Powder processing

Powder processing

Increasing particle size: Granulation

The size of individual particles in a powder determines bulk properties of the powder such as its flow, density, and compactibility. In addition, the surface characteristics of these particles, such as electrostatic charge and cohesivity, determine interparticle interactions that further influence bulk properties of the powder. Often, the bulk properties of a powder need to be changed for facilitating the processing and use of powders. For example, a cohesive, finely powdered API may not mix well with the inactive ingredi-ents of a formulation (excipients) and may not flow rapidly and uniformly through the equipment used in pharmaceutical manufacturing. These problems can compromise the dose uniformity of a drug between differ-ent dosage units. Therefore, size and surface characteristics of powders are often modified in pharmaceutical processing by granulation of powders.

Granulation is the process of preparing granules, or physical aggre-gates of powders, in which the original particles can still be identified. Granulation commonly involves adhesion of multiple particles of more than one type of powders. This may be achieved with or without the use of water or naturally adhesive hydrophilic polymers, known as bind-ers. Accordingly, granulation is classified based on the means of achiev-ing the adhesion of its powder components into dry granulation or wet granulation.

·           Dry granulation involves compaction of a powder under compressive force of stainless steel rolls, followed by breaking of the compacts into granules of a desired size range. It does not involve any addition of water. The characteristics of the powder particles, such as adhesion, cohesion, fragility, and plasticity, determine the compactibility of a powder.

·           Wet granulation involves the addition of water, and a binder, to a powder, followed by mixing and removal of water. The binder that becomes well mixed and forms interparticle bonds during granula-tion maintains granules as loosely adhered powder masses even after drying and removal of water.

Dry granulation

Dry granulation involves compaction of a powder mixture. Compaction is usually carried out by roller compaction. As shown in Figure 19.3, roller compaction involves a continuous flow of powder through two rolls con-currently counter rotating in the direction of the powder flow. The rolls are hydraulically pressurized to press on the powder as it passes through the rolls. This causes the powder particles to be deformed and/or fragmented, resulting in the formation of a compact ribbon of material. This ribbon of compacted material is then force passed through an appropriate-sized screen, using equipment such as a comil. This results in the production of granules.

Figure 19.3 Roller compaction process. (From He, X., Am. Pharm. Rev., 6, 26–33, 2003. With Permission.)

The important quality attributes of the granules produced by roller compaction include the percentage of fines, or the proportion of powder that did not get compacted when the compacts were passed through the comil, and the density of the granules. These can be modified using process parameters such as the distance between the rolls, pressure applied to the rolls, and the feeding rate of the powder.

Wet granulation

Wet granulation involves the use of a binder and water to aid the agglom-eration of particles. A binder is a substance with intrinsic cohesive and adhesive properties that can help form particle agglomerates. Typically, the binders used in pharmaceutical processing are hydrophilic polymers, such as PVP (also known as povidone), HPC, and starch. The binder can be added to the powder in either a dry or a solution form.

·           A dry binder addition process of wet granulation involves addition and mixing of the binder as a dry powder to the powder mixture to be gran-ulated. Granulation is carried out by the addition of water, whereas mixing is carried out in a granulator mixer. After the addition of water and mixing are complete, the granulation is force passed through an appropriate screen, using equipment such as a comil, followed by dry-ing to obtain granules of desired size. The dried granules are passed again through the screen using the comil to obtain the final granules.

·           A wet binder addition process of wet granulation involves dissolv-ing the binder in water prior to granulation. The powder mixture to be granulated is loaded in a granulator mixer. Granulation is carried out by the addition of the binder solution followed by force passed through an appropriate screen using a comil, drying, and passing the dried granules again through the comil to obtain the final granules.

The wet granulation process is further classified as a high-shear or a low-shear process depending on the equipment used for granulation.

·           A high-shear granulation process is carried out in a granulator that imparts high shearing and compacting force on the powder mixture. As shown in Figure 19.4, a typical high-shear granulator involves the move-ment of horizontally placed impellers at the bottom of the powder bed. The weight of powder bed increases the shear in this granulator design.

·           A low-shear granulation process is carried out in a granulator that imparts relatively less shearing and compacting force on the powder mixture. As shown in Figure 19.5, a typical low-shear granulator involves the move-ment of vertically placed impellers around the powder bed.

Figure 19.4 A high-shear granulator.

Figure 19.5 A low-shear granulator.

The drying process involves exposure of the wet granules to a dry and hot air, which leads to the drying of granules. It is typically carried out in a tray drier or a fluid bed dryer.

·           A tray drier represents a static drying process whereby the granules are spread on flat metallic trays and exposed to dry and hot air in a convection oven. This process is less efficient, time consuming, and may lead to uneven drying of granule surfaces.

·           A fluid bed drying process involves suspending the granules in a cur-rent of dry and hot air that flows vertically upward through the pow-der bed. This process is usually more efficient but can lead to greater attrition of the granules during drying due to interparticle collisions.

