To prevent segregation of the constituents of the powder mix

Segregation (or demixing, discussed in Chapter 11) occurs primarily due to differences in the size and/or density of the components of the mix; the smaller particles and/or denser particles concentrate at the base of a container with the large particles and/or less dense above them. An ideal granulation will contain all the constituents of the mix in the correct proportion in each granule, and if this is achieved segregation of individual ingredients will not occur (Fig. 28.1).

It is also important to control the particle size distribution of the granules because, although the individual components may not segregate, if there is a wide size distribution of the granules themselves, the granules may segregate. If this occurs in the hoppers of sachet-filling machines, capsule-filling machines or tabletting machines, products having large weight variations will result. This is because these machines fill by volume rather than weight. If different regions in the hopper contain granules of different sizes (and hence different bulk density), a given volume from each region will contain a different weight of granules. This will lead to an unacceptable variability of the drug content within the batch of finished product even if the drug is evenly distributed, weight per weight, through individual granules.

To improve the flow properties of the mix

Many powders, because of their small size, irregular shape or surface characteristics, are cohesive and do not flow well. Poor powder flow will also often result in a wide weight variation within the final product due to variable fill of tablet dies, etc. The resulting granules produced from irregular particles will be larger and more isodiametric, both factors contributing to improved flow properties (discussed more fully in Chapter 12).

To improve the compaction characteristics of the mix

Some primary powder particles are difficult to compact into tablets even if a readily compactable adhesive is included in the blend. Granules of the same formulation are often more easily compacted and produce stronger tablets. This is associated with the method employed to produce the granule and its resulting structure. Often solute migration (see Chapter 29) may occur during the post-wet granulation drying stage and this can result in a binder-rich outer layer to the granules. This in turn leads to direct binder–binder bonding which assists the consolidation of weakly bonding materials.

Other reasons

The above are the primary reasons for the granulation of pharmaceutical products but there are others which may necessitate the granulation of powdered material:

• effervescent granules

• coated granules

• gastro-resistant granules

• modified-release granules.

Dry granulation

In the dry methods of granulation, the primary powder particles are aggregated at high pressure. There are two main intermediate processes. Either the production of a large tablet (known as a ‘slug‘) in a heavy-duty tableting press (a process known as slugging) or the powder is squeezed between two rollers to produce a sheet or flakes of material (roller compaction). In both cases, the intermediate product is broken using a suitable milling technique to produce granular material which is usually sieved to separate the desired size fraction. The unused fine material may be reworked to avoid waste. This dry method may be used for drugs which do not compress well after wet granulation or those which are sensitive to moisture.

Wet granulation (involving wet massing)

Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid. The granulating fluid contains a solvent that must be volatile, so that it can be removed by drying, and is non-toxic. Typical suitable liquids include water, ethanol and isopropanol either alone or in combination. The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved adhesive (also referred to as a binder or binding agent) which is used to ensure particle adhesion once the granule is dry.

Water is commonly used for economic and ecological reasons. The disadvantages of water as a solvent are that it may adversely affect drug stability, causing hydrolysis of susceptible products, and it needs a longer drying time than organic solvents. This long drying time increases the duration of the process and again may affect chemical stability of the drug(s) because of the extended exposure to heat. The primary advantage of water is that it is non-flammable, which means that expensive safety precautions such as the use of flame-proof equipment need not be taken. Organic solvents are used as an alternative to dry granulation when water-sensitive drugs are processed, or when a rapid drying time is required.

In the traditional wet granulation method, the wet mass is forced through a sieve to produce wet granules which are then dried. A subsequent screening stage breaks agglomerates of granules and removes the fine material which can be recycled. Variations of this traditional method are dependent upon the equipment used but the general principle of initial particle aggregation using a liquid remains in all of the processes.

An alternative to the traditional wet-granulation process is melt granulation whereby thermosetting polymers are used to form the granules. This process is described below.

Effect of granulation method on granule structure

The type and capacity of granulating mixers significantly influence the work input and time necessary to produce a cohesive mass, adequate liquid distribution and intragranular porosity of the granular mass. The method and conditions of granulation affect intragranular pore structure by changing the degree of packing within individual granules. It has been shown that precompacted granules, consisting of drug and binder particles, are held together by simple bonding formed during consolidation. Granules prepared by wet massing consist of intact drug particles held together in a sponge-like matrix of binder. Fluidized-bed granules are similar to granules prepared by the wet massing process but possess greater porosity, and the granule surface is covered by a film of binding agent. With spray-dried systems, the granules consist of spherical particles composed of an outer shell with an inner core of particles or air. Thus, the properties of the granule are influenced by the manufacturing process.

