Granulation With Rapid Mixer Granulator (RMG) - A Review - Pharma Info

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Granulation With Rapid Mixer Granulator (RMG) : A Review

Submitted by on Fri, 01/04/2008 - 04:02
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Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net
Dhaval Patel, Bharat Pagi Middle Row-Sitting (Left to right): Vivek Patel, Aniket Ladani, Bhavik Patel Last Row-Sitting (Left to right): Amar Rana, Praful Vahoniya, Kalpen Patel
Krishnakant Sarvaiya and Stavan Nagori
1. INTRODUCTION
1.1 HISTORY 1.2 COMPARISION OF DIFFERENT GRANULATION TECHNIQUES 1.1 HISTORY (1) 1892:
Figure -1 The starting (1) In 1892, Walloon engineer, Emiel Collette, lost his heart to a girl from Antwerp. This love story led to the foundation of "Werkhuizen Collette" in the center of Antwerp. "Werkhuizen Collette" was a mechanical construction company that produced mainly dough mixer-kneaders for the bakery industry. During the first decades of the 20th century the company knew a steady growth and became widely known for the robust and reliable execution of their equipment. 1920 TO 1930: After World War I, Mr. Alfred Collette took over the lead of the company from his father and focussed on the growing industrialization. Collette NV was now producing machinery for several other industry sectors than the bakery industry. For example, paint mixers, potato scrapers and almond crushers were part of the machine range Collette NV had to offer.
Figure -2 Expansion (1) 1940 TO 1960: INTERNATIONALIZATION After World War II, Collette NV knew a revival by expanding the scope of their equipment to the pharmaceutical industry. Besides industrial mixers they now
also manufactured planetary mixers for both food and pharmaceutical industry. At the end of the fifties, Alfred Collette's son-in-law, Ir. Emiel Sanctorum, came in charge of the company and he invested a lot in research for new machinery and in export activities, especially to France and the BENELUX. Under his impulse, Collette NV knew a tremendous growth and the company had to move to a more suitable location then the centre of Antwerp. In 1963, the factory was moved to Wommelgem, where it is still located. As for the investment in new technologies, the most important developments from this time were the high speed kneader (SM-series), which would later turn out to be the predecessor of the first machine especially designed for pharmaceutical industry, and the MICO Collette, an automatic grinding machine originally designed for in-house use, but now still used by many large companies in the automotive industry. 1970 TO 1980: THE PHARMACEUTICAL INDUSTRY The definite breakthrough in the pharmaceutical industry came with the incorporation of Collette NV into the GEI-group in 1972 and with the introduction of the first High Shear Mixer Granulator (GRAL) in 1975. From that time on, Collette NV has become an established name in the pharmaceutical industry. Collette NV stands for innovation, new technologies and service. In 1980 the onepot concept was introduced with the TOPO-design and the GRAL-processor. In 1982, the TOPO-house opened a test lab for the customers, now better known as the Process development Center (PDC). 1990: CONTINUING INNOVATIONS
Figure -3 Innovations (1) With the introduction of the Vactron in 1990, Collette NV was one of the first machine manufacturers to promote microwave drying for pharmaceutical applications, emphasizing its focus towards this industry. But Collette NV also remained true to its roots, and still invested a lot in the development of machinery for the food industry. In 1993 for example, they introduced the CONVERTICOLL, a continuous mixeraerator, and in 1998 the CREAM MASTER has been introduced, a continuous fat cream aeration system. In 1992, when Collette celebrated its 100th anniversary, the original TOPO-house has been expanded, re-planned and re-equipped to become the Process Development Center. By now it has become a household word in the industry and many of our customers come there to run tests with their own products. 2000: LOOKING FORWARD TO THE NEW MILLENIUM Another major event at the beginning of the 21st century was the introduction of a new range of high shear mixers and single pot processors, the ULTIMATM
range. This new range is the successor of the GRAL and VACTRON ranges and answers to the strictest cGMP requirements. Its introduction signals the continuing focus of Collette on innovation and customer satisfaction. Today, Collette NV is still located in Wommelgem, near Antwerp, but its premises have grown over the years. Under the leadership of Mr. Emiel De Naeghel, the Managing Director of Collette NV until 2002, the company has continued to grow and invest in new developments for both food and pharmaceutical industry. 1.2 GRANULATION (4) The term granulation regularly refers to processes whereby aggregates with sizes ranging from about 0.1 to 2.0 mm are produced. The term pelletization is used synonymously with granulation, but in pharmacy this term is usually refers to the manufacture of aggregates, preferably spherical, with a narrow size distribution in the range of about 0.5 to 1.5 mm. (4)
1.2.1 DEFINITION (4)
Granulation is a process of size enlargement whereby small particles are gathered into larger, permanent aggregates in which the original particles can still be identified.(4) The major reason for granulating the powdered starting material in the manufacture of tablets and granules are to: To improve the flow properties so that, the mass uniformity of the dose. To prevent segregation of ingredients in the mixture. To improve the compression characteristics of the mixture. To reduce the environmental hazards for the working personnel due to dust formation from toxic materials. To reduce the bulk volume of voluminous powders and make them more convenient for storage and transport. To improve the appearance of the product.(4) The granules being heavier do not blow out of the die and do not clog the lower punch. (12)
1.2.2 TYPES OF GRANULATION (5)
GENERAL PROCESS Wet granulation
SPECIFIC METHODOLOGY Wet massing Fluid bed granulation Spray drying Pan granulation Extrusion and palletizing
Dry granulation
Roller compaction Slugging
Other processes
Humidification Melt pelletization
TABLE 1 PROCESS USED FOR PHARMACEUTICAL GRANULATIONS (5)

