senior pharmaceutical technologist Niro Pharma Systems

Harald Stahl

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 choose which one to use simply based on their own experience. This article introduces different processes, compares them objectively and offers unbiased advice on the merits of each system. It then looks at the implications of selection on two different applications.  

 A mixer/granulator that dries granules in the same equipment without discharging is commonly called a single pot (Figure 1). The granulation is done in a normal high shear processor; however, care must be taken to avoid the formation of lumps as they cannot be broken down before drying. 

 Table I : Comparison of processes Ã¢ÂÂ general aspects.      

There are various options for drying in single pots.  The traditional 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 related 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.  

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 vapour removal. However, 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). 

Table II : Comparison of processes Ã¢ÂÂ formulation aspects.

Microwave energy can be used to overcome these limitations. 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. 

 Granulation can be performed using fluid beds fitted with spray nozzles. During the last 10 years, fluid beds have improved dramatically in response to single pot technology competition. It is possible to have completely closed material handling by a closed linking with upstream and downstream equipment (Figure 2). Also, fully automatic cleaning (clean-in-place [CIP] and wash-in-place [WIP]) in fluid beds using stainless steel filters now compares favourably with what is possible in a single pot.  

High shear granulation/fluid bed drying combination

This is the most common configuration used at an industrial scale for the production of pharmaceutical granules (Figure 3). Again, 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.               

A configuration enabling this process is shown in Figure 4. For start-up, 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. The process can be controlled by monitoring the pressure drop over the product bed. The inlet air is segmented, which allows the product in different areas to be treated with different temperatures. Although the process is essentially plug flow, a significant amount of back mixing occurs during processing. 

Figure 2 : Bed top spray granulation.      

 Fluidized spray drying (FSD) produces granules from a liquid in a one-step process (Figure 5). One option is to produce the active in the primary production as granules, so that it only requires blending with excipients suitable 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 5. 

During the FSD process, the liquid feed is atomized at the top of the tower in a cocurrent 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. 

However, this type of equipment is difficult to clean, particularly the external pipework, when changing to another product. Systems have, therefore, been developed where the external pipework does not come into contact with the product (Figure 6). 

Table III : Comparison of granule characteristics.

To form granules from powders, granulation liquid and mechanical energy are needed. Alternatively, an extruder may be used similar to that used for pellet manufacture. In a typical set-up, all ingredients are preblended in a container after dispensing. Depending on the extruder design, the liquid can be added in the extruder or mixed separately to the correct consistency. The material produced is transferred directly into a continuous fluid bed where it is dried to the desired moisture level rather than rounded in a spheronizer (as it would be for pellet manufacture). An example of such a system is shown in Figure 7.       

Tables I-III provide a brief overview of the implications of particular granulation methods. All information shown assumes 'normal' products. Some special products may behave differently. 

Figure 3 : A typical set-up nstallation at an industrial scale for the production of pharmaceutical granules.              

 Option 1 is available in a range of 3-1200 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 presented as Options 4-6, 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 appropriate for very small scale production, even at the laboratory trial level, as some processing time is needed to reach equilibrium conditions.       

 This is irrelevant to batch technologies presented in Options 1-3, but requires some discussion for the continuous technologies, particularly 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 collect 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 selected to meet the batch size of a tablet coater. 

Figure 3 : A typical set-up nstallation at an industrial scale for the production of pharmaceutical granules.

 As developments are usually started in a laboratory, up-scaling 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. 

 Production-scale singe pots can weigh up to 10 tonnes. Therefore, a floor of appropriate 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 are 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 several metres 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 4-6), these systems must be integrated into the building or, better still, the building must be tailored around the installation. 

Figure 6 : An FSD spray dryer with internal filters.

 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 figures in Table I assume average cases. 

 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. 

Table IV : Key figures of production scenario 1.

 This is essential if processing toxic or very potent substances. In this case it is important to know if it is possible to achieve a closed material flow into and out of the equipment; if the equipment is tight; and if it can be cleaned automatically (including upstream and downstream connections), at least to a level where it can be opened without any danger. 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. 

Table V : Key figures of production scenario 2.

 If processing with organic solvents, the equipment must be gastight. To eliminate the risk of an explosion it is necessary to either ensure 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. Additionally, 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. 

 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. The nature of the product dictates which is the more appropriate  treatment. 

 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 act 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 Âµm 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 poorly 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.  

 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. Also, 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. 

 If the percentage of fine particles (<63 Âµm) 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, and show a clear pattern. 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, this can be reduced by adjusting the formulation. 

 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. 

