• The oral route represents a convenient and safe way of drug administration.

• Compared to liquid dosage forms, tablets (and other solid dosage forms) have general advantages in terms of the chemical, physical and microbiological stability of the dosage form.

• The preparation procedure enables accurate dosing of the drug.

• Tablets are convenient to handle and can be prepared in a versatile way with respect to their use and the delivery of the drug.

• Finally, tablets can be relatively cheaply mass produced, with robust and quality-controlled production procedures giving an elegant preparation of consistent quality.

1. The tablet should include the correct dose of the drug.

2. The appearance of the tablet should be elegant, and its weight, size and appearance should be consistent.

3. The drug should be released from the tablet in a controlled and reproducible way.

4. The tablet should be biocompatible, i.e. not include excipients, contaminants and microorganisms that could cause harm to patients.

5. The tablet should be of sufficient mechanical strength to withstand fracture and erosion during handling at all stages of its lifetime.

6. The tablet should be chemically, physically and microbiologically stable during the lifetime of the product.

7. The tablet should be formulated into a product acceptable to the patient.

8. The tablet should be packed in a safe manner.

Stages in tablet formation

The dominating technique of forming tablets (although alternative procedures are in use, as indicated in the definition of tablets in the European Pharmacopoeia, 2011) is by powder compression, i.e. forcing particles into close proximity to each other by confined compression. This enables the particles to cohere into a porous, solid specimen of defined geometry. The compression takes place in a die by the action of two punches, the lower and the upper, by which the compressive force is applied. Powder compression is defined as the reduction in volume of a powder owing to the application of a force. Because of the increased proximity of particle surfaces accomplished during compression, bonds are formed between particles which provide coherence to the powder, i.e. a compact is formed. Compaction is defined as the formation of a solid specimen of defined geometry by powder compression.

The process of tableting can be divided into three stages (sometimes known as the compaction cycle) (Fig. 30.1).

Tablet presses

There are two types of press in common use during tablet production: the single-punch press and the rotary press. In addition, hydraulic presses are used in research and development work for the initial evaluation of the tableting properties of powders and prediction of the effect of scale-up on the properties of the formed tablets (scale-up refers to the change to a larger apparatus for performing a certain operation on a larger scale).

Technical problems during tableting

A number of technical problems can arise during the tableting procedure, among which the most important are:

Such problems are related to the properties of the powder intended to be formed into tablets and also to the design and conditions of the press and the tooling. They should therefore be avoided by ensuring that the powder possesses adequate technical properties and also that a suitable, well-conditioned tablet press is used, e.g. in terms of the use of forced-feed devices and polished and smooth dies and punches.

Important technical properties of a powder that must be controlled to ensure the success of a tableting operation are:

The technical properties of the powder are controlled by the ingredients of the formulation (i.e. the drug and excipients) and by the way in which the ingredients are combined into a powder during precompaction processing. The precompaction processing often consists of a series of unit operations in sequence. The starting point is normally the drug in a pure, most often crystalline form; the subsequent treatment of the drug particles is sometimes referred to as downstream processing. The unit operations used during this precompaction treatment are mainly particle size reduction, powder mixing, particle size enlargement and powder drying. For further details of these procedures see Chapters 10, 11, 28 and 29, respectively. Granulation of a fine powder is a common means used to preserve the fineness of the drug within larger particles that are suitable for tableting (see below) and granulation procedures are traditionally in common use in preparing a powder for tableting. To save time and energy, precompaction processing without a particle size enlargement operation is chosen if possible. This procedure is called tablet production by direct compression or direct compaction.

Tablet production via granulation

Tablet production by direct compaction

An obvious way to reduce production time and hence cost is to minimize the number of operations involved in the pretreatment of the powder mixture before tableting. Tablet production by direct compaction can be reduced to only two operations in sequence: powder mixing and tableting (Fig. 30.6). The advantage with direct compaction is primarily a reduced production cost. However, in a direct compactable formulation, specially designed fillers and dry binders are normally required, which are usually more expensive than the traditional ones. They may also require a larger number of quality tests before processing. As heat and water are not involved, product stability can be improved. Finally, drug dissolution might be faster from a tablet prepared by direct compaction owing to fast tablet disintegration into primary drug particles.

The disadvantages of direct compaction are mainly technological. In order to handle a powder of acceptable flowability and bulk density, relatively large particles must be used which may be difficult to mix to a high homogeneity and may be prone to segregation. Moreover, a powder consisting mainly of drug will be difficult to form into tablets if the drug itself has poor compactability. Finally, a uniform colouring of tablets can be difficult to achieve with a colourant in dry particulate form.

Direct compaction may be considered in two common formulation cases; firstly, relatively soluble drugs which can be processed as coarse particles (to ensure good flowability) and secondly, relatively potent drugs which are present in a few milligrams in each tablet and can be mixed with relatively coarse excipient particles (in this latter case the flow and compaction properties of the formulation are mainly controlled by the excipients).

Filler (or diluent)

In order to form tablets of a size suitable for handling, a lower limit in terms of powder volume and weight is required. Tablets normally weigh at least 50 mg. Therefore, a low dose of a potent drug requires the incorporation of a substance into the formulation to increase the bulk volume of the powder and hence the size of the tablet. This excipient, known as the filler or the diluent, is not necessary if the dose of the drug per tablet is high.

The ideal filler should fulfil a series of requirements, such as:

As all these requirements cannot be fulfilled by a single substance, different substances have gained use as fillers in tablets, mainly carbohydrates but also some inorganic salts.

Lactose is the most common filler in tablets. It possesses a series of good filler properties, e.g. dissolves readily in water, has a pleasant taste, is non-hygroscopic, is fairly non-reactive and shows good compactability. Its main limitation is that some people have an intolerance to lactose.

Lactose exists in both crystalline and amorphous forms. Crystalline lactose is formed by precipitation and, depending on the crystallization conditions, α-monohydrate or β-lactose (an anhydrous form) can be formed. By thermal treatment of the monohydrate form, crystalline α-anhydrous particles can be prepared. Depending on the crystallization conditions and the use of subsequent size reduction by milling, lactose of different particle sizes is obtained.

Amorphous lactose can be prepared by spray drying a lactose solution (giving nearly completely amorphous particles) or a suspension of crystalline lactose particles in a lactose solution (giving aggregates of crystalline and amorphous lactose). Amorphous lactose dissolves more rapidly than crystalline and shows better compactability. Its main use is therefore in the production of tablets by direct compaction. Amorphous lactose is, however, hygroscopic and physically unstable, i.e. it will spontaneously crystallize if crystallization conditions are met as a result of elevated temperature or high relative humidity (see Chapter 8 for more details).

Other sugars or sugar alcohols, such as glucose, sucrose, sorbitol and mannitol, have been used as alternative fillers to lactose, primarily in lozenges or chewable tablets because of their pleasant taste. Mannitol has a negative heat of solution and imparts a cooling sensation when sucked or chewed.

Apart from the sugars, perhaps the most widely used fillers are powdered celluloses of different types. Celluloses are biocompatible, chemically inert and have good tablet-forming and disintegrating properties. They are therefore also used as dry binders and disintegrants in tablets. They are compatible with many drugs but, owing to their hygroscopicity, may be incompatible with drugs prone to chemical degradation in the solid state.

The most common type of cellulose powder used in tablet formulation is microcrystalline cellulose. The name indicates that the particles have both crystalline and amorphous regions, depending on the relative position of the cellulose chains within the solid. The degree of crystallinity may vary depending on the source of the cellulose and the preparation procedure. The degree of crystallinity will affect the physical and technical properties of the particles, e.g. in terms of hygroscopicity and powder compactability.

Microcrystalline cellulose is prepared by hydrolysis of cellulose followed by spray drying. The particles thus formed are aggregates of smaller cellulose fibres. Depending on the preparation conditions, aggregates of different particle size can be prepared which have different flowabilities.

A final important example of a common filler is an inorganic substance, dicalcium phosphate dihydrate. This is insoluble in water and non-hygroscopic, but is hydrophilic, i.e. easily wetted by water. The substance can be obtained in both a fine particulate form, mainly used in granulation, and an aggregated form. The latter possesses good flowability and is used in tablet production by direct compaction. Calcium phosphate is slightly alkaline and may thus be incompatible with drugs sensitive to alkaline conditions.

Matrix former

In order to affect or control the release of the drug from the tablet, i.e. to speed up or to slow down its release rate, the drug may be dispersed or embedded in a matrix formed by an excipient or a combination of excipients. This type of excipient may thus be referred to as a matrix former. An alternative term is base, a term used in the European Pharmacopoeia (2011) and there defined as ‘the carrier, composed of one or more excipients, for the active substance(s) in semi-solid and solid preparations’.