1. adhesion and cohesion forces in the immobile liquid films between individual primary powder particles

2. interfacial forces in mobile liquid films within the granules

3. the formation of solid bridges after solvent evaporation

4. attractive forces between solid particles

5. mechanical interlocking.

Adhesion and cohesion forces in immobile films

If sufficient liquid is present in a powder to form a very thin, immobile layer, there will be an effective decrease in interparticulate distance and an increase in contact area between the particles. The bond strength between the particles will be increased because of this, as the van der Waals forces of attraction are proportional to the particle diameter and inversely proportional to the square of the distance of separation.

This situation will arise with adsorbed moisture and accounts for the cohesion of slightly damp powders. Although such films may be present as residual liquid after granules prepared by wet granulation have been dried, it is unlikely that they contribute significantly to the final granule strength. In dry granulation, however, the pressures used will increase the contact area between the adsorbed layers and decrease the interparticulate distance and this will contribute to the final granule strength.

Thin, immobile layers may also be formed by highly viscous solutions of adhesives. The resulting bond strength will be greater than that produced by the mobile films discussed below. The use of starch mucilage in pharmaceutical granulations may produce this type of film.

Interfacial forces in mobile liquid films

During wet granulation, liquid is added to the powder mix and will be distributed as a film around and between the particles. Sufficient liquid is usually added to exceed that necessary for an immobile layer and this produces a mobile film. The three states of water distribution between particles are illustrated in Figure 28.2.

At low moisture levels, termed the pendular state, the particles are held together by lens-shaped rings of liquid. These cause adhesion because of the surface tension forces of the liquid–air interface and the hydrostatic suction pressure in the liquid bridge. When all the air has been displaced from between the particles, the capillary state is reached, and the particles are held by capillary suction at the liquid–air interface, which is now only at the granule surface. The funicular state represents an intermediate stage between the pendular and capillary states. Moist granule tensile strength increases about three times from the pendular to capillary state.

It may appear that the state of the powder bed is dependent upon the total moisture content of the wetted powders but the capillary state may also be reached by decreasing the separation of the particles. In the massing process during wet granulation, continued kneading/mixing of material originally in the pendular state will densify the wet mass, decreasing the pore volume occupied by air and eventually producing the funicular or capillary state without further liquid addition.

In addition to these three states, a further state, the droplet, is illustrated in Figure 28.2. This will be important in the process of granulation by spray drying of a suspension. In this state, the strength of the droplet is dependent upon the surface tension of the liquid used.

These wet bridges are only temporary structures in wet granulation because the moist granules will be dried. They are, however, a prerequisite for the formation of solid bridges formed by adhesives present in the liquid, or by materials which dissolve in the granulating liquid.

Solid bridges

These can be formed by:

Attractive forces between solid particles

In the absence of liquids and solid bridges formed by binding agents, there are two types of attractive force which can operate between particles in pharmaceutical systems.

Electrostatic forces may be of importance in causing powder cohesion and the initial formation of agglomerates, e.g. during mixing. In general they do not contribute significantly to the final strength of the granule.

Van der Waals forces, however, are about four orders of magnitude greater than electrostatic forces and contribute significantly to the strength of granules produced by dry granulation. The magnitude of these forces will increase as the distance between adjacent surfaces decreases and in dry granulation this is achieved using pressure to force the particles together.

Nucleation

Granulation starts with particle–particle contact and adhesion due to liquid bridges. A number of particles will join to form the pendular state illustrated in Figure 28.2. Further agitation densifies the pendular bodies to form the capillary state and these bodies act as nuclei for further granule growth.

Transition

Nuclei can grow by two possible mechanisms: 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. Providing that the size distribution is not excessively large, this point represents a suitable endpoint for granules used in capsule and tablet manufacture as relatively small granules will produce a uniform tablet die or capsule fill. Larger granules may give rise to problems in small-diameter dies due to bridging across the die and uneven fill.

Ball growth

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, over-massed system, although this is dependent upon the amount of liquid added and the properties of the material being granulated.

Although ball growth produces granules which may be too large for pharmaceutical purposes, some degree of ball growth will occur in planetary mixers and it is an essential feature of some spheronizing equipment.

The four possible mechanisms of ball growth are illustrated in Figure 28.3.

Shear granulators

The older shear granulators have largely disappeared and have been replaced by the much more efficient high-speed mixer/granulators. In the traditional shear (or planetary) granulation process, dry-powder blending usually has to be performed as a separate initial operation using different powder-mixing equipment. The older process suffered from a number of major disadvantages: its long duration, the need for several pieces of equipment and the high material losses which can be incurred because of the transfer stages between the different equipment. The process served the pharmaceutical industry well for many years but the advantages of modern mixer/granulators have proved too attractive for their continued use.