1.2.3 GRANULATION MECHANISMS
(A) PARTICLE-BONDING MECHANISMS
During granulation, particles adhere and agglomerate due to bond formation. These bonds should be strong enough to allow granules to withstand handling without breakdown. (14)(16) TABLE 2 CLASSIFICATION OF THE BONDING MECHANISMS RELEVANT TO DRY AND WET GRANULATION PROCESS: - (15) CLASS Solid bridges MECHANISM Sintering, heat hardening Incipient melting due to pressure or friction. Deposition during drying Immobile liquids Viscous binders Adsorption layers Mobile liquids Liquid bridges Capillary forces Intermolecular and long-range forces Van der waals forces Electrostatic forces Mechanical interlocking Shape-related bonding
(B) GRANULE GROWTH MECHANISMS
In the dry methods, particle adhesion takes place because of applied pressure. A compact or sheet is produced which is larger than the granule size required, and milling and sieving can attain therefore the required size. (3) The compact masses are called as slugs, and the process is referred to as slugging.(13) In wet granulation methods, liquid added to dry powders has to be distributed through the powder by the mechanical agitation created in the granulator (3) . The liquid plays a key role in the granulation process. Liquid bridges developed between particles, and the tensile strength of these bonds increases as the amount of liquid added is increased. These surface tension forces and capillary pressure are primarily responsible for initial granule formation and strength. (13) The particles adhere to each other because of liquid films, and further agitation and/or liquid addition causes more particles to adhere. The precise mechanism by which a dry powder is transformed into a bed of granules varies for each type of granulation equipment, but the mechanism discussed below serves as a useful broad generalization of the process. (3) The proposed granulation mechanism can be divided into three stages.
1.Nucleation: The granulation starts with adhesion among particles due to liquid bridges and the formation of agglomerates at capillary state. These structures may act as nucleus for successive enlargement of granules. (17)(18)(19) 2. Transition: (5) Nuclei can grow in two possible ways: either single particles can be added to the nuclei by pendular bridges, or two or more nuclei may combine. The combined nuclei will be reshaped by the agitation of the bed. This stage is characterized by the presence of a large number of small granules with a fairly wide size distribution. If the size distribution is not excessively large, this point represents a suitable end point for granules used in capsule and tablet manufacture. 3.Ball growth: (5) Further granule growth produces large, spherical granules and the mean particle size of the granulating system will increase with time. If agitation is continued, granule coalescence will continue and produce an unusable, overmassed system, although this is dependent upon the amount of liquid added and the properties of the material being granulated. The four possible mechanisms of ball growth are illustrated in Figure. a) Crushing and layering: (3) Granules break into fragments that adhere to other granules, forming a layer of material over the surviving granule. b) Coalescence: (3) Two or more granules join to form a larger granule. c) Abrasion transfer: (3) Agitation of the granule bed leads to the attrition of material from granules. This abraded material adheres to other granules, increasing their size. d) Layering: (3) When a second batch of powder mix is added to a bed of granules the powder will adhere to the granules, forming a layer over the surface and increasing the granule size. This mechanism is only relevant to the production of layered granules using spheronizing equipment. There is always some degree of overlap between these stages and it is very difficult to identify a given stage by inspection of the granulating system. For endproduct uniformity it is desirable to finish every batch of a formulation at the same stage, and this may be a major problem in pharmaceutical production. Using the slower processes, such as the planetary mixer, there is usually sufficient time to stop the process before overmassing occurs. With faster granulation equipment the duration of granulation can only be used as a control parameter when the formulation is such that granule growth is slow and takes place at a fairly uniform rate. In many cases, however, the transition from a nongranulated to an overmassed system is very rapid, and monitoring equipment is necessary to stop the granulation at a predetermined point, known as granulation end-point control.
Figure 4. Mechanism of Ball growth*

1.2.4 DIFFERENT GRANULATION TECHNIQUES (2)
Granulation is one of the most important unit operations in the production of pharmaceutical oral dosage forms. However, there are many different technologies each having different strengths and weaknesses. Most companies prefer which one to use merely based on their own experience.
(A) SINGLE POT
Processing: A mixer/granulator that dries granules in the same equipment without discharging is commonly called a single pot (Figure 5). The granulation is done in a normal high shear processor; however, care must be taken to shun the formation of lumps as they cannot be broken down before drying.
Figure - 5 A typical single pot set-up (2) Various options for drying :-
For small scale: - The conventional heat source comes from the dryer walls, which are heated; the boiling temperature and vacuum are used to reduce and remove vapours. The heat transfer is linked to the surface area of the dryer walls and the volume of product treated. Therefore, this direct heating method is only effective for small scale use. For large scale: - Introducing stripping gas into the pot allows large scale operation. A small quantity of gas is introduced in the bottom of the equipment, which passes through the product bed, improving the heat flow from the wall into the product. The gas also improves the efficiency of vapours removal. Limitation:- As the heated wall is the only source of drying energy, linear scale-up is not possible. This problem is exacerbated if the material to be processed is heat sensitive (as this limits the wall temperature); if water is used as a granulation liquid (it has a high boiling temperature under vacuum and a high heat of evaporation); and if used for larger-scale production (the surface/volume ratio deteriorates as the volume increases). To overcome these limitations: - Microwave energy can be used. This provides a further source of energy and has the additional advantage, with organic solvents, that only pure organic vapours must be treated on the exhaust side, and not a mixture of solvent and large volumes of process gas, as would be required in most other wet granulation technologies.
(B) FLUID BED TOP SPRAY GRANULATION
Figure - 6 Bed top spray granulation (2) Processing:Granulation can be performed using fluid beds fitted with spray nozzles. It is possible to have completely closed material handling by a closed linking with upstream and downstream equipment (Figure 6) Also, fully automatic cleaning (cleaning- place [CIP] and wash-in-place [WIP]) in fluid beds using stainless steel filters now compares favorably with what is possible in a single pot.
(C) HIGH SHEAR GRANULATION/FLUID BED DRYING COMBINATION
Figure -7 A typical set-up installation at an industrial scale for the production of pharmaceutical granules (2) This is the most common pattern used at an industrial scale for the making of pharmaceutical granules (Figure 7). Advantages:This system allows full integration with upstream and downstream equipment, and even includes a wet mill between the granulator and dryer. With modern control systems it is easy to load, mix and granulate a second batch in the high shear granulator whilst drying the previous batch in the fluid bed prior to discharge. All equipment can be CIP in a single automatic process. Whereas a single shaker might be acceptable for drying applications, a twin shaker or blowback filter design should be used for granulation processes.
(D) CONTINUOUS FLUID BED GRANULATION
Processing: The equipment is filled with raw material similar to a batch unit. After the material has been granulated, the process is switched to the continuous mode allowing material to be introduced via the rotary inlet valve and discharged as granules by a second outlet valve. Monitoring the pressure drop over the product bed can control the process. The inlet air is segmented, which allows the product in different areas to be treated with different temperatures. Although the process is effectively plug flow, a significant amount of back mixing occurs during processing.
Figure -8 Continuous fluid bed granulation (2)

(E) FLUIDIZED SPRAY DRYING (FSD)
Processing Fluidized spray drying (FSD) produces granules from a liquid in a one-step process Figure 9. One option is to produce the active in the primary production as granules, so that it only requires blending with excipients appropriate for direct compression for secondary processing.
This can only be done with actives that are tacky (in a wet state), otherwise the addition of a binder is necessary. Another possible use of FSD technology is to mix all the ingredients into a solution or suspension and to produce granules in a one-step operation. A principle drawing of an FSD set-up is shown in Figure 9(a). During the FSD process, the liquid feed is atomized at the top of the tower in a concurrent mode. After the liquid is evaporated, the particles generated leave the drying chamber together with the exhaust air. These particles are then separated in a cyclone or filter and reintroduced into the drying chamber where they come into contact with
wet droplets and form agglomerates. After these agglomerates have reached a certain weight they cannot leave via the top of the tower with the exhaust air, but fall down into the integrated fluid bed at the bottom of the drying chamber. Here they are dried and cooled before being discharged. Limitation: - this type of equipment is not easy to clean, particularly the exterior pipework, when changing to another product. To overcome these limitations: - Systems have, therefore, been developed where the exterior pipework does not come into contact with the product (Figure 9(b)).
1.2.5 COMPARISON OF GRANULATION PROCESSES (2)
Tables 3-5, a brief overview of the implications of particular granulation methods.