 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.  

 All technologies presented generally show no problems with product homogeneity. Mixing all components in a liquid stage followed by granule production in a one-step operation will give the best homogeneity level. The material produced in the continuous fluid bed granulator might, in rare cases, show some homogeneity problems, particularly 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. 

Articles

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 choose which one to use simply based on their own experience. This article introduces different processes, compares them objectively and offers unbiased advice on the merits of each system. It then looks at the implications of selection on two different applications.

Comparing Different Granulation Techniques

Oral dosage forms are the most popular way of taking medication, despite having some disadvantages compared with other methods. One such disadvantage is the risk of slow absorption of the active pharmaceutical ingredient (API), which can be overcome by administering the drug in liquid form and, therefore, possibly allowing the use of a lower dosage. However, because many APIs only show a limited level of stability in liquid form, effervescent tablets, which are dissolved in water before administration, have been formulated as an alternative dosage form. 	

Advantages of effervescent tablets compared with other oral dosage forms include:	

an opportunity for formulators to improve the taste;

a more gentle action on a patient's stomach;

marketing aspects (fizzy tablets may have more consumer appeal than traditional dosage forms).

The disadvantages of effervescent dosage forms are the need for larger tablets, a complex production process and, very often, the need for specialist packaging materials.	

Effervescents consist of a soluble organic acid and an alkali metal carbonate salt, one of which is often the API. Carbon dioxide is formed if this mixture comes into contact with water. Typical examples of the acids and alkalis used include:				

See sidebar "Citric acid and sodium bicarbonate" for an example.	

Producing effervescent tablets requires a conventional solid dosage form manufacturing process that has been adapted to include additional features because of the unique characteristics of the product.		

Figure 1:  Example of closed powder handling using IBCs, docking stations and split valve technology (courtesy of Gallay Systems Ltd, UK).				

Material handling. The primary material used in the manufacture of effervescents is relatively hygroscopic, that is, it absorbs moisture from the air. However, this must be prevented because it will initiate the effervescent reaction. One of the principle strategies used to overcome this problem is a completely closed material handling system, which includes intermediate bulk containers (IBCs), docking stations and split valve technology (Figure 1). In addition, the ventilating air must contain a sufficiently low moisture content. This method is particularly useful if potent actives are handled that require a high level of operator protection. The alternative is the open handling of a product, which allows the use of standard equipment - although the ventilating air must still contain minimum moisture levels.	

Because most tablets are compressed by high speed rotary tablet presses, the material fed into the presses has to have properties that prevent segregation and ensure homogeneous filling of the dies, to produce tablets of equal weight. The most common approach to achieving materials with these characteristics is to granulate the raw materials. Because wet granulation will initiate the effervescent reaction, several alternatives have been established.				

Dry methods. Dry methods, such as slugging, direct compression and roller compaction are regularly used to produce solid dosage forms.2 These are the preferred methods of producing effervescents because no liquid is involved, which means that no additional drying step is required. Another advantage is the reduced need for equipment because of the limited number of unit operations required and, as a consequence, ventilation of the machinery and/or the facility can be simplified. 	

Indeed, the roller compaction method, if properly automated, can lead to very high throughput. However, the main argument against the use of dry methods is the need for expensive excipients.	

Wet granulation. For the wet granulation process, two separate granulation steps are run (one each for the alkaline and the acid components) with a subsequent dry blending step. This can be done in a high shear granulator (with subsequent drying), a single pot or in a fluid bed spray granulator.2 The advantage of this method is that only conventional equipment is needed, which could also be used for granulating and drying other materials. The major disadvantages are the running time required and the cleaning, particularly if two parallel lines are not available for the two granulations. The blending process can be a critical step and may affect the homogeneity of the tablets because not all the materials are bonded into one granule as in a conventional wet granulation process.	

Organic solvents. Because the effervescent reaction is only started if the materials come into contact with water - and not if they come into contact with organic solvents - one possibility is to use such solvents as a granulation fluid. This can be executed in a high shear granulator (with subsequent drying), a single pot or in a fluid bed spray granulator. 	

The method offers a number of advantages, which originate from the lower heat of evaporation when compared with water; high throughput; the possibility of drying at lower temperatures; and the freedom to use a number of different excipients to achieve the desired product characteristics. 	

The only disadvantage of this method is the need for more complex equipment to handle the fluids. If a fluid bed is used, then a complex system for exhaust gas treatment is required because the mixture of organic vapour and a large amount of non-condensable process gas has to be treated. This would not be the case in a tray dryer or a single pot as only the organic vapour has to be handled. Figure 2 shows an example of a single pot.	