High-speed mixer/granulators

This type of granulator (e.g. Diosna) is used extensively for pharmaceutical granulation. They were developed from traditional planetary mixers in order to speed up the process and to reduce the number of pieces of equipment and separate process steps required. The machines have a stainless steel mixing bowl containing a three-bladed main impeller which revolves in the horizontal plane and a three-bladed auxiliary chopper (or breaker blade) which revolves in either the vertical or horizontal plane (Fig. 28.4). The main blade is designed to rotate at about 150–300 rpm and the high-speed chopper rotates at about 1500 and 3000 rpm.

The unmixed dry powders are placed in the bowl and mixed by the rotating impeller for a few minutes. Granulating liquid is then added via a port in the lid of the granulator whilst the impeller is turning. The granulating fluid is mixed into the powders by the impeller. The chopper is usually switched on when the moist mass is formed as its function is to break up the wet mass to produce a bed of granular material. Once a satisfactory granule has been produced, the granular product is discharged, passing through a wire mesh, which breaks up any large aggregates, into the bowl of a fluidized-bed drier.

Like most modern process equipment, high-speed mixer/granulators are available in a wide range of sizes. These are often designed to have similar geometric and powder movement characteristics in an attempt to minimize scale-up problems when a product moves from development to production. Bowl volumes between 1 L and 1250 L are available. The weight of powder that each holds will depend on its bulk density and the optimum fill capacity (working volume) of each bowl. Bowls are manufactured from high-quality polished stainless steel.

The advantage of the process is that powder blending, wet massing and granulation are all performed in a few minutes in the same piece of equipment. The process needs to be controlled with care as the granulation progresses so rapidly that a usable granule can be transformed very quickly into an unusable, overmassed system. Thus it is often necessary to use a suitable monitoring system to indicate the end of the granulation process, i.e. when a granule of the desired properties has been attained. The process is also sensitive to variations in raw materials but this may be minimized by using a suitable granulation endpoint monitor.

A variation of the Diosna type of design is the Collette UltimaGral mixer (GEA Collette, Vanguard) (Fig. 28.5). This is based on the bowl and overhead drive of the planetary mixer but the single paddle of a planetary mixer is replaced with two mixing shafts. One of these carries three blade arms which rotate in the horizontal plane at the base of the bowl and the second carries smaller blades which act as the chopper and rotate rapidly in the upper regions of the granulating mass. Thus, the operating principle is similar to that of the Diosna type described above.

This design is available in sizes ranging from 10 L to 200 L volume (capable of processing about 3 kg to 80 kg batches, respectively). The main mixing blade rotates at 450–600 rpm in the 10 L model and at 150–200 rpm in the 200 L model. This rotational speed variation is to attempt to maintain the same linear velocity of movement of the blades, as this has been found to help scale-up. In all models the high-speed chopper rotates at 1500–3000 rpm.

An attractive feature of high-speed granulators is the fact that the product is usually granular and a separate step to granulate the wet mass is avoided (the granules being produced by the action of the high-speed chopper). Occasionally this is not fully satisfactory and the moist mass then has to be transferred to a granulator such as an oscillating granulator (Fig. 28.6). The rotor bars of the granulator oscillate at an adjustable rate between 60 and 100 rpm and force the moist mass through the sieve screen, the size of which determines the granule size. The mass should be sufficiently moist to form discrete granules when sieved. If excess liquid is added at the wet massing stage, strings of material will be formed and if the mix is too dry, the mass will be sieved to a powder, and granules will not be formed.

This type of granulator can also deal with the size reduction of dry material. They are available in a range of sizes capable of dealing with 300–500 kg of wet mass per hour or 700–1200 kg/h of dry mass.

Fluidized-bed granulators

Fluidized-bed granulators (e.g. Aeromatic-Fielder, Glatt, Vanguard) have a similar design and operation to fluidized-bed driers, i.e. the powder particles are fluidized in a stream of air, but in addition granulation fluid is sprayed from a nozzle onto the bed of powders (Fig. 28.7).

