The oral route of drug administration, utilizing tablets and capsules, is still very popular. Pharmaceutical scientists in R&D prefer to use wet granulation, despite being the most complex means of tablet processing. The popularity of wet granulation is because it can be applied to all drug substances, and for many formulators it is the method of choice for drugs with a high dose and a very low dose.

Types of Wet Granulation

Wet granulation can be divided into three main processes: low shear, high shear, and fluid bed granulation.

Low Shear Granulation

This is the traditional means of granulation employing low speed planetary or trough mixers in which the active ingredients 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.

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.

Fluidised Bed Granulation

The 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; (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; and drying, in which the spraying is stopped and the powder bed is gently fluidised until the granulation is dry.

Excipients used in Wet Granulation

Typically a wet granulated formulation will contain one or more diluents for bulk or to aid processing, a binder to facilitate granule growth and to aid compaction into hard tablets, a disintegrant and a lubricant. Additionally wetting agents, stabilising agents and colourants are used as required.


For low to medium dose drugs the diluents are likely to make up the majority of the tablet. But diluents do more than provide bulk and some properties of commonly used diluents are discussed below.

Microcrystalline cellulose

Microcrystalline cellulose (MCC) and silicified microcrystalline cellulose (SMCC) is frequently used in wet granulation, and typically these are 101 grades with median diameter of about 50 microns. MCC allows water to be distributed evenly through the granulation and lends robustness to the process. MCC is very highly compactable and its inclusion can add strength and robustness to a tablet.


Lactose (lactose monohydrate and anhydrous lactose) is a very frequently used in wet granulation, and it is preferable to use milled grades of α-lactose monohydrate for this purpose. Finer grades of lactose possess improved compaction properties, and the most commonly used grade is “200 mesh” in which the majority of the particles will pass a 75 microns sieve. Alternatives to lactose include fructose and trehalose.


Mannitol is an isomer of sorbitol. It used in wet granulation in milled form. The most stable form for wet granulation is the beta form, and it has been reported that mannitol undergoes moisture activated transition back to this form on wet granulation. Another polyols similar to mannitol is maltitol.

Dibasic calcium phosphate

Dibasic calcium phosphate (DCP), in milled form, is a wet granulation diluent. Anhydrous dibasic calcium phosphate appears to be more stable than the dihydrate, which is transformed partially or wholly to the anhydrous form on wet granulation. Alternatives to dibasic calcium phosphate include tricalcium phosphate, talc and calcium carbonate.


Binder are usually natural or synthetic water soluble polymers that may be used as solutions, but in high or low shear granulation they may also be added to the dry powder mix and granulation effected using water only.


Starch is the most traditional binder, but in native form it has to be gelatinised (cooked) in hot water to form a paste. However nowadays pregelatinised starch is available and a fully pregelatinised form is preferred. Starches are typically used in relatively high concentrations of about 5% of the tablet weight, or higher for partly pregelatinised starch. Various botanical sources are found in pharmacopoeia, but maize and potato based starches are the most common.

Cellulose derivatives

Cellulose derivatives, most commonly hydroxypropyl cellulose and hypromellose are frequently used binders. They are available in a wide variety of viscosity grades and are typically used at levels of about 1% to 3% by weight.


Povidone and copovidone is available in a range of viscosities ranging from K12 to K90, and again is typically used at levels of 1% to 3%.


Superdisintegrants are highly effective at disintegrating tablets when used at low concentrations (typically 2% to 6%) and they are the most preferred. Croscarmellose sodium, sodium starch glycolate and crospovidone are the most commonly used superdisintegrants. Partly pregelatinised starch is additionally a disintegrant as well as a binder.


As with all tablet formulations, magnesium stearate is the commonest lubricant. Sodium stearyl fumarate is an effective lubricant that is not hydrophobic. Mixtures of talc and stearic acid can also be effective.


Since one purpose of wet granulation is to prepare a free flowing compression mix, the need for a glidant should in principle be unnecessary. However in practice colloidal silica at 0.1% to 0.3% is sometimes used.


Wet granulation is possibly the most frequently used means of producing a compression mix for tablets, and a process that is applicable to just about any drug, but the downside is that numerous formulation and process factors and their interaction results in complex development programmes even for apparently simple formulations.


  1. Development of low dose formulations using fluidised bed granulation, JJ Zhou and R Lipp in Formulation and Analytical development for Low Dose Oral Drug Products, J. Zheng, Wiley & Sons, (2009)
  2. Effect of several cellulosic binders on particle size distribution of granules in fluidised bed granulation, H Kokubo, S Nakamura and H Sunada, Pharm. Bull., (1995), 4 3 (8), 1402 – 1406