• 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.

Concerning the tablet strength-reducing effect of a lubricant, apart from the degree of surface coverage of the lubricant film obtained during mixing, the compression behaviour of the substrate particles will also be important. Drugs and fillers can thus be evaluated in terms of their lubricant sensitivity, i.e. the reduction in tablet strength due to the addition of a lubricant compared to a tablet formed from a powder without a lubricant. An important property for this lubricant sensitivity seems to be the degree of fragmentation the substrate particles undergo during compression (see below). It is thus assumed that, during compression, particle surfaces which are not covered with a lubricant film are formed during particle fragmentation and that these clean surfaces will bond differently from the lubricant-covered particle surfaces.

To explain the effect of lubricant film formation on the tensile strength of tablets, a coherent matrix model has been developed. This suggests that when a continuous matrix of lubricant-covered particle surfaces exists in a tablet, along which a fracture plane can be formed, the tablet strength is considerably lower than that of tablets formed from unlubricated powder. However, if the mixing and compression processes do not result in such a coherent lubricant matrix within the tablet, for example due to irregular substrate particles or particle fragmentation, the lubricant sensitivity appears to be lower.

Antiadherent

The function of an antiadherent is to reduce adhesion between the powder and the punch faces and thus prevent particles sticking to the punches. Many powders are prone to adhere to the punches, a phenomenon (known in the industry as sticking or picking) which is affected by the moisture content of the powder. Such adherence is especially prone to happen if the tablet punches have markings or symbols. Adherence can lead to a build-up of a thin layer of powder on the punches, which in turn will lead to an uneven and matt tablet surface with unclear markings or symbols.

Many lubricants, such as magnesium stearate, also have antiadherent properties. However, other substances with limited ability to reduce friction can also act as antiadherents, such as talc and starch.

Sorbent

Sorbents are substances that are capable of sorbing some quantities of fluids in an apparently dry state. Thus, oils or oil-drug solutions can be incorporated into a powder mixture which is granulated and compacted into tablets. Microcrystalline cellulose and silica are examples of sorbing substances used in tablets.

Flavour

Flavouring agents are incorporated into a formulation to give the tablet a more pleasant taste or to mask an unpleasant one. The latter can also be achieved by coating the tablet or the drug particles.

Flavouring agents are often thermolabile and so cannot be added prior to an operation involving heat. They are often mixed with the granules as an alcohol solution.

Colourant

Colourants are added to tablets to aid identification and patient compliance. Colouring is often accomplished during coating (see Chapter 32 for further information) but a colourant can also be included in the formulation prior to compaction. In the latter case, the colourant can be added as an insoluble powder or dissolved in the granulation liquid. The latter procedure may lead to a colour variation in the tablet caused by migration of the soluble dye during the drying stage (see Chapter 29 for more information on the phenomenon of solute migration).

Classification of tablets

Several categories of tablets may be distinguished and the denomination and definitions of different types of tablets can be found in pharmacopoeias. The tablet dosage forms described in the European Pharmacopoeia (2011) appear in the monographs for tablets and for oromucosal preparations (the monograph on oromucosal preparations includes some types of tablets, i.e. compressed lozenges, sublingual tablets and buccal tablets that are intended for administration to the oral cavity and/or the throat to obtain a local or systemic effect).

A common means of classifying tablets is based on the drug release pattern from the tablets. The following categories are often used in this context: immediate release, prolonged release, pulsatile release and delayed release. The latter three types are also referred to as modified-release tablets.

For immediate-release tablets, the drug is intended to be released rapidly after administration, or the tablet is dissolved in liquid before intake and thus administered as a solution. Immediate-release tablets are the most common type of tablet and include disintegrating, chewable, effervescent, sublingual and buccal tablets.

Modified-release tablets should normally be swallowed intact. The formulation and thus also the type of excipients used in such tablets might be quite different from those of immediate-release tablets. The term prolonged-release tablet is used to indicate that the drug is released slowly at a nearly constant rate. If the rate of release is constant during a substantial period of time, a zero-order type of release is obtained, i.e. M = kt (where M is the cumulative amount of drug released and t is the release time). This is sometimes described as an ideal type of prolonged-release preparation.

A pulsatile release is another means to increase the time period for drug absorption after a single administration and is accomplished by releasing the drug in two or more pulses.

For delayed-release tablets the drug is liberated from the tablet some time after administration. After this period has elapsed, the release is normally rapid. The most common type of delayed-release tablet is a gastro-resistant (also known as enteric-coated) tablet, for which the drug is released in the upper part of the small intestine after the preparation has passed the stomach. However, a delayed release can also be combined with a prolonged drug release, e.g. for local treatment in the lower part of the intestine or in the colon.

The type of release obtained from immediate-, prolonged- and delayed-release tablets is illustrated in Figure 30.10. In the following sections, the most common types of tablets are described.

Disintegrating tablets

The most common type of tablet is intended to be swallowed and to release the drug in a relatively short time thereafter by disintegration and dissolution, i.e. the goal of the formulation is fast and complete drug release in vivo. Such tablets are often referred to as conventional or plain tablets. A disintegrating tablet includes normally at least the following types of excipients: filler (if the dose of the drug is low), disintegrant, binder, glidant, lubricant and antiadherent.

