More than 90% of all therapeutic compounds are administered via the oral route, for which the tablet dosage form is by far the most popular. The quality of these solid oral dosage forms is governed by the physicochemical properties of the powders/granulations used in their formulation.
Although direct compression of APIs (active pharmaceutical ingredients) and excipients is an ideal and economical way of producing tablets, most APIs are not suitable for such compression in either their crystalline or amorphous forms. This is because they lack the proper characteristics for binding together into a compact entity, and do not normally possess the lubricating/disintegrating properties required for tablet formulation. For these reasons, APIs must be pre-treated – either alone or in combination with a filler – to form granules. The granulation process makes the materials easier to handle and improves the overall appearance of the tablets.
A pioneering concept of the granulation of APIs into a form known as the Pharmaceutical Formulation Intermediate (PFI), is based on a ‘ready-to-compress’ mix of APIs and excipients that can be fed directly into a hopper for compression into tablets – so that all the dosage form manufacturer has to do is complete the final steps of compression, thereby achieving a reduction in the overall costs of production.
The Granulation Process
Granulation is defined as a size-enhancement process during which small particles are formed into larger, physically stronger agglomerates. These granules are then blended with lubricants and glidants to make them directly compressible (DC granules or drum-to-hopper granules).
The primary reasons for granulating APIs are as follows:
> To increase the uniformity of drug distribution in the final product
> To improve compressibility
> To improve the density of the material
> To enhance the flow rate
> To reduce the generation of dust
> To reduce sticking and capping during compression
> To provide overall better handling
> To improve the appearance of the final product
Wet granulation is a versatile process, which is widely used in tablet formulation. The advantages of wet granulation are well-established, and the advent of high shear mixers, fluidised bed granulators and drying equipment has made the process much more efficient than it was before. While dry granulation techniques have been employed, their effectiveness depends on the bonding properties of APIs and excipients, and so they are not suitable for the majority of cases.
Two types of wet granulation take precedence: High Shear Granulation and Fluid Bed Granulation.
In high shear granulation, blending and wet massing is accomplished by high mechanical agitation by an impeller and a chopper. Mixing, densification and agglomeration of wetted materials are achieved through shearing and compaction forces exerted by the impeller. The liquid binder is either poured into the bowl or sprayed onto the powder to achieve a more homogeneous liquid distribution.
The advantages of high shear granulation are as follows:
> Process times are shorter
> Less liquid binder is needed and so drying times are shorter
> Highly cohesive materials can be granulated
> Voluminous materials can be densified
> Granulation is done in a closed system and cleaning operations are easy
Fluid bed granulation is a process by which granules are produced in a single piece of equipment by spraying a binder solution onto a fluidised powder bed. This involves heating process air, directing it through the material to be processed and then having the same air (together with moisture) exit the unit void of the product. Materials processed by fluid bed granulation produce finer, more free-flowing granules. The end-result is a more homogeneous mixture of granules which, after compression, produce stronger and faster-disintegrating tablets.
The excipients used in granulation can be mainly divided into two categories – bulking agents (fillers) and functional additives. Some fillers also act as functional additives, but fillers generally differ from functional additives in that they are usually inert and relatively inexpensive. Commonly used fillers are lactose, dicalcium phosphate, starch, microcrystalline cellulose and pre-gelatinised starch; the starches and microcrystalline cellulose also act as disintegrants. Functional additives include agents like binders, disintegrants, lubricants, glidants and colourants. A wide variety of polymers and sugars are used as binders; examples include polyvinyl pyrrolidine (PVP), sucrose, starch, ethylcellulose, methylcellulose and hydro-xypropylmethylcellulose (HPMC). Commonly used disintegrants are sodium starch glycolate, croscarmellose sodium and crospovidone. Lubricants like magnesium stearate, talc and stearic acid are most commonly used. Colloidal silicon dioxide is the most commonly used glidant to improve the flow characteristics of a granulation.