WO2018138569A1

WO2018138569A1 - New design for double cone blender dryer used to produce pharmaceutical ready-to-press granules

Info

Publication number: WO2018138569A1
Application number: PCT/IB2017/058401
Authority: WO
Inventors: Khashayar Karimian; Ahmad YARI
Original assignee: Khashayar Karimian
Priority date: 2017-01-25
Filing date: 2017-12-26
Publication date: 2018-08-02

Abstract

The present invention relates to an innovative apparatus and its application in the production of granules used in various industries. The said apparatus consists of a double cone blender dryer, which has been modified for horizontal air flow (intake and exhaust) as well as a horizontal line for spraying solution. The process for the production of ready-to- press granules involves blending the ingredients to obtain a homogeneous mixture. Thereafter, a solvent is sprayed using a pump and a spray gun through the hollow rotation shafts for an adequate period of time in which damp granules form. The damp granules are dried with filtered, pre-heated air (heated to an appropriate temperature). A suction fan is used to facilitate air exhaust. The above-said apparatus offers numerous advantages in terms ease of operation, reduced energy consumption and simplicity of cleaning and validation for product change over.

Description

NEW DESIGN FOR DOUBLE CONE BLENDER DRYER USED TO PRODUCE PHARMACEUTICAL READY-TO-PRESS GRANULES

FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

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. The wet granules are then dried using a dielectric energy source, such as radio frequency (RF), microwave energy, or both. 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).

It is known that the use of 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. On the other hand, 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. Generally, 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. This is a cumbersome, energy-intensive process that also suffers from cumbersome and difficult cleaning and validation of the equipment (specially the drier) that are to be used for the production of a different product. Second, dry granulation in which no liquid is used in the process (see Handbook of Pharmaceutical Granulation Technology, Informa Healthcare USA, Inc., 3rd edition, 2010:625-626; International Journal of Pharmaceutical Sciences and Research (IJPSR), 2013; Vol. 4(1): 55-67). Dry granulation uses mechanical compression (slugs) or compaction (roller compaction) to facilitate the agglomeration. The product is then milled to required particle size distribution. This is a much superior method as compared to wet granulation in terms of efficiency, energy consumption, equipment cleaning and validation, and more importantly, drug product stability (see Handbook of Pharmaceutical Granulation Technology, Informa Healthcare USA, Inc., 3 edition, 2010: 164, 182) since the API used in wet granulation may be sensitive to moisture and heat (see The Pharma Innovation Journal 2016; 5(10): 134-141). The type of process selection requires comprehensive knowledge and understanding of physicochemical properties of the API, excipients, flow requirements and content uniformity, compressibility, dissolution, disintegration, and friability of the final drug product.

A number of different granulation and compression technologies are available to pharmaceutical manufacturers, all of which have individual strengths and weaknesses depending on the specific application. Among currently available technologies, roller compaction, low-shear granulators, medium-shear granulators, for example, fluid-bed granulators and high shear granulators are worth noting (see 1. The Pharma Innovation Journal 2016; 5(10): 134-141; 2. Granulation techniques and technologies, Bioimpacts, 2015; 5(1): 55-63; 3. Handbook of Pharmaceutical Granulation Technology, Informa Healthcare USA, Inc., 3^rd edition, 2010).

Dry compaction techniques, such as roller 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. However, one of the disadvantages of 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).

On the other hand, the process of 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. In some cases direct compression is not applicable to mixture of powders containing certain APIs and wet granulation of the said mixture affords better re-workability. However, 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.

In the early stages of wet granulation technology development, low-shear mixers such as ribbon mixers were used and continue to be used. Although process control and efficiency has increased over the years, the industry has embraced high-shear granulators over wet granulation because of its efficient and reproducibility and modern process control capabilities. On the other hand, high cost of high-shear equipment as well as its maintenance and cleaning costs for product switch over are considerable disadvantages of the high- shear granulator.

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. These particles are then separated in a cyclone or filtered and reintroduced into the drying chamber where they come into contact with wet droplets to form larger agglomerates. The process is repeated until the particle reach the desired weight at which point they cannot leave the chamber with the exhaust air. They remain there and fall down into the integrated fluid bed at the bottom of the drying chamber. Here they are dried and cooled before being discharged. The use of this method is product- dependent in that the product must have the desired properties at the end of the granulation process. However, this type of equipment is difficult to clean. Numerous mechanical items must be cleaned individually. Cleaning and validation of fluid bed granulators is a major drawback especially for product switch overs (see Handbook of Pharmaceutical Granulation Technology, Informa Healthcare USA, Inc., 3 edition, 2010:249).

BRIEF DESCRIPTION OF THE INVENTION

Granules are produced for further processing in various industries. In the pharmaceutical industry, ready-to-press granules are used for the production of various solid forms of drug products. In our process, 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). 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. Thereafter, 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. In the final step of the granulation process, 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.

SUMMARY OF THE INVENTION

It is the main object of the present invention to provide an apparatus designed for efficient production of granules in industrial scale. 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. Moreover, there is fitted 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. Therefore, 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).

DETAILED DESCRIPTION OF THE INVENTION Schematic of BDG is represented below:

tablets and capsules. 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. As it has been shown in the above schematic presentation, 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. For high potency material, 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.). In the final step of the granulation process, 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. Upon reaching the desired weight of the material in the drum, 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.

Air Seale

Scissors

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.

The details of the invention, its objects and advantages with reference to certain preferred embodiments are illustrated below in greater details by the examples provided, which are for illustrative purpose only and are not intended to limit the scope of the invention in any way. The present invention of BDG has been used to produce pharmaceutical ready-to-press granules of the following APIs in our facility: Imatinib Mesylate, Capecitabine, Erlotinib HC1 and Sunitinib Malate. The process for the production of Imatinib Mesylate pharmaceutical oral dosage form is discussed in further details in the following example.

