Manufacture Of Tablet By Wet Granulation Process

Wet granulation is a process of dry mixing, wet mixing, and particle size enlargement, and is a process of particle attachment (agglomeration). Wet granulation techniques consist of homogeneously mixing the active pharmaceutical ingredient (API) with other powder excipients and wetting them in the presence of a binder or granulating fluid, forming larger agglomerates/granules. The wet granules are dried to remove moisture and then either screened or milled to eliminate oversized agglomerates and to control the particle size distribution.

Granules

Wet granulation is a complex process with a combination of several critical formulation and process variables greatly affecting the outcome. For example, determination of the granulation endpoint is still considered by many to be a fine art, requiring knowledge gained through years of hands-on experience. The window for liquid addition can be very narrow and over-wetting of powder can lead to the entire batch being completely unusable.

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Wet Granulation Steps

It consists of seven steps:

1. Weighing and blending: all the powder API and excipients are weighted according to specifications and mixed together. There are different types of machines for weighing and mixing.

2. Wet granulate prepared by adding the binder solution: a liquid binder is added to the powder mixture. This results in wet granules. Method of mixing binder and powder include trituration.

3. Screening the damp mass into pellets or granules (6-8mesh): to convert the wet granules into pellets, they are passed through a mesh of small size. This results in segregation of solid pellets.

4. Drying the granulation in thermostatically controlled ovens: the pellets are dried using ovens. The temperature of the oven is controlled to make sure the ingredients are not destroyed by heat but hot enough to dry out the pellet.

5. Dry screening: the dried pellets are passed through another mesh to achieve granules of similar sizes. It is similar to sieving garri in Nigeria using filters. The fine small grain passes through the mesh or filter leaving behind the big ones in the mesh or filter.

6. Mixing with other ingredients: A dry lubricant, antiadherent and glidant is added to the granules either by dusting over the spread-out granules or by blending with the granules. Dry binder, colorant or disintegrant may be also added in this step.

7. Tableting: Last step in which the tablet is fed into the die cavity and then compressed.

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Type Of Wet Granulation

Wet granulation can be divided into four main processes of low shear, high shear, fluid bed granulation and extrusion and spheronization. Additionally there is a drive towards continuous wet granulation for improvement in manufacturing efficiency. Each process has its own pros and cons which may be useful for different formulations, but in practise a formulator may not have the choice of which process to use for a particular product, the selection being determined by equipment availability and company preference. 

Low Shear Granulation

This is the traditional means of granulation employing low speed planetary or trough mixers in which the drug and intragranular excipients are granulated with a binder solution, the resulting wet mass is screened to form discrete granules which are typically dried in a tray drier. The dried granules are rescreened or milled to the required size, blended with extragranular excipients, lubricated and compressed.

The main disadvantages of this process are the open nature of the equipment and the manual transfer of the materials being processed, the long drying times, potential for migration of soluble components during tray drying and the general lack of instrumentation for inprocess control.

High Shear Granulation

High shear mixer granulators are characterised by their use of two mixing blades. An impeller that rotates in the base of the mixer and a high speed “chopper” that continually breaks up the wet mass as granulation proceeds. This combination provides for very effective mixing of components and usage of small amounts of water compared to low shear granulation. The entire process of mixing and granulation can be completed in a few minutes and the systems can be fitted with a variety of devices to monitor and determine the end point of granulation. 

A high shear mixer granulator is a closed vessel, and the granules produced are generally able to be transferred to a fluid bed dryer in a closed system thus minimising the extent of handling necessary. 

A key advantage of high shear granulation is its wide applicability to almost any formulation.

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However, the intensity of the mixing process can rapidly lead to overgranulation with adverse effects on granule tabletability. In general any process factor that increases the extent of granulation (increasing water, massing time or impeller speed) tends to increase granule density and reduce tabletability. It may be possible to counteract the effect of overgranulation to some extent by milling the dried granules.

Our general advice, based on published studies and work in our own laboratories, is to make a light granulation but one that is consistent with good flow. Such a granulation is achieved by carefully controlling the relative proportions of diluents, the amount of granulating water and the duration of wet massing. 

Thus with high shear granulation it is important to control the end point of the granulation process to achieve consistency of granule properties such as size and density. Typically end point determination is achieved by monitoring the power consumption of the impeller motor, although many other methods have been investigated. 

A disadvantage shared by both low and high shear granulation is that water is intimately mixed with the formulation components. The water may be in contact with these components for a significant time, and thus water activated changes to drug and excipients can occur. Reported water activated transitions of actives usually involve formation of hydrates. Examples include amlodipine besylate (6), caffeine, carbamazepine, sulfaguanidine (7), theophylline (8) and baclofen (9). In some cases the transition can be minimised by the inclusion of polymeric excipients such as hypromellose (7, 8), in other cases these polymers had no effect on drug transformation. There appears to be generally applicable formulation approaches therefore to preventing such transitions. 

Water induced transitions have also been observed for excipients such anhydrous βlactose to αlactose monohydrate (10) and δmannitol to βmannitol (11). However it is possible to granulate anhydrous βlactose without the reported transition by employing fluidised bed granulation, and this technique may reduce such transitions for sensitive activities. 

Fluid Bed Granulation

Drug and excipients are loaded into a fluid bed processor, fluidised with air, and granulating fluid is sprayed into the bed, usually from above, with a continuous stream of warm drying air. This is often a three stage process of;

1. Blending, in which the drug and excipients are blended with a low volume of fluidising air to achieve homogeneity and to warm the dry powders. Care needs to be taken in this stage so that fine drug particles are not removed from the bed by entrainment in high velocity air.

Effective fluidisation depends in part on the particle size of the powders to be fluidised, and in practise an easily fluidised powder will have a mean particle size of 30 to 120m and many diluents such as milled lactose and microcrystalline cellulose lie in this range. 

2. Granulation, in which water or a binder solution is sprayed onto the fluidised bed. Granule growth during this phase depends on a number of factors such as granulating fluid viscosity and droplet size and spray rate. In general increasing any of these factors tends to increase granule growth rate. 

3. Drying, in which the spraying is stopped and the powder bed is gently fluidised until the the granulation is dry. The end point is usually determined by the bed temperature. During this phase there may be some granule attrition.

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Advantages of fluidised bed granulation are that it is a contained process, that a single piece of equipment may be used for granulation and drying, thus representing a capital saving over high shear granulation, and that fluid bed processed granules are typically low density and compressible. 

Disadvantages are that some combinations of drugs and excipients are incapable of being mixed by fluidisation before granulation, and in these cases a premix has to be prepared. Finely milled or micronized drugs may be entrained in the fluidising airstream and lost from the powder to be granulated. 

Again a practical solution is to prepare a preblend and to start spray granulation immediately.

Extrusion-spheronization

A uniform blend is required for the extrusion-spheronization process, which is wetted prior to manufacture. The process involves two manufacturing steps, extrusion through a circular die or multiple-die plate (often a screen) to generate rods or strings of material; followed by spheronization where the extrudate is spun on a patterned plate, causing the rods to be fractured and become rounded into granules.

The size distribution and surface characteristics of the spheres are controlled by batch size, speed, process time and the characteristics of the extruded mass. The main issue with extrusion-spheronization is that it is a multistep, labour intensive and time-consuming process.