Heated and filtered air is blown or sucked through the bed of unmixed powders to fluidize the particles and mix the powders; fluidization is actually a very efficient mixing process. Granulating fluid is pumped from a reservoir through a spray nozzle or multiple nozzles positioned over the bed of particles. A variety of spray nozzles is available to cope with a wide range of products. The granulating fluid causes the primary powder particles to adhere when the droplets and powders collide. Escape of material from the granulation chamber is prevented by exhaust filters which are periodically agitated to reintroduce the collected material into the fluidized bed. Sufficient liquid is sprayed to produce granules of the required size at which point the spray is turned off – but the fluidizing air continued. The wet granulates are then dried in the heated fluidizing air stream.

Commercial apparatus ranges from laboratory models that, by changing the bowl, have a volume between 0.2 and 2 L, giving a capacity of a few grams up to about 1 kg, up to production machines. A wide range is available to cope with the wide variety of production volumes encountered in the pharmaceutical industry. They can be obtained in sizes suitable for batches between 5 kg and a massive 1550 kg, these calculations being based on an optimum 70% bowl fill and a powder/granule bulk density of 0.5 kg/L.

Spray driers

These differ from the method discussed above in that a dry, granular product is made from a solution or a suspension rather than from dry primary powder particles. The solution or suspension may be of drug alone, a single excipient or a complete formulation.

The process of spray drying is discussed more fully in Chapter 29. The resultant granules are free-flowing hollow spheres and the distribution of the binder in such granules (at the periphery following solute migration during drying) results in good compaction properties.

This process can be used to make tablet granules although it is probably economically justified for this purpose only when suitable granules cannot be produced by the other methods. Spray drying can convert hard elastic materials into more ductile materials. Spray-dried lactose is the classic example and its advantages over α-lactose monohydrate crystals when compacted are discussed in Chapter 30.

The primary advantages of the process are the short drying time and the minimal exposure of the product to heat due to the short residence time in the drying chamber. This means that little deterioration of heat-sensitive materials takes place and it may be the only process suitable for this type of product.

Spheronizers/pelletizers

For some applications it may be desirable to have a dense, spherical pellet of the type difficult to produce with the equipment described above. Such pellets are used for controlled drug release products following coating with a suitable polymer coat and filling into hard gelatin capsules. Capsule filling with a mixture of coated and non-coated drug-containing pellets would give some degree of programmed drug release after the capsule shell dissolves.

A commonly used process involves the separate processes of wet massing, followed by extrusion of this wet mass into rod-shaped granules and subsequent spheronization of these granules. Because this process is used so frequently to produce modified-release multiparticulates, this process will be discussed in some detail.

• dry mixing of ingredients to achieve a homogeneous powder dispersion

• wet massing to produce a sufficiently plastic wet mass

• extrusion to form rod-shaped particles of uniform diameter

• spheronization to round off these rods into spherical particles

• drying to achieve the desired final moisture content

• screening (optional) to achieve the desired narrow size distribution.

Applications of extrusion/spheronization

Potential applications are many but relate mainly to controlled drug release and improved processing.

Desirable properties of pellets

Uncoated pellets have:

and once coated:

Process

Formulation variables

The composition of the wet mass is critical in determining the properties of the particles produced. During the granulation step, a wet mass is produced which must be plastic, deform when extruded and break off to form uniformly sized cylindrical particles which are easily deformed into spherical particles. Thus the process has a complex set of requirements that are strongly influenced by the ingredients of the pellet formulation.

Summary

Extrusion/spheronization is a versatile process capable of producing spherical granules having very useful properties. Because it is more labour intensive than more common wet massing techniques, its use should be limited to those applications where a sphere is required and other granulation techniques are unsuitable.

The most common application of the process is to produce spherical pellets for controlled drug release.

Care must be taken to understand the required properties of the pellets and the manner in which the process and formulation influence the ability to achieve these aims.

Introduction

Melt granulation is a size enlargement process in which a thermosetting material (hot-melt binder) is used to bind the primary powder particles into granules. It is a water-free alternative to wet granulation. The binder/granulating agent is a semi-solid or solid hydrophilic polymer or a hydrophobic wax. There are two variants to the technique:

In either case, liquid bridges are formed by the molten binder and powder agglomeration (i.e. granulation) takes place. The mechanism of granulation is analogous to wet granulation described above. The initial particle-particle bonds are formed by the surface tension of a liquid (this time the molten hot-melt binder). On subsequent cooling, the molten binder solidifies forming solid bridges that permanently bind the particles together.

Hot-melt binders

Hot-melt binders can be either hydrophilic/water soluble or hydrophobic/water insoluble. The most commonly used hydrophilic water-soluble binders are the polyethylene glycols (PEGs). Polyethylene glycol is the ideal hot-melt binder for granules intended for immediate release products. Grades between PEG 2000 and PEG 6000 can be used with PEG 3000 being well suited (melting point 48–54 °C).