(A) GENERAL ASPECTS $
TABLE 3 GENERAL ASPECTS (2) Option Option Option 3 1 2 Top spray Single High granulation pot(1) shear (2) force mixer and FBD (1) SCALES AVAILABLE LS TS LS TS PS LS TS PS Option 4 Option 5 Option 6
Continuous Spray Pelleting top spray drying (3) (4) process (2)
(TS) PS
TS PS
(TS) PS
LABORATORY PS SCALE (LS) TECHNICAL SCALE (TS) PRODUCTION SCALE(PS) DEFINITION OF ++ BATCH SCALABILITY +
++
++
Material container ++(down?)
Material Material container container ++(down? ++(down?) ) Integration into building >0.5 kW/kg >98%
NEED FOR SPECIAL BUILDING
Weight Height Height
Integration Height into building
ENERGY/kG(5) >0.25 kW/kg YIELD
>0.25 >0.37 kW/kg >0.3 7kW/kg >7.5 kW/kg kW/kg >99% >99% >99%
>99.5% >99%
Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net All information shown assumes normal products. Some special products may behave differently (1) Granulation with 10% granulation liquid (TS15%) (2) Granulation with 15% granulation liquid (TS15%) (3) Mix all components of formulation in liquid form (TS20%); drying step at the end of primary production can be saved (4) Granulation with 20% granulation liquid (TS15%) (5) Only drying energy ++ very good; + good; +- fair; - poor; -- very poor
SCALES Option 1 is obtainable in a range of 31200 L. Option 2 can handle up to 1800 L. In fluid beds, batches between 30 g and 2 tonnes can be granulated. For the continuous granulation technologies offered as options 46, the situation is different. Whereas there exists no upper limit (milk powder granules are produced by spray drying at a rate of up to 10 tonnes/h), these technologies are not suitable for very small scale production, even at the laboratory test level, as some processing time is required to achieve equilibrium conditions. BATCH DEFINITION This is immaterial to batch technologies offered in Options 13, but requires some discussion for the continuous technologies, mainly if the raw materials are fed in continuously without dispensing and preblending; for example, out of large tanks or silos. The most straightforward approach is to accumulate the dry granulates in containers and define the load of each container as one batch. This method is used when operating a tablet press. Often, the size of such a container is elected to meet the batch size of a tablet coater. SCALABILITY As developments are frequently started in a laboratory, upscaling must be considered. For Options 1-3, users will only face normal up-scaling problems. Often, processes run better when scaled-up. Linear up-scaling for the single pot is only possible if microwaves are used, otherwise drying time will be increased. For continuous processes, up-scaling is easy because operation time is the only parameter to be changed. The situation becomes more complicated if it cannot be done by just running the final production plant for short periods. BUILDING REQUIREMENTS Production scale single pots can weigh up to 10 tonnes. Therefore, a floor of suitable strength must be prepared and the logistics of getting the equipment into the building considered, particularly if the equipment is not to be installed on the ground floor. For the high shear granulator/fluid bed dryer combination, both a vertical and horizontal product flow is possible. Because the transfer of wet granules is a critical step, the high shear granulator being in an elevated position makes this easier and safer. Therefore, additional height (a platform or separate floor) is
required. Production-scale fluid beds can be some meters high; however, it is not necessary to install the whole unit in the production room. If it is built as a through the wall design, all necessary technical installations can be positioned in a technical area. The upper part of the fluid bed tower can also be in a technical area above the production room. Because of the complex material handling requirements of continuous production (Options 46), these systems must be integrated into the building or, better still, the building must be tailored around the installation. ENERGY As energy consumption for drying is significantly higher than that generated by motors or vents, only the required drying energy amount is discussed. To evaporate 1 kg of water, 0.66 kWh of energy are required. The total amount of energy is both a function of the amount of liquid to be evaporated and the grade in which the equipment utilizes the energy supplied. The numbers in Table I assume average cases. YIELD The yield of a process is particularly influenced by the time the process takes and formulation. Longer processes increase yield. The wetter the granulation process, the greater the material loss (as it sticks to the walls). A third important factor is the total surface area in contact with the product. These factors are not independent from each other. They are also influenced by product characteristics. It is, therefore, not possible to provide exact figures; however, the data shown in Table 1 reflect typical scenarios.
(B) FORMULATION ASPECTS
TABLE 4 FORMULATION ASPECTS (2) OPTION 1. OPTION OPTION 3. OPTION 4. OPTION 5. OPTION 6. 2. SINGLE TOP CONTINUOUS SPRAY PELLETING POT HIGH GRANULA- TOP SPRAY DRYING SHEAR TION PROCESS FORCE MIXER AND FBD CONTAINMENT ++ HANDLE ORGANIC SOLVENTS HEAT SENSETIVE MATERIAL ++ + + ++ + + + + + +
++
(+)
(+)+(+)
(+)
LIMITATION BY none
none
PSD of raw PSD and flow fine grades limited
DIFFERENT (behaviour FORMULATIONS material if exposed to microwaves)
materials
properties of of raw raw materials materials required if worked from suspension 15-30% >100% 15-50%
AMOUNT 8-15% GRANULATION LIQUID REQUIRED CONTAINMENT
8-15% 15-30%
This is necessary if processing toxic or very potent substances. In such case it is important to know is it possible to achieve a closed material flow into and out of the equipment; if the equipment is tight; and is it possible automatically (including upstream and downstream connections). Closed material flow is possible for all processes shown. Even the very sensitive process of transferring wet granules via a wet mill from a high shear granulator into a fluid bed can be done closed. This is achieved by using modern split valve technology for contained docking to intermediate bulk containers. Although, the first five process options can be supplied in a gastight design, this is not possible for the pelletizing line (Option 6). There are also automatic cleaning problems. Whereas individual machines such as fluid beds, high shear granulators, single pots or spray dryers can be cleaned using very efficient automatic cleaning systems (WIP/CIP depending on the product), fully automatic cleaning becomes increasingly complicated as more upstream and downstream equipment are integrated. Other important factors affecting containment are how easily exhaust air filters can be changed without the risk of contamination; whether the equipment is operated continuously under negative