Figure 19.6 Fluid bed process, showing the granulation chamber with the flow dynamics of granules, granulating fluid spray, and the fluidization air.

An alternative process for low-shear granulation involves fluid bed granu-lation (Figure 19.6). This process involves spray of water or binder solution on the powder suspended in a vertical current of dry and hot air, leading to simultaneous equilibrium processes of wetting, granulation, and drying of the particles.

The binder fluid used in wet granulation can be other than water, or it can be a mixture of water with another fluid. For example, ethanol or hydroethanolic solutions have been used as binder fluids. The use of non-aqueous fluids places stringent requirements on the processing plant to con-trol potential explosive potential and environmental egress of the solvents. Therefore, most, if not all, modern wet granulation processes use water as a granulation fluid.

Figure 19.7 An illustration of the mechanisms involved in wet granulation. (From Iveson, S.M. et al., Powder Technol., 117, 3–39, 2001. With Permission.)

The mechanism of wet granulation involves four processes (Figure 19.7):

1.        Agglomeration of primary powder particles into coarse aggregates or granules

2.        Breakage of large aggregates into two or smaller aggregates due to the shear or impact of collision

3.        Consolidation, involving the densification of granules by shear and compressive forces leading to reduced porosity of granules

4.        Attrition due to shear forces and interparticle collisions leading to breakage of particles from the surface of granules

The important quality attributes of the granules produced by wet granula-tion include the PSD and density of the granules. These can be modified using process parameters such as the amount of water and binder, duration and speed of mixing during granulation, use of a high- or low-shear granu-lator, and the size of the screen used for sizing the granulation.

Decreasing particle size: Comminution or milling

Comminution, or milling, is the mechanical process of size reduction of powder particles or aggregates. Particle size reduction is often also called micronization, which indicates reducing the size of powder particles to micrometer level in diameter. A finely divided particulate nature of pow-ders is frequently needed for their efficient use. In addition to the reduction of size, milling also changes the shape of the particles toward a spherical shape. This can improve the cohesivity and flow of powders with needle- or irregular-shaped particles. Powders of similar particle size flow better and are more likely to show good uniformity of content when mixed together. Also, dispensing of powders can be more precise if the powders are of finely divided and of uniform nature.

Techniques for particle size reduction

Based on the type of equipment employed, comminution may be termed as follows:

· Cutting: For example, extrusion spheronization and hot melt granulation involves cutting a uniform stream of granulation mix into smaller particles that are then rounded off into uniform granules. This may also be necessary for the production of fibrous materials, such as cellulosic excipients, used in pharmaceutical manufacturing.

· Grinding: For example, colloid mill operates on the principle of grinding a coarse suspension between static and rotating stones, leading to the reduction of particle size of suspended particles.

· Trituration: For example, the manual process of using a pestle and a mortar to crush and/or mix fine powders together leads to some reduction of particle size.

· Milling: Several mills are utilized in the pharmaceutical industry. Depending on their principal of operation, they may be subclassi-fied as follows:

o    Ball mill, which utilized steel balls to impact powders in a close container. The size of balls and duration and intensity of impact are the process parameters that determine the extent of particle size reduction.

o    Air jet mill, which utilizes a high-speed stream of air impacting the powder flowing through a closed loop. Air pressure and mate-rial flow rate are the key process parameters in this case.

o    Fitzmill, which impacts the powder with a high-speed rotating blade or hammer configuration of steel rods. Process parameters that determine the extent of particle size reduction, in this case are the material flow rate and the speed of the mill.

· Comil: This mill operates on the principle of forcing by scrubbing the granules through a screen of defined pore size and shape. It is commonly used for the sizing of granules.

Selection of size reduction technique

Selection of appropriate techniques for particle size reduction depends on the characteristics of powders as starting materials, desired particle size of the milled powder, and their use. Examples of material characteristics that influence the selection of particle size reduction method include the following:

·           Strength and plasticity: Size reduction of high melting point (which indicates high strength of their crystalline lattice) crystalline solids can be carried out using high-impact processing equipment. However, low melting point solids, such as polyethylene glycols, may not be efficiently processed using high-impact equipment. The heat gener-ated during processing can lead to plastic deformation or melting of these solids and compromise the unit operation. This is also true for materials that are inherently soft or pliable. In addition, the presence of moisture can frequently increase the plasticity of materials, leading to difficulty in processing.

·           Brittleness: Powders that contain highly brittle particles can be eas-ily processed using, for example, a fitzmill or air jet mill. However, strong particles that are not brittle may require relatively low effi-ciency and high-impact processing equipment such as a ball mill.

·           Chemical stability: Particle size reduction is an inherently high-energy process that frequently also involves generation of heat. Therefore, powders that are chemically unstable may not be suitable for one or more of the size reduction techniques. For example, colloid milling may be preferred over ball mill for powders that show thermal deg-radation because the presence of the aqueous suspending medium in the colloid mill helps dissipate the heat generated during the process.