets. Thorough wetting of the powder mixture with the solvent, which may contain the binder, is followed by initial granule formation.
  • Hot filtered air is applied to dry the granules to remove the growth solvent and to harden the granules. Reduced pressure may be applied to the chamber to expedite removal of the solvent.
  • the moisturizing/drying process is successively repeated until the granules reach the desired properties (size, hardness, bulk density, etc.).
  • the content of the BDG is milled through the suitable mesh sieve and collected into an appropriate container.
  • the process may further include incorporating a flow enhancer, disintegrant, wetting agent and lubricant or a mixture thereof.
  • Unloading the product to a mill is carried out through a butterfly discharge valve which is attached to the inlet of a CoMill (air sealed).
  • Inner bag of a double polyethylene bag previously put in a drum that was placed on a tarred balance, is attached to discharge port of the CoMill (air sealed).
  • the content of the BDG is gradually directed into the mill through the discharge butterfly valve of the BDG.
  • the butterfly valve is closed and the polyethylene bag is heat-sealed four times with a distance of about 5 cm between the seals ⁇ vide infra).
  • a pair of scissors is used to cut the polyethylene bag 1 cm above and 1 cm below the 2 middle heat seals (sample), separating the BDG and the polyethylene bag containing the product as well as providing a small sealed sample in a polyethylene tube for quality control.
  • This provides a closed system for the production of high potency (HiPo) material.
  • One of the main advantages of the present invention that makes it desirable for granules production is its simplicity and cost effectiveness in design and convenience in operation and ease of cleaning and validation for product switch-over, which takes no more than an hour. It should be noted that cleaning and validation of fluid granulators takes days and is very cumbersome in the case of high potency drug products.
  • Imatinib Mesylate 54.50 kg
  • Microcrystalline Cellulose 13.68kg
  • Lactose Monohydrate 21.04 kg
  • PVP K30 2.794kg
  • the mixture was blended for 15 min. Thereafter, the spray tank was loaded with absolute ethanol (180 lit) and sprayed at a rate of 380 ml per minute to moisturize of the powdery material for 6-8 hr, concomitant with bending at a rate of 8-10 RPM.
  • Pre-heated filtered air was then introduced through the driveshaft to dry the ethanol- damp granules.
  • a suction fan attached to the second driveshaft was used to remove the solvent vapor from the BDG.
  • a sample of the granules was tested for desired bulk density of 0.4-0.6 g/ml.
  • the content of the BDG was further sprayed with the binding solvent (growth solvent) and dried to meet the bulk density requirement.
  • the granules were then sifted using a #30 Mesh sieve and then transferred back into the BDG using the auto- feed.
  • a flow enhancer, disintegrant, wetting agent and lubricant were added.
  • sodium lauryl sulfate (0.45 kg), Colloidal Silicon Dioxide (1.10 kg) and Crospovidone (8.81 kg) were first sifted using a #30 Mesh sieve and then added into the BDG via the auto-feed. The content of the BDG was blended for 30 min at 8-10 RPM. Finally, magnesium stearate (0.77 kg) was added into the BDG and mixed for 10 min at 8-10 RPM. A sample of the product was taken for loss on drying (LOD ⁇ 3.0 %. bulk density 0.4-0.6g/ml), purity and assay tests as per house validated method of analysis.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un appareil innovant et son application dans la production de granulés utilisés dans diverses industries. Ledit appareil est constitué d'un sécheur mélangeur à double cône, qui a été modifié pour un courant d'air horizontal (admission et échappement) ainsi qu'une ligne horizontale pour pulvériser une solution. Le processus de production de granulés prêtes à la compression consiste à mélanger les ingrédients pour obtenir un mélange homogène. Ensuite, un solvant est pulvérisé à l'aide d'une pompe et d'un pistolet de pulvérisation à travers les arbres de rotation creux pendant une période de temps adéquate dans laquelle des granules humides se forment. Les granules humides sont séchés avec de l'air préchauffé filtré (chauffé à une température appropriée). Un ventilateur d'aspiration est utilisé pour faciliter l'évacuation de l'air. L'appareil susmentionné offre de nombreux avantages en termes de facilité de fonctionnement, de consommation d'énergie réduite et de simplicité de nettoyage et de validation de changement de produit.
PCT/IB2017/058401 2017-01-25 2017-12-26 Nouvelle conception pour un sécheur mélangeur à double cône utilisé pour produire des granules pharmaceutiques prêtes à la compression WO2018138569A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IR13953013583 2017-01-25
IR139550140003013583 2017-01-25

Publications (1)

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WO2018138569A1 true WO2018138569A1 (fr) 2018-08-02

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PCT/IB2017/058401 WO2018138569A1 (fr) 2017-01-25 2017-12-26 Nouvelle conception pour un sécheur mélangeur à double cône utilisé pour produire des granules pharmaceutiques prêtes à la compression

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1938780A2 (fr) * 2006-12-22 2008-07-02 Collette NV Appareil pour la granulation et le séchage en continu
DE202007019511U1 (de) * 2007-06-25 2013-03-14 Gala Industries, Inc. Gerät zur Herstellung von Polymerpellets enthaltend flüchtige organische Stoffe und/oder flüchtige organische Stoffe erzeugendes Material

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1938780A2 (fr) * 2006-12-22 2008-07-02 Collette NV Appareil pour la granulation et le séchage en continu
DE202007019511U1 (de) * 2007-06-25 2013-03-14 Gala Industries, Inc. Gerät zur Herstellung von Polymerpellets enthaltend flüchtige organische Stoffe und/oder flüchtige organische Stoffe erzeugendes Material

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