pressure; and to what extent a sample can be contained. ORGANIC SOLVENTS If processing with organic solvents, the equipment must be gastight. To remove the risk of an explosion it is necessary to either make sure that the mixture of organic vapours and oxygen is outside the explosion limits (which can sometimes be achieved in a spray granulation process) or that nitrogen is used as a process gas. If such processes are to rely entirely on the elimination of all potential spark sources, they must be carefully checked, case-by-case. In addition, passive measures, such as a pressure shock design, suppression or venting, are always required except when using a single pot. This is because the risk of explosion exists only during the drying step, which is done under vacuum conditions. If the exhaust gas contains organic vapours it must be cleaned. This can be done in a closed cycle by cooling, adsorption or catalytic burning. Again, the single pot, particularly if used without stripping gas, has an advantage: only the pure organic vapours must be treated. HEAT SENSITIVE MATERIALS To treat heat sensitive materials successfully, the temperatures and exposure time must be carefully controlled, as should the presence of moisture and oxygen. Single pot technology provides safe drying under vacuum, particularly if the
granulation is done with organic solvents because the corresponding temperature is even lower. In a spray dryer, however, relatively high temperatures are involved, but only for a very short time. A batch fluid bed granulator can operate at higher air inlet temperatures while spraying and during the beginning of drying, reducing the inlet temperature afterwards to maintain a low product temperature. FORMULATION LIMITATIONS High shear granulators are able to granulate all types of formulations. For single pot use, the behaviour of all components exposed to microwave energy must be considered. Although this is not critical for most materials, it should be tested for new materials because of the small risk of an unexpected thermal runaway the (microwave) absorption behaviour relies on the moisture content or on the actual temperature. Fluid beds inherently at as a classifier; that is, the particle size distribution (PSD) of all raw materials should be similar. Processing very fine powders can also be problematic because these particles tend to stay in the filter area. Sometimes this can be solved by introducing the spray liquid. If a suspension is used to feed the spray dryer the suspended particles need to be smaller than 30 m to allow a proper atomization. Tailor made formulations containing, for example, a high amount of microcrystalline cellulose are needed to run an extrusion process. For inadequately soluble actives in particular, the maximum drug load that can be achieved is limited. From a processing point of view, very soluble drugs can also cause many problems. GRANULATION LIQUID For the production of oral dosage forms, high shear granulators have almost replaced medium and low shear versions because their increased mechanical energy requires less granulation liquid to produce granules of similar properties. Smaller amounts of liquid added during granulation requires less evaporation during drying, resulting in a higher throughput and lower thermal stress for the active. The numbers provided in Table I largely depend on the nature of the formulation; whether the binder is added in a liquid or a solid form; and the granule characteristic required (C) COMPARISON OF GRANULE CHARACTERISTICS OBTAINED BY DIFFERENT MAETHOD TABLE 5 CHARACTERISTICS OF GRANULES (2) OPTION OPTION OPTION 3. OPTION 4. OPTION OPTION 6. 1. 2. TOP CONTINUOUS 5. PELLETING SINGLE HIGH GRANULA- TOP SPRAY SPRAY POT SHEAR TION PROCESS DRYING FORCE MIXER AND FBD DUST/ FINE <12% <8% <5% <3% <1% none
PARTICLES D50;PSD 100-800 120-800 150-600 m 120-400 m m m 2.5-3 2.5 + +(+) 2 + + 2.5 (+) + 150-300 800-2000 m m 1.5 ++ + <1 + ++
SPAN (6)
HOMOGENEITY + FLOW PROPERTIES +
BULK DENSITY 0.7g/cm 3 0.8g/cm 3 0.7g/cm 3
0.7g/cm 3
0.6g/cm 3 near physical density ++ -
DISOOLUTION + (6) Span =(D90_D10)/D50
++
++
AMOUNT OF FINE PARTICLE If the percentage of fine particles (63 m) is too large, flow problems, segregation and poor tablet formation become common issues. The numbers shown in Table III are a reflection of the formulation and process parameters. If Option 6 is taken, no fine particles in the final product occur as all material is incorporated into the extrudate. For Options 4 and 5, fine particles cannot be discharged (because of the way in which the equipment operates), but are blown back into the operation zone where they are likely to be bound into granules. The relatively high amount of fines for the single pot process is typical of all types of vacuum drying. If seen as problematic, but adjusting the formulation can reduce this. MEAN PARTICLE SIZE All processes allow the mean particle size to be controlled by varying some process parameters. The given limits can, in some cases, be extended for bespoke equipment. SPAN The span describes how narrow a PSD is. All results shown are not critical for tablet compression, but may be of some interest if the granules are sold as a final product. HOMOGENITY All technologies presented generally show no problems with product homogeneity. Mixing all components in a liquid stage followed by granule production in a onestep operation will give the best homogeneity level. The material produced in the continuous fluid bed granulator might, in rare cases, show some homogeneity problems, mainly if the material produced just after start-up and just before close down is examined separately and is not blended with the material produced in between. FLOW PROPERTIES Achieving free flowing materials is a major reason for including granulation. Therefore, only processes able to fulfill this requirement are of interest.
The slight differences shown in Table III result from the fact that high shear granulation in general produces more dense and mechanically more stable granules. During vacuum drying, some of these granules are destroyed and a larger amount of fines is generated. BULK DENSITY The bulk density required depends on the physical densities of the materials used, from the amount and type of binder liquid, the process parameters selected and the process by which the granulation is done. The numbers shown in Table III may, therefore, vary for different materials or process conditions, but a clear pattern is shown illustrating which process will drive the bulk density in a particular direction. DISSOLUTION How easily granules dissolve (instant properties) depends on their surface energy and structure. Granules produced with lower shear forces, such as in Options 35, show a more open porous structure, therefore, they show fast dissolution profile, however they are mechanically less stable.
2. RAPID MIXER GRANULATOR (RMG) (6)