Figure 2:  Single pot processor Ultima 75 (courtesy of Collette NV, Belgium).	

Water. It is actually possible to use water as a granulation fluid. Only a very small amount of water is added, which initiates a pre-effervescent reaction; this results in some carbon dioxide being released but water is also produced, which consequently acts as the granulation fluid, producing more carbon dioxide and more water. The cycle must be stopped at a certain point by starting the drying process and removing the water. This can be done using a high shear granulator with subsequent drying by discharging the material into a pre-heated fluid bed dryer at the end of the granulation process. The most critical step is the discharge and transfer operation, hence this method works well for small and medium batch sizes; however, it may may lead to problems for larger batch sizes because of the long time needed for this operation. 	

A second variation is to use a single pot,3 in which the granulation process can be aborted by switching to the drying mode. Drying, in this situation, can be enhanced by using a double jacket and vacuum system or by using gas or microwave technology. Again, this would be acceptable for small or medium batches but, because of a poor surface:volume ratio, would be too slow for larger batches.	

Fluid bed spray granulation. Fluid bed spray granulation is a unique process in which granulation and drying take place simultaneously. This ensures a constant low moisture level, limiting the pre-effervescent reaction to a minimum. In addition, when using a fluid bed for drying, it is easy to achieve a very low final moisture level for storage. The dis-advantage is that more granulation fluid is needed than in a high shear process.	

It is common practice in tablet production to add a lubricant after granulation; the most commonly used substance is magnesium stearate. Its function is to improve the flow of the material, which is extremely important because the dies of a tablet press are filled by volume. A second function is to prevent the tablet sticking to the punch faces or to the walls of the dies. 				

During effervescent production, substances such as magnesium stearate should not be used because they are insoluble in water and, consequently, a film will form on top of the water after the tablet has dissolved. Strategies to overcome this problem are the use of other lubricants that are soluble in water; for example, a mixture of spray dried L-leucine and polyethylene glycol.4,5 Alternatively, not using any lubricant has the advantage of avoiding the blending step, but the disadvantage of special requirements for the tablet press.	

The compression of effervescent tablets is different from the compression of normal tablets. For long-term storage, a very low moisture content is required - typically less than 0.3% water compared with approximately 2% for traditional tablets. Additionally, effervescent tablets are usually quite large, which often leads to insufficient tablet hardness and consequently broken or damaged tablets. This, in turn, results in a poor yield and also a need to stop the press or packaging line. One way of overcoming this problem is to increase dwell time by modifying the precompression assembly of the tablet press. 				

If working without a lubricant, the poorer flow characteristics of the material can be addressed using a constant level powder feed system. This consists of a rotary valve guaranteeing constant powder pressure on the forced filling station which, in connection with two independently driven feed wheels, will ensure accurate filling of the dies. The second problem, when working without a lubricant, is that the tablets may stick to the die walls or on the punch faces. This issue can be overcome using a punch face and die wall lubrication system, which allows the addition of a very small amount of solid or liquid lubricant to the punch faces and the die walls just before they come in contact with the granules (Figure 3).		

Figure 3:  Punch face and die wall lubrication system (courtesy of Courtoy NV, Belgium).	

It should be noted that because of their design, tablet presses easily accommodate the processing of effervescent materials and only release dry air into the compression zone, removing the need to vent the complete room.	

After the material has been pressed into tablets, the surface area of the material has been significantly reduced, which means that the rate at which moisture is absorbed from the air has also been reduced. Consequently, the dehumidification of the environmental air is now less critical. 				

Blisters and tube arrangements are used for packaging; for example, standard packaging materials are used in the packaging of food products or some nutraceuticals where shelf-life is not critical. This is not acceptable for pharmaceutical products. Aluminium, which has low water permeability, is used instead of standard polymer blister materials. If ten or more individual tablets are packed into one tube, very dry air can be added but as the patient opens the tube to take out the first tablet, ambient moist air will enter and destroy the remaining effervescent tablets. To overcome this, silica gel or other drying agents are incorporated into most tube lids.	

Effervescents are an interesting pharmaceutical dosage form offering some unique advantages compared with traditional tablets. The manufacturing process involves some critical steps that need to be addressed carefully during formulation and factory design.	

Oral dosage forms are the most popular way of taking medication, despite having some disadvantages compared with other methods. One such disadvantage is the risk of slow absorption of the active pharmaceutical ingredient (API), which can be overcome by administering the drug in liquid form and, therefore, possibly allowing the use of a lower dosage.