EXAMPLES

1. Process for Closed System Production of Imatinib Mesylate Ready-to-Press Granules

Imatinib Mesylate (54.50 kg), Microcrystalline Cellulose (13.68kg), Lactose Monohydrate (21.04 kg) and PVP K30 (2.794kg) were sieved using #30 Mesh and transferred into the BDG using an auto-feed. 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. After the completion of the drying process, a sample of the granules was tested for desired bulk density of 0.4-0.6 g/ml. In case of unsatisfactory results for bulk density test 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. In the final step of preparation of ready-to-press granules, a flow enhancer, disintegrant, wetting agent and lubricant were added. To this end, 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.

2. Process for Closed System Milling of Imatinib Mesylate Ready-to-Press Granules

Claims

BDG of Example 1 was 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, was attached to discharge port of the CoMill (air sealed). The content of the BDG was gradually directed into the mill through the bottom butterfly valve of the BDG. Upon reaching the desired weight of the material in the drum, the butterfly was closed and the polyethylene bag was heat-sealed four times with a distance of about 5 cm between the heat seals. A pair of scissors was used to cut the polyethylene bag 1 cm above and 1 cm below the 2 middle heat seals, 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. 3. Process For Cleaning and Validation of Blender Dryer Granulator Upon completion of product discharge, the best solvent system for the dissolution of the API (min 250 mg/ml at 25 °C) is loaded into the BDG through the solvent intake valve on the manhole lid. In the case of Imatinib Mesylate, best solvent system is water. The volume of the wash solvent is typically 1/30 of the volume of the BDG. The apparatus is operated at 10 RMP for 10 minutes. The wash solvent is discharged, via the butterfly valve, into the mill and then into the heat-sealed polyethylene bag, which punctured to allow slow discharged in to a drum. The process of washing is repeated two more times. Sodium hypochlorite (15%) is then loaded into the BDG through the solvent intake valve to neutralize any trace of high potency API. The volume of sodium hypochlorite is typically 1/50 of the volume of the BDG. The apparatus is operated at 10 RMP for 30 minutes. The neutralizing solution is discharged in the same manner discussed above for wash solvent. The neutralization process is repeated once more. A sample of the neutralization solution is tested to complete disintegration of the high potency API. Upon QC approval, the BDG is washed with deionized water twice in the same manner as above. A sample is provided to QC for release of BDG and the CoMill. What is claimed is:

1. A closed system apparatus that can be used for the production of granules, including ready to press granules material, consisting of a vertical mixing chamber and two hollow drive shafts through which heated filtered air or gas, spray solvent, heating medium to the jacket as hot air or electrical wires for heating the vertical mixing chamber are provided.

2. A closed system apparatus of claim 1 in which heating is provided by electric wires conduit through drive shafts

3. A closed system apparatus of claim 1 in which heating is provided by a heating medium such as water, oil or steam conduit through drive shafts using stuffing box or mechanical seals for connecting the incoming and outgoing piped to the jacket.

4. A closed system apparatus of claim 1 that can be used for the production of granules that contain high potency (hazardous) ingredients.

5. An apparatus of claim 1 consisting of a vertical mixing chamber attached to two hollow drive shafts that rest on two support columns and attached to a gearbox to control rotation of the apparatus on the axis of the two drive shafts.

6. An apparatus of claim 1 in which air or an inert gas is heated to a desired temperature and filtered prior to being guided via horizontal drive shaft into the vertical chamber.

7. An apparatus of claim 1 in which spray solvents can be applied to the powder or a mixture thereof, in the mixing chamber via a horizontal drive shaft.

8. An apparatus of claim 1 in which the exit air or inert gas can be removed from the vertical chamber using a suction device such as a fan.

9. An apparatus of claim 1 in which the vertical chamber is jacketed and the heating medium is applied through a horizontal pipe located in one of the a drive shaft and removed from the jacket through the second horizontal drive in which mechanical seals or stuffing boxes provide pipe-to-pipe horizontal rotation.

10. An apparatus of claim 1 in which the vertical chamber is heated using heating wires and electricity is provided by horizontal wires that are located in the horizontal drive shafts.

11. An apparatus of claim 1 used for the production of granules in which the product is unloaded through a butterfly valve into the loading port of a CoMill using a open ended soft polyethylene tube to form air tight seals between the exit port of the butterfly valve and the intake port of the CoMill, and the milled product in unloaded into a bin or a polyethylene bag which make an air tight connection to the unloading port of the CoMill.

12. A closed system apparatus that can be subjected to very simple cleaning and validation for product switch-over in the production of a variety of granules, including high potency granules .

13. A simple, efficient, and cost effective industrial process for the production of granules using the apparatus of claim 1.

14. A process for the production of granule, including ready-to-press granules, for manufacturing pharmaceutical solid dosage forms such as tablets and capsules.

15. A process of claim 13 for the production of high potency granules.

16. A process for cleaning and validation of the apparatus of claim 1 in which the apparatus is

a. Loaded with appropriate wash solvent, rotated for a period of time and the wash solvent discharged into a containment drum containing an appropriate neutralization mixture.

b. Loaded with a neutralization mixture, rotated for a period of time and the neutralization mixture is discharged into the containment drum of claim 16a.

c. Loaded with appropriate wash solvent and rotated for a period of time and the wash solvent discharged into a containment drum containing an appropriate neutralization mixture.

d. Repeating steps 16a, 16b, or 16c as may be necessary for cleaning and validation of the cleaning of a particular product.