2.1 DEFINITION 2.2 VARIABLES 2.3 GENERAL PRODUCTION DESIGN OF RMG 2.4 WORKING PRINCIPLE OF RMG 2.5 INDIAN MANUFACTURED MACHINES 2.6 GLOBALLY AVAILABLE MACHINES 2.7 ADVANTAGES AND DISADVANTAGES 2.1 DEFINITION (21) High shear mixer Granulator guaranties a homogeneous and foreseeable end product. Because with it you obtain: Compressibility and fluidity properties in powders Mechanical properties to pills Bio-disponibility Mixture homogeneity in low actives doses Doses homogeneity in final product 2.2 VARIABLES
2.2.1 PROCESS VARIABLES
Process variables that affect granulation process are as follow: Impeller rotation speed
Chopper rotation speed Liquid flow rate Load of the mixer Liquid addition method Wet-massing time (subsequent of liquid addition time)
2.2.2 PRODUCT VARIABLES
Product variables that affect granulation process are as follow: Amount of liquid binder Characteristics of liquid binder Surface tension Viscosity Adhesiveness Characteristics of the feed materials Particle size and size distribution Particle specific surface area Solubility in the liquid binder Wettability Packing properties
2.2.3 APPARATUS VARIABLES
The instrumental variables affecting the granulation characteristics are: Size and shape of mixing chamber Size and shape of impeller Size and shape of chopper 2.3 GENERAL PRODUCTION DESIGN OF RMG (20) The High Shear Mixer/Granulator is a multi-purpose processor equally suitable for high speed dispersion of dry powders, aqueous or solvent granulations, and effervescent products and melt pelletization. (11) There should be both simplicity and flexibility in plant design. User-selected process options, cleaning equipment, control systems and PAT technologies combine in a system to meet process requirements exactly. This approach ensures that qualification and validation procedures are kept to a minimum. (20)
2.3.1 THROUGH-THE-WALL CONFIGURATION (20)
Through-the-wall offers the best option in terms of cleanliness, maintenance and ATEX. By keeping the motors out of the process room, you are preventing risk of contamination coming from these difficult to clean items. Maintenance is carried out from the technical area, minimizing the need for the maintenance engineer to work in a GMP area. This makes the job easier and again reduces the risk of contamination.
For ATEX, the design allows us to classify the technical area as safe. This avoids the need for costly flameproof motors, making the upgrade The frame mounting provides a standard format for the machine, allowing it to be constructed and installed using the same structure. This structure may be raised using standard modules to achieve the customers desired height. For some installations it is also possible to mount control panels on the structure, allowing qualification of the complete system prior to shipping, significantly reducing the installation time on site.
2.3.2 IMPELLER & CHOPPER OPTIONS (20)
(A) STANDARD PMA IMPELLER
Standard impeller designed for use with the conical bowl of the PMA high shear granulator.
(B)U-SHAPED CHOPPER
Standard chopper for use with the conical bowl of the PMA high shear granulator.
(C) M8 IMPELLER
Innovative swept-back design; for improved mixing characteristics,faster processing and a more clearly defined end-point.
(D) MULTI-BLADED CHOPPER
Flush mounted, multi-blade design improves binder solution dispersion and product movement at slow speeds.
2.3.3 FILTRATION (20)
(A) MATERIAL FILTER & SHROUD
Production filtration is achieved using an easily removable material filter that can be cleaned and re-used. For vacuum and CIP applications stainless steel may be utilized.
2.3.4 DISCHARGING
(A) THROUGH-THE-WALL MILL
Product can be discharged from the high shear granulator directly into a receiving container, or via a sizing mill. This breaks down the granules to produce more even sizing for subsequent processing. through-the-wall hinge-mounted sizing mill, directly connected to the discharge port, using inflatable seals. For maintenance, cleaning and product changeovers, the seals are deflated and the
mill hinged away from the port, allowing full access. The TTW mounting ensures the motor and controls are kept away from the clean process area. Pressure Shock Resistant options are available, matching the containment and safety credentials of the main machine.
(B) CONCEALED HINGE MECHANISM
The cover is mounted on a concealed hinge mechanism allowing the cover tobe lifted with the minimum effort, but keeping the counterweight in the technical area. This leads to a more GMP design, reducing surfaces, making cleaning easier. On equipment supplied with the Pressure Shock Resistant design option the hinge interlocking system is power assisted to provide safe and comfortable opening to the bowl cover.
2.3.5 LOADING (20)
(A) GRAVITY LOADING
Simple open / close ports may be mounted on the cover and used to dispense product into the mixing bowl. For potent powders, split-valve technology provides full containment during loading. The PMA-Advanced can also be delivered with a cone loading port, allowing for the removal of the powder loading ports from the cover, but giving permanent connection to a Gravity Loading Station, but also continuous access to open the cover.
(B) VACUUM LOADING
Rapid loading can be achieved using vacuum technology. Aeromatic- Fielders innovative killed-vacuum technique makes for easy operation and maintenance, and only requires a standard-sized filter.
2.3.6 BINDER SOLUTION ADDITION (20)
(A) NOZZLE
A range of nozzles are available to give the optimum binder liquid droplet size for an even distribution throughout the powder mass.
(B) PUMP
The binding solution required for granulation may be pumped into the mixing bowl using a mechanical or peristaltic pump to deliver the binder liquid to the spray nozzle. Special pumps are available for the dosing of high viscosity binders.
(C) PRESSURE POT
Alternatively a pressure pot offers fast, high-pressure delivery of the binder
solution, for excellent dispersion of liquid via the binder nozzle spray system. These systems are chosen typically for small scale, R&D-sized granulators.
2.3.7 STANDARD PLATFORM DESIGNS (OPTIONAL) (20)
Two standard platforms are available to integrate with the PMA-Advanced. The "Medium" platform provides room adjacent to the bowl for the operator to carry out all filling and cleaning operations. The XL platform additionally provides space for other items / operators on the platform and also provides sufficient space to allow the operator interface to be mounted at the platform level. Due to the clean lines of this design the bowl/ cover area can be easily accessed using mobile steps. Additionally we can offer bespoke platform design and construction services to provide the optimum integration within the available plant area.
Figure 10 Standard platform designs (20) 2.4 WORKING PRINCIPLE OF RMG (5) The mixers originally designed for mixing of thermoplastics and have later been adopted and redesigned to meet the good manufacturing practice (GMP) requirements in the pharmaceutical industry. The high shear mixers have been further developed as one pot unit, including the drying process, by use of vacuum assist and microwave or air- stripping systems. The high shear mixers have been applied to wet granulation, melt granulation and pelletization, and are set up with process control systems. Pelletization, i.e., the preparation of granulations with a controlled granule size and shape, has gained great interest since the 1970s because of its potential for controlled-release preparations for peroral administration. Wet processes like extrusion and spheronization and powder or suspension layering are most commonly used.(4) Blending and wet massing is accomplished by high mechanical agitation by an impeller and chopper. Figure shows a vertical high mixer, which is the most widely used version in the pharmaceutical industry. Mixing, densification, and agglomeration of wetted materials are achieved through shearing and compaction forces exerted by the impeller. The impeller rotates on the vertical shaft at a rotational speed corresponding to a radial blade tip speed of approximately 5-15 m/s. the chopper rotates at a similar tip speed which, because of its small diameter, corresponds to a very high rotation speed in revolutions per minute (rpm)(i.e. 1500-4000 rpm). The primary function of chopper is to cuts lumps into smaller fragments and aids the bowl or sprayed onto the powder to achieve a more homogeneous liquid distribution. The granulation is conventionally performed in the following process steps:
1. Mixing of dry material at high impeller and chopper speeds for a few minutes (approx. 2-5 min). 2. Addition of liquid binder by pouring it onto the powder, while both the impeller and chopper are running at a low speed (approx.1-2min.) 3. Wet massing with both agitators running at high speed (approx.1-5min.) 4. Wet sieving the granules. 5. Drying the granulate. 6. Dry sieving the granulate 2.5 INDIAN MANUFACTURED MACHINES
2.5.1 RAPID MIXER GRANULATOR (CHITRA) (7)