As discussed above, the drug is released from a disintegrating tablet in a sequence of processes, including tablet disintegration, drug dissolution and drug absorption (see Fig. 30.7). All these processes will affect, and can be rate-limiting steps for, the drug bioavailability. The rate of the processes is affected by both formulation factors and production conditions.

The disintegration time of the tablet is a function of the composition and manufacturing conditions and may thus depend on several factors. Regarding composition, the choice of disintegrant (Fig. 30.11) is of obvious importance but also other excipients, such as the type of filler and lubricant can also be of significant importance for tablet disintegration.

Tablet disintegration may also be affected by production conditions during manufacture. Important examples that may affect tablet disintegration time are the design of the granulation procedure (which will affect the physical properties of the granules), mixing conditions during the addition of lubricants and antiadherents, the applied punch force during tableting and the punch force-time relationship. It has been reported that an increased compaction pressure can either increase or decrease disintegration time, or give complex relationships with maximum or minimum disintegration times.

In many cases, the drug dissolution rate is the rate-limiting step in the drug release process, especially for drugs that are poorly soluble in water but that are readily absorbed in the intestine (i.e. typically class II drugs in the Biopharmaceutics Classification System, see Chapter 21). Since many drugs show very poor solubility, the problem of the rate of drug dissolution is often a critical issue during the development of an immediate release tablet. The most common means to achieve acceptable drug dissolution rate for poorly soluble compounds are:

The apparent solubility can be increased by changing the solid-state form of the drug, such as a polymorph, using a salt of the drug or using amorphous particles. The surface area of a solid is inversely proportional to particle size and particle size reduction is an obvious means to increase drug dissolution rate. However, a reduced particle size will make a powder more cohesive. A reduction in drug particle size might produce aggregates of particles which are difficult to break up, with the consequence that the drug dissolution rate is not related to the surface area of the primary drug particles. It is thus important to ensure that the tablet is formulated in such a way that it will disintegrate and that the aggregates so formed break up into small drug particles in order that a large surface area of the drug is exposed to the dissolution medium. The preparation and use of small particles, i.e. down to the sub-micrometre range (nano-sized particles), and the use of drug dissolution enhancers and matrix formers in tablet compositions of poorly soluble drugs are important issues in the formulation of disintegrating, immediate-release tablets.

For drugs with poor absorption properties, the absorption can be affected (see Chapter 20) by modifying the drug’s lipophilicity, e.g. by esterification of the drug as well as by adding absorption enhancers.

Single disintegrating tablets can also be prepared in the form of multilayers, i.e. the tablet consists of concentric or parallel layers cohered to each other. Multilayer tablets are prepared by repeated compression of powders and are made primarily to separate incompatible drugs from each other, i.e. incompatible drugs can be incorporated into the same tablet. Although intimate contact exists at the surface between the layers, the reaction between the incompatible drugs is limited. The use of parallel layered tablets where the layers are differently coloured represents an approach to preparing easily identifiable tablets.

Another variation of the disintegrating tablet is coated tablets which are intended to disintegrate and release the drug quickly (in contrast to coated tablets intended for modified release). The rationale for using coated tablets and detailed descriptions of the procedures used for tablet coating are given in Chapter 32.

Chewable tablets

Chewable tablets are chewed and thus are mechanically disintegrated in the mouth. The drug is, however, normally not dissolved in the mouth but swallowed and dissolves in the stomach or intestine. Thus, chewable tablets are used primarily to accomplish a quick and complete disintegration of the tablet – and hence obtain a rapid drug effect – or to facilitate the administration of the tablet. A common example of the former is antacid tablets. In the latter case, the elderly and children in particular have difficulty swallowing tablets and so a chewable tablet is an attractive form of medication. Important examples are vitamin tablets. Another general advantage of a chewable tablet is that this type of medication can be taken when water is not available.

Chewable tablets are similar in composition to conventional tablets except that a disintegrant is normally not included in the composition. Flavouring and colouring agents are common and sorbitol and mannitol are common examples of fillers.

Effervescent tablets

Effervescent tablets are dropped into a glass of water before administration, during which carbon dioxide is liberated. This facilitates tablet disintegration and drug dissolution; the dissolution of the tablet should be complete within a few minutes. As mentioned above, the effervescent carbon dioxide is created by a reaction in water between a carbonate or bicarbonate and a weak acid such as citric or tartaric acids.

Effervescent tablets are used to obtain rapid drug action, for example for analgesic drugs (Fig. 30.12), or to facilitate the intake of the drug, for example for vitamins.

The amount of sodium bicarbonate in an effervescent tablet is often quite high (about 1 g). After dissolution of such a tablet, a buffered water solution will be obtained which normally temporarily increases the pH of the stomach. The result is a rapid emptying of the stomach and the residence time of the drug in the stomach will thus be short. As drugs are absorbed in the small intestine rather than in the stomach, effervescent tablets can thus show a fast drug absorption, which can be advantageous, for example, for analgesic drugs. Another aspect of the short drug residence time in the stomach is that drug-induced gastric irritation can be avoided, e.g. for aspirin tablets, as the absorption of aspirin in the stomach can cause irritation.

Effervescent tablets also often include a flavour and a colourant. A water-soluