General aspects of granulation

Scales

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.

Batch Definition

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.

Scalability

As developments are usually 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

Productionscale 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.

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 figures 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.

Containment

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.

Organic solvents

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.

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

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 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 µm to allow a proper atomization. Tailormade 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.

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. 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.

Fine Particle Amount

If the percentage of fine particles (< 63 µm) 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.

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.

Homogeneity

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.

Flow Properties

Achieving free flowing materials is a major reason for including granulation. Therefore, only processes able to fulfil 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 3-5, show a more open porous structure, therefore, they have better instant properties, but are mechanically less stable. Further, it is assumed that cleaning is required once a week for only a few hours because it is a dedicated installation; the plant is operated in three shifts for 5 days each week; and the plant achieves 20 productive hours per day and 200 productive days per year.