Figure 11 Rapid Mixer Granulator (CHITRA) (7) Rapid Mixer Granulator is designed to achieve excellent mixing and consistent granules at lower operating cost along with higher productivity. Better mixing and closed control of granule size leads to faster tableting speeds with improved quality and least rejections. Salient Features : Homogeneous binder distribution. Short batch time and reduce cleaning time. Maximize CIP effectiveness. Air purge sealing system for main stirrer shaft and granulator shaft. All internal contact parts are polished to the mirror finish. PLC based operating panel for precise control of process & automation. A high-speed granulator is inserted horizontally through wall of bowl to assist blending of powder and to break the product to the granules of required size. The seal housing and drive shaft may be flushed with cleaning water, which is then drained away from the machine through built in drain tubes. Granulator motors is provided with a removable stainless steel shroud which covers the motor and simplify cleaning. All moving parts of the machine are totally enclosed to eliminate accident.
The machine cannot be started unless and until the mixer cover is properly closed. All contact parts are made out of SS304. SS316 provided on demand on extra cost. Flush wall type discharge valve eliminates pockets at the port of discharge valve.
2.5.2 RAPID MIXER GRANULATOR (SAMS)(8)
Figure 12 Rapid Mixer Granulator (SAMS) (8) The Sams Rapid Mixer Granulator was developed in close co-operation with pharmaceutical and chemical industry. With the help of RMG wet sifting is generally no longer necessary. After the mixing of the dry components, subsequent wet granulation occurs (without transfer of dry mixture) producing loose granules in RMG. RMG is specially designed to meet the GMP requirements of the pharmaceutical industry.
WORKING PRINCIPLE
The Sams RMG working principle is based on 2 decisive factors essential for the mixing systems. 1. Spinning close to the bottom of the mixing bowl. 2. The impeller sets the entire mixture in a whirling-rising tumbling motion ensuring a quick and even distribution of all dry components, which leads to an even wetting of every granule. The large lumps occurred during wet mixing are broken up, by the strategically located chopping tool rotating at 1440/2880 RPM. The mix can be discharged with the impeller running through the outlet located on the side of the mixing bowl flush to the bottom. Easy accessibility for cleaning is guaranteed by the low profile. The mixing tool is easily removed from the drive shaft providing an unobstructed mixing area which may be cleaned very easily.
CONTROL PANEL
Figure 13Control panel(8) Control Panel is made up of S. S. sheet metal. It is with special feature DISPLAY SYSTEM and MICROPROCESSOR with member keys. Display system consists of indicator lamps for compressed air supply, main motor, chopper motor, bowl lid limit switch and for closed / open status of discharge valve. In case of insufficient compressed air supply pressure switch contained in the panel will prevent the machine from starting. Limit switch is provided on main bowl lid, and discharge valve, which will deenergise the system when the lid is open
MIXING BOWL
Figure 14 Mixing Bowl (8) Dome shaped processing bowl which directs loose particles into whirling motion with the help of impeller. Impeller consists of 2 full and 2 half solid mixing blades. Inclination of the mixing blades accelerates rising and tumbling motion of the product in the bowl. Specially designed chopper blades driven at high speed gives fast and even granulation, throughout the whole mass in the product bowl. For easy accessibility in cleaning the side discharge assembly is provided with hinges.
SPECIAL FEATURES
Unit is designed to meet requirements of GMP. Contact Parts can be SS 304 / 316 quality.
Specially designed control panel with display system and microprocessor. Bowl, lid mixing agitator, discharge housing and all other contact parts will be stainless steel. All M.S. parts of the machine are cladded / covered with stainless steel Components of the machine are having easy accessibility for cleaning. All electrical & pneumatic parts are pre-wired to simplify installation. Limit switch is provided on main lid and discharge valve for safe operation. Discharge can be provided on either side to suit client requirement. 2.6 GLOBALLY AVAILABLE MACHINES (7) Sr. No. 1. MFR Size (liter) COLLETTE 400 ONE (1) Used Collette High Shear Granulating Mixer, Model Gral 400, 400 liter capactiy, stainless steel construction, with 960 MM diameter X 600 MM deep bowl with pneumatically operated plug valve discharge, with bowl lifter and cart, 3 speed main blade, 2 speed chopper blade, 15/22 KW motor, Serial No. 92GR10400147, New 1992. ONE (1) Used Diosna high shear granulating mixer, model P25,25 liter capacity, stainless steel construction, jacketed bowl rated 3 bar (43.5 PSI), 2/2.4 KW high speed chopper, 2/2.4 KW main drive, 460 volt, manually operated plug valve discharge, WIP design, mounted on stainless steel enclosure with controls, serial no. 241-081. ONE (1) Used Fuji Powrex High Shear Granulating Mixer, Model FM-VG-10, 10 liter capacity, sanitary polished stainless steel construction, manually operated plug valve discharge, 2.2 KW variable speed main drive, .75 KW two speed chopper drive, on portable base with controls, Serial No. 903235, New 1990. ONE (1) Used Fukae Powtec High Shear Granulating Mixer, Model LFS-GS-2J, 2 liter capacity, sanitary stainless steel construction, jacketed bowl, hinged cover with filter, side chopper, variable speed main and chopper drives with control panel, Serial No. 662, New 1993. ONE (1) Used Glatt High Shear Granulating Mixer, Model VG50,50 liter Description
2.
DIOSNA
25
3.
FUJI
10
4.
FUKAE
5.
GLATT
50
capacity, stainless steel construction, jacketed bowl, with 1.5 KW 3000 RPM high speed side mounted chopper, 5.5 KW 25550 RPM main drive, mounted on stainless steel enclosure with PLC controller, serial no. 00761, new 1996. 6. GLATT POWREX 25 ONE (1) Used Powrex High Shear Granulating Mixer, model FM-VG-25, 25 liter capacity, sanitary polished stainless steel construction, jacketed bowl, manually operated plug valve discharge, 3.7 KW variable speed main drive, 1.5 KW variable speed chopper drive, on portable base with controls, serial no. 933306, new 1994. ONE (1) Used 15 liter Key International High Shear Granulating Mixer/Dryer, Model KG15, 316 stainless steel products contacts, chamber rated for rull vacuum internal, jacketed bowl rated to 105 degrees C, 3 H.P. DC main motor with 0550 RPM shaft speed, top mounted .5 H.P. DC chopper motor, mounted on portable base with Mokon Hot Oil Unit, Siemans Vacuum Pump and 6 Line Alpha Numeric PLC Controls. Unit New in 1993 and in like new condition. ONE (1) Used Diosna high shear granulating mixer, model P-Vac 10/60, stainless steel construction, with 60 liter and 20 liter interchangeable bowls, high speed chopper and main drive, mounted on stainless steel enclosure with controls, serial no. 370-004, new 2000. ONE (1) Used Niro Fielder High Shear Granulating Mixer, model PMA25, 25 L capacity, stainless steel construction, jacketed bowl, 1.3/1.8 KW high speed chopper, 5.5 KW DC maindrive, 440 volt, pneumatically operated plug valve discharge, mounted on stainless steel enclosure, with controls, serial no. 8012, new 1990. ONE (1) Used T.K. Fielder High Shear Granulating Mixer, Model PMA5026, 50 liter capacity, sanitary stainless steel construction, pneumatically operated plug valve, with integrally mounted control panel, 10/7.5 H.P. 220 volt main drive, 2.27/1.54 H.P. 220 volt chopper drive, Serial #2324.
7.
KEY INTERNATIONAL
15
8.
N/A
60
9.
NIRO FIELDER
25
10.
T.K. FIELDER
50
65
ONE (1) Used TK Fielder High Shear Mixer / Granulator / Dryer, Model SP65, stainless steel construction, 65 liter bowl, 7.5 KW main drive, 0-400 RPM main impeller speed, 1.3-1.8 KW high speed chopper, 1.5 KW microwave heating source, Serial No. 7829. ONE (1) Used T.K. Fielder High Shear Granulating Mixer, Model PMA3002G, 300 liter capacity, sanitary stainless steelconstruction, pneumatically operated flush plug valve, 10/7.5 side entry chopper, operator panel, control cabinet, 440 volt DC main drive with SCR Controller, 220 volt controls, Serial No. 2249, Built Feb. 1982, mounted on stainless steel base. ONE (1) Used T.K. Fielder High Shear Granulating Mixer, Model PMA-400, 400 liter capacity, sanitary stainless steel construction, jacketed bowl rated 2 bar (29 PSI), 10/7.5 H.P. 1800-3600 RPM chopper, 25/30 H.P. 0-200 RPM main drive,on base with variable speed controllers, with platform, dustcollector, blower, rotary air lock and associated parts and controls, Serial No. 8268, new 1994. ONE (1) Complete 1200 liter TK Fielder/Niro Pharma Systems Mixer/Granulator/Dryer Installation including: ONE (1) Model SP1200 Mixer, with microwave heat source, bowl jacketed for 70 PSI, 0-140 RPM rotor speed, chopper blade assembly. System includes Vac-U-Max Dust Collector, KEU S/SMill, 200 gallon Lee Tank with agitator, 40 gallon Lee Tank with agitator, S/S Plate Exchanger, Toledo Platform Scale, Bal-Trol Pneumatic Hoist, Acme Package Chiller, Model DDCA-95, Niagara Series HP Custom Air Handling Unit. System is complete with all inter-connected piping, controlsSerial No. 7865, New 1989. ONE (1) Unused Zanchetta Roto P Processor, Mixer/Granulator/Dryer, Model 400P, 400 liters total capacity, sanitary stainless steel construction, plug style discharge valve pneumatically operated, hinged cover, telescopic chopper, tilting bowl, hydraulic drive, jacketed bowl and cover.
300
400
1200
11.
ZANCHETTA
400
2000
ONE (1) Used Zanchetta Roto Granulating Mixer, Model Roto 2000G, 2000 liter capacity, all sanitary stainless steel construction, variable speed hydraulic drivetelescopic high speed adjustable chopper, standard paddle style granulating mixer blade, stainless steel base, cover and control console, vacuum rated, jacketed bowl, complete system New in 1992, 1859 total hours of service.
2.7 ADVANTAGES AND DISADVANTAGES OF RAPID MIXING GRANULATOR(4)

2.7.1 ADVANTAGES:-
Gravity loaded Unit formula maintained Forms desired wet granule rapidly Less wetting and more rapid drying Homogeneously dry mixes quickly: color distribution is excellent; can eliminate premixes of addition by geometric progression Self-discharging Improved coefficient of weight variation Improved content uniformity Sanitary construction Relatively easy to clean Mixing bowl may be jacketed Option to dry granulation with mixer Adequate safety devices Conforms to good manufacturing practices(GMP)
2.7.2 DISADVANTAGES:-
Relatively high cost High noise level Adding material directly is not convenient Temperature rise from head of friction Non movable Must be raised to working height Foreign spare part
3 INNOVATIONS
3.1 UltimaGral (9) The basic UltimaGral design, first introduced in 1972, is a high shear mixer granulator, in which the processes of dry mixing, wet mixing, and granulation can be executed. The most important features of this basic design are the top-driven mixer and chopper, the removable bowl, and the "through-the-wall" installation of the larger machines.
Figure 15Ultima 25 (9) The basic UltimaGral design ranges from 10 L to 1200 L machines.The range of UltimaGral processors extends the concept of the basic UltimaGral and allows us to execute the whole cycle of mixing, granulating and drying in a totally contained environment. The UltimaGral processors are equipped with a vacuum system to allow drying of the granulate. The Transflo system (gas-assisted vacuum drying) can also be provided on UltimaGral processors. Same design of process bowl, mixer and chopper make sure that process and validation wise there is no difference to the Collette Gral. This unique design of process bowl, mixer and chopper makes the UltimaGral not only a perfect wet granulator but also an ideal machine for melt granulation and pelletizing.
STAND ALONE ULTIMAGRAL
Any applications of a high-shear mixer-granulator do not require integration with other equipment. The UltimaGral design allows for different ways of setting up a stand-alone machine in a GMP-compliant way: The through-the-wall execution: Space saving, GMP compliant. In the freestanding execution, all mechanical parts are completely covered and sealed, so the machine remains GMP compliant.
CLEAN IN PLACE (CIP)
Contained processing also requires that the equipment can be cleaned in a contained fashion. The UltimaGral can be equipped with a full CIP system that ensures cleaning-in-place of product feed, product filter, bowl and lid and discharge valve.Downstream equipment such as a mill can be incorporated in the CIP system.
PROCESS TECHNOLOGIES
Apart from executing standard wet granulation processes, the UltimaGral can be used for many other applications, such as: Melt granulation Pelletization The UltimaGral can produce a wide variety of products which are as follows:Effervescents formulation
Formulations developed for alternative technologies Low binder formulations Moisture, heat or light sensitive products Vitamins Highly potent or toxic drugs
CONTROL SYSTEMS
Basic solution: OP/PLC based (standard) Operator panel as user-friendly interface with the machine Paperless recorder for historical trending High end version: PC/PLC based, batch oriented software with process visualization. Software compliant with ISA S88.01 and NAMUR batch processing standards, quasi-3D process visualization, and unlimited number of recipes. Software designed to be compliant with FDA 21 CFR Part 11.
Real-time storage of batch information in a relational database. Possible integration into higher level business and enterprise planning systems such as SAP, etc. Video camera for easy visual process monitoring. The basic UltimaGral design is a high-shear mixer-granulator without drying capacities. The features of a basic UltimaGral high-shear mixer-granulator are the following:
STANDARD FEATURES
Top driven mixer and chopper. Vertical chopper shaft. No seals in direct contact with the product. Free standing machine OR through-the-wall design (only for 75 L or larger). Easy to wash-in-place (WIP). Built to GMP-standards. Easy validation. Full stainless steel construction in process room. Total containment of the product. Twin speed chopper and mixer. Full interlocked guarding. Operator control panel on the machine. Easy access for maintenance. 3.2 VG SERIES (10) A Glatt VG (Vertical Granulator) allows extremely fast Wet granulation with high granulate densities and thus very good particle stability. Batch sizes varies from
100l to 3000l/batch.
Figure 16 Vertical Granulator (10)