The matrix former is often a polymer or a lipid and may constitute a significant fraction of the total tablet weight. When the objective is to increase drug dissolution, the matrix former can be a water-soluble substance or a lipid and the drug is dissolved or suspended as fine particles in the matrix. An example of a water-soluble matrix former is poly ethylene glycol (PEG). When the objective is to prolong the drug release, the matrix former can be either an insoluble substance (a polymer or a lipid) or a substance that forms a gel in contact with water. The drug is normally dispersed in particulate form in the matrix (for more details, see below). A common gel-forming substance in tablets is hydroxy propyl methyl cellulose (HPMC). Matrix formers are discussed in more detail in Chapter 31.

Disintegrant

A disintegrant is included in the formulation to ensure that the tablet, when in contact with a liquid, breaks up into small fragments, which promotes rapid drug dissolution. Ideally, the tablet should break up into individual drug particles in order to obtain the largest possible effective surface area during dissolution.

The disintegration process for a tablet occurs in two steps. First, the liquid wets the solid and penetrates the pores of the tablet. Thereafter, the tablet breaks into smaller fragments. The actual fragmentation of the tablet can also occur in steps, i.e. the tablet disintegrates into aggregates of primary particles which subsequently deaggregate into their primary drug particles. A deaggregation directly into primary powder particles will set up conditions for the fastest possible dissolution of the drug. A scheme for the release of the drug from a disintegrating tablet is shown in Figure 30.7.

Several mechanisms of action of disintegrants have been suggested, such as swelling of particles, exothermic wetting reaction, particle repulsion and particle deformation recovery. However, as two main processes are involved in the disintegration event, disintegrants to be used in plain tablets are here classified into two types:

The disintegrant most traditionally used in conventional tablets is starch, among which potato, maize and corn starches are commonly used. The typical concentration range of starch in a tablet formulation is up to 10%. Starch particles swell in contact with water and this swelling can subsequently disrupt the tablet. However, it has also been suggested that starch particles may facilitate disintegration by particle-particle repulsion.

The most common and effective disintegrants act via a swelling mechanism and a series of effective swelling disintegrants has been developed which can swell dramatically during water uptake and thus quickly and effectively break the tablet. These are normally modified starch or modified cellulose. High-swelling disintegrants are included in the formulation at relatively low concentrations, typically 1–5% by weight.

Disintegrants can be mixed with other ingredients prior to granulation and thus be incorporated within the granules (intragranular addition). It is also common for the disintegrant to be mixed with the dry granules before the complete powder mix is compacted (extragranular addition). The latter procedure will contribute to an effective disintegration of the tablet into smaller fragments.

A third group of disintegrants functions by producing gas, normally carbon dioxide, when in contact with water. Such disintegrants are used in effervescent tablets and normally not in tablets that should be swallowed as a solid. The liberation of carbon dioxide is obtained by the decomposition of bicarbonate or carbonate salts in contact with acidic water. The acidic pH is accomplished by the incorporation of a weak acid in the formulation, such as citric acid and tartaric acid.

Dissolution enhancer

For drugs of low aqueous solubility, the dissolution of the drug may be the rate-limiting step in the overall drug release and absorption processes. Agents, other than matrix formers, may therefore sometimes be found in the composition of a tablet with the role to speed up the drug dissolution process by temporarily increasing the solubility of the drug during drug dissolution. An important example of a dissolution enhancer is the incorporation into the formulation of a substance that forms a salt with the drug during dissolution, e.g. increasing the dissolution rate of aspirin by using magnesium oxide in the formulation.

Absorption enhancer

For drugs with poor absorption properties, the absorption can be affected (see Chapter 20) by using substances in the formulation that affect the permeability of the intestinal cell membrane and thus increase the rate at which the drug passes though the intestinal membrane. An additive that modulates the permeability of the intestine is often referred to as an absorption enhancer.

Binder

A binder (also sometimes called an adhesive) is added to a drug-filler mixture to ensure that granules and tablets can be formed with the required mechanical strength. Binders can be added to a powder in different ways:

Both solution binders and dry binders are included in the formulation at relatively low concentrations, typically 2–10% by weight. Common traditional solution binders are starch, sucrose and gelatin. More commonly used binders today, with improved adhesive properties, are polymers such as polyvinylpyrrolidone and cellulose derivatives (in particular hydroxypropyl methylcellulose). Important examples of dry binders are microcrystalline cellulose and crosslinked polyvinylpyrrolidone.