Hydrophobic water-insoluble binders are particularly useful in producing controlled-release dosage forms. Many different hydrophobic waxes have been found to be suitable. These include: carnauba wax, hydrogenated castor oil, hydrogenated cottonseed oil, stearic acid and a wide variety of fatty acid derivatives (glyceryl behanate, glyceryl monostearate, glyceryl trilaurate, glyceryl trimyristate, glyceryl tripalmitate, glyceryl tristearate, hexadecyl palmitate, octadecyl stearate and sorbitan monostearate). Most of these are miscible when molten and can be used in combination.

Hot-melt processes

The heating procedure can be performed in a mixing vessel that is jacketed with hot water. In some formulations, the temperature rise can be generated by friction alone during agitation/mixing. High-speed mixers can sometimes generate a sufficient temperature rise in an acceptable processing time. Experimentation has shown that 60 °C can be achieved in as little as 10 minutes and that this can be reduced to 5 minutes with additional jacket heating.

There is also a variant of the standard extrusion/spheronization process in which low melting point waxes and heating are used in the extrusion process. Spheronization and cooling are carried out simultaneously. This is hot-melt extrusion/speronization.

The main factors influencing the efficiency of the hot-melt granulation process are the amount and melting point of the binder, its viscosity when molten, impellor rotation speed, massing time and temperature achieved.

The amount of binder needed varies widely. Indeed manipulation of the amount, and the creation of mixtures, of hydrophobic hot-melt binders can be part of the formulation development when designing modified-release products and adjusting the drug release versus time profile. For immediate-release systems, PEG 3000 25–30% by weight has been found to be a good starting point.

Following cooling of the melt-granulation granules or pellets back to room temperature, they follow the same fate as other granules, i.e. following an optional size reduction and screening procedure, they are either used in their own right as a dosage form, filled into hard gelatin capsule shells or compacted into tablets together with other excipients.

Advantages and limitations

The advantages of using a hot-melt granulation compared with aqueous wet granulation is that the use of water is avoided and so damage to hydrolytic drug molecules is minimized. Melt granulation also avoids the use of organic solvents that are sometimes employed as an alternative in such cases. However, thermal degradation can still be a problem. A limitation in the use of melt granulation for immediately-release products is that at the moment there is little alternative to the use of polyethylene glycols.

Slugging

The dry powders can be compacted using a conventional tablet machine or, more usually, a large heavy-duty rotary press can be used. This process is often known as slugging, the compacts made in the process (typically 25 mm diameter by about 10–15 mm thick) being termed slugs. A hammer mill is suitable for breaking the slugs. This is an old process that is being replaced by the more modern, and better, roller compaction process. Many pharmaceutical tableting materials suffer from a property known as work hardening which results in poor recompaction of these already compacted granules.

Roller compaction

Roller compaction is an alternative gentler method, the powder mix being squeezed between two counter-rotating rollers to form a compressed sheet (Fig. 28.12). The roller rotation speeds can be adjusted to allow variation in the compression time as the material passes between the rollers. Additionally, roller pressure can be adjusted and is maintained constant during a run by means of a hydraulic control system to yield granules of constant crushing strength. Even rollers with different surface grooves are available if a particular product is troublesome.

The sheet so formed is normally weak and brittle and breaks immediately into flakes that can be somewhat similar to cornflakes in their geometry. These flakes need gentler treatment to break them into granules. An oscillating granulator of the type shown in Figure 28.6 can be used with care, but often the conversion of these flakes to granules can be achieved by screening alone. Separation of fines (small powder particles) formed during the size reduction stage is often necessary. With suitable documentation, these may be recycled.

Advantages of the roller compaction process

Again, like most modern pharmaceutical process machinery, a wide range of sizes is available capable of operating with a wide range of throughputs and compaction forces (e.g. Alexanderwerk, Powtec). In the case of roller compactors, this range is enormous, being available for throughputs between 10 and 2000 kg/h and compaction forces between 16 and 64 kN/cm of roller length. This is achieved by the choice of machines with roller diameters of between 100 mm and 450 mm and roller lengths of 30 mm to 115 mm. This allows a wide range of APIs (active pharmaceutical ingredients, i.e. drugs) and excipients to be processed (or co-processed) and enables easy scale-up from a few hundred grams in development to very large-scale production of a successful product.

The Protec or Hutt type (Fig. 28.12b) has a vertical screw feeder in the hopper which produces an even flow of the material. Due to its design, it also has a precompacting and de-aerating effect on the powder charge. The speed of the screw, and that of the rollers, can be adjusted to provide control to the process.