IDEAL PROCESS PARTNER
A vertical granulator is the perfect partner for a fluid bed dryer for optimum economy. Pellets can be manufactured if the vertical granulator is combined with a spheronizer/pelletizer for subsequent spheronization of the granulate. SinglePot systems provide the facility to dry the granulate. For the use of organic solvents, the vertical granulator can be combined with a special vacuum system with integral solvent recovery.
UNIQUE TECHNOLOGY
Due to the consistent modular design, the system can be configured individually and easily matched to the constructional circumstances and specific requirements. The heart of the Glatt vertical granulator is the patented "Z"shaped rotor blade.This and various product-optimized chopper designs are the result of many years of successful development and cooperation with the Japanese specialist, Powrex.
Figure 17Patented "Z"-rotor (10)

CYLINDRICAL WORKING VESSEL
It is used for non-sticky products in campaign production.
Figure 18Glatt vertical granulator with cylindrical working vessel(10)

CONICAL WORKING VESSEL
It is used for sticky products and similar processes with identical accessory configurations.
Figure 19 Glatt vertical granulator with conical working vessel(10)

SIMPLE HANDLING
It can easily be incorporated into horizontal or vertical product flow. The vertical granulator can be filled manually by means of containers with lift and transporter devices (or charging stations) or pneumatically by means of suction conveyor systems. The granulate is discharged from the working vessel into a fluid bed machine or a container, either gravimetrically or by means of pneumatic conveyors. A GSF rotor mill is often used downstream in order to achieve a homogeneous granulate spectrum.
USER-FRIENDLY CONTROL SYSTEM
Glatt offers the customized EcoView and MegaView control systems with simple, logically designed operator guidances, clear process visualizations as well as detailed and informative process documentation. Qualification and validation of the control systems are possible up to GAMP 4. All control systems are designed in-house by Glatt based on hardware and software that has become established throughout the world. Advantages are long-term investment security, superior plant availability, and immediate and rapid support.
Figure 20Glatt vertical granulator (10)

THE VG PRO DESIGN
Figure 21 Underside of VG cover with recessed washing nozzles and stainless steel CIP filters (10) The advantage of VGPROdesign includes:Globally unique 12 bar pressure shock resistance. Contained design. New design and special materials for low weight. Pneumatic sealing with Glatt-C flanges. No need for explosion protection measures between fluid bed dryer and vertical
granulator. Confirms to ATEX standards with CE labels or EC Manufacturer's Declarations (for partial machines). Can be fitted through-the-wall - clean separation of production and equipment. Maintenance and service work can be carried out on the unit during production and without bringing maintenance personnel into the GMP area. Suitable for WIP/CIP * The figure or table represented to express the comparison or concept which is not available in any of the reference book. It is drawn by our self to simplify the concept.
4. REFERENCES
1. www.niropharma.com/granulation/history/14 th January 2007 2. www.ptemagazine.com/14 th January 2007,(pharmaceutical techno l og y, Europe, November 2004) 3. Aulton M.E., second Edition Granulation, Pharmaceutics The science of dosage form design, Churchill Livingstone, Edinburgh, Second edition, 181,187,188, 2002 4.Swarbrick J, Boylan J.C, Granulation, Encyclopedia of pharmaceutical technology, Marcel Dekker INC, New York, Volume- 7, 121123, 1992 5. Dilip M. Parikh, Theory of Granulation, Handbook of Pharmaceutical Granulation Technology, Marcel Dekker INC, New York , 8,15,16,152, 1997 6. Dilip M. Parikh, High Shear Mixer Granulators, Handbook of Pharmaceutical Granulation Technology, Marcel Dekker INC, New York, 165181, 1997 7. www.bhagwatipharma.co.in/22 th January 2007 8. www.samsmachines.com/22th January 2007 9. www.niroinc.com/22 th January 2007 10. www.glatt.com/22 th January 2007 11. www.niropharma.com/22th January 2007 12. S.J.Carter, Powder flow and Compaction, Cooper and Gunns Tutorial pharmacy, 6 th edition, CBS publishers & distributors, New Delhi, 217, 2000 13. Leon Lachman, Herbert A. Liberman, Joseph L. Kanig, Tablets, The Theory and Practice of Industrial Pharmacy, 3 rd edition, Varghese publishing house, Bombay, 318-320, 1991 14. Rumpf H., The Strength of Granules and agglomerates Agglomeration (W.A.Knepper,ed.), Interscince publisers, New york,379-419, 1958 15. Rumpf H., The Strength of Granules and agglomerates Agglomeration (W.A.Knepper,ed.), John Wiley, New york, 97-129, 1962 16. Ghebre-Sellassie I., Mechanism of Pellet Formation and Growth, Pharmaceutical Pelletization Technology, (I. Ghebre-Sellassie,ed.), Marcel Dekker,Inc.,New York, vol.37,123-143, 1989 17.Summers M.P., Granulation, Pharmaceutics, The science of Dosage
Forms Design, (M.E.Aulton,ed.), Churchill livingstone, New York,616-628, 1988 18. Worts O.M., Rev.Port.Farm.23, 438-449, 1973 19. capes C.E., Size Enlargement Methods and Equipment, Handbook of powder Science and Technology, (M.E. Fayed and L. Otten, eds.), Van Nostrad Reinhold, new York, 230-251, 1984 20. www.niropharma.com/design/High shear mixer granulator/9 th march 2007 21. www.cronimosr.com/product/High shear mixer granulator/9 th march 2007
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Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.

Validation Training Pharmaceutical Validation Courses GMP Compliance and Consultancy

Granulation With Rapid Mixer Granulator (RMG) : A Review

Fluidbed dryer for Chemical and Food Industries made by Vibra-Schultheis

Dr. Mukesh Gohel

Pelletizing needed? Machines for pellet production, extrusion and spheronization!

Dr. Rajesh Parikh

Freeze Granulation Homogeneous granules nano ceramic powders, chemicals, pharmaceuticals

Top Row-Standing (Left to right): Dharmendra Chaudhary, Manoj Patel

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Krishnakant Sarvaiya and Stavan Nagori

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

GENERAL PROCESS Wet granulation

Roller compaction Slugging

Humidification Melt pelletization

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

TABLE 1 PROCESS USED FOR PHARMACEUTICAL GRANULATIONS (5)

(A) PARTICLE-BONDING MECHANISMS

(B) GRANULE GROWTH MECHANISMS

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Figure 4. Mechanism of Ball growth*

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Figure -8 Continuous fluid bed granulation (2)

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Tables 3-5, a brief overview of the implications of particular granulation methods.

Material container ++(down?)

NEED FOR SPECIAL BUILDING

Weight Height Height

Integration Height into building

ENERGY/kG(5) >0.25 kW/kg YIELD

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

PSD of raw PSD and flow fine grades limited

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

DIFFERENT (behaviour FORMULATIONS material if exposed to microwaves)

AMOUNT 8-15% GRANULATION LIQUID REQUIRED CONTAINMENT

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

HOMOGENEITY + FLOW PROPERTIES +

BULK DENSITY 0.7g/cm 3 0.8g/cm 3 0.7g/cm 3

0.6g/cm 3 near physical density ++ -

DISOOLUTION + (6) Span =(D90_D10)/D50

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

2. RAPID MIXER GRANULATOR (RMG) (6)

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

(A) STANDARD PMA IMPELLER

(A) MATERIAL FILTER & SHROUD

(A) THROUGH-THE-WALL MILL

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

(A) GRAVITY LOADING

Alternatively a pressure pot offers fast, high-pressure delivery of the binder

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net

Granulation With Rapid Mixer Granulator (RMG) : A Review | Pharmainfo.net