Solution binders are generally considered the most effective and this is therefore the most common way of incorporating a binder into granules; the granules thus formed are often referred to as binder–substrate granules. It is not uncommon, however, for a dry binder to be added to the dry binder–substrate granules before tableting in order to further improve the compactability of the granulation.

Glidant

The role of the glidant is to improve the flowability of the powder. Glidants are used in formulations for direct compaction but are often also added to granules before tableting to ensure that sufficient flowability of the tablet mass is achieved for high production speeds.

Traditionally, talc has been used as a glidant in tablet formulations, in concentrations of about 1–2% by weight. Today, the most commonly used glidant is probably colloidal silica, added in very low proportions (about 0.2% by weight). Because the silica particles are very small they adhere to the particle surfaces of the other ingredients (i.e. an ordered or structured mixture is formed; see Chapter 11) and improve flow by reducing interparticulate friction. Magnesium stearate, normally used as a lubricant, can also promote powder flow at low concentrations (<1% by weight).

Lubricant

The function of the lubricant is to ensure that tablet formation and ejection can occur with low friction between the solid and the die wall. High friction during tableting can cause a series of problems, including inadequate tablet quality (capping or even fragmentation of tablets during ejection and vertical scratches on tablet edges) and may even stop production. Lubricants are thus included in almost all tablet formulations.

Lubrication is achieved mainly by two mechanisms: fluid lubrication and boundary lubrication (Fig. 30.8). In fluid lubrication a layer of fluid is located between and separates the moving surfaces of the solids from each other and thus reduces the friction. Fluid lubricants are seldom used in tablet formulations. However, liquid paraffin has been used, for instance in formulations for effervescent tablets.

Boundary lubrication is considered as a surface phenomenon, as here the sliding surfaces are separated by only a very thin film of lubricant. The nature of the solid surfaces will therefore affect friction. In boundary lubrication, the friction coefficient and wear of the solids are higher than with fluid lubrication. All substances that can affect the interaction between sliding surfaces can be described as boundary lubricants, including adsorbed gases. The lubricants used in tablet formulations acting by boundary lubrication are fine particulate solids.

A number of mechanisms have been discussed for these boundary lubricants, including that lubricants are substances that show a low resistance towards shearing. The most effective of the boundary lubricants are stearic acid or stearic acid salts, such as magnesium stearate. Magnesium stearate has become the most widely used lubricant owing to its superior lubrication properties. The stearic acid salts are normally used at low concentrations (<1% by weight).

Besides reducing friction, lubricants may cause undesirable changes in the properties of the tablet. The presence of a lubricant in a powder is thought to interfere in a deleterious way with the bonding between the particles during compaction, thus reducing tablet strength (Fig. 30.9). Because many lubricants are hydrophobic, tablet disintegration and dissolution are often retarded by the addition of a lubricant. These negative effects are strongly related to the amount of lubricant present and a minimum amount is normally used in a formulation, i.e. concentrations of 1% or below. In addition, the way in which the lubricant is mixed with the other ingredients should also be considered. It can, for example, be important if the excipients are added sequentially to a granulation rather than simultaneously. The total mixing time and the mixing intensity are also important in this context.

The commonly observed retardation of disintegration and dissolution of tablets is related to the hydrophobic character of the most commonly used lubricants. In order to avoid these negative effects, more hydrophilic substances have been suggested as alternatives to the hydrophobic lubricants. Examples are surface-active agents and polyethylene glycol. A combination of hydrophobic and hydrophilic substances might also be used.

The lubricant’s effect on friction and on the changes in tablet properties is related to the tendency of lubricants to adhere to the surface of drugs and fillers during dry mixing. Lubricants are often fine particulate substances which thus are prone to adhere to larger particles. In addition, studies on the mixing behaviour of magnesium stearate have indicated that this substance has the ability to form a film which can cover a fraction of the surface area of the drug or filler particles (the substrate particles). This film can be described as being continuous rather than particulate. A number of factors have been suggested to affect the development of such a lubricant film during mixing and hence also affect friction and changes in tablet properties, such as the shape and surface roughness of the substrate particles; the surface area of the lubricant particles; mixing time and intensity; and the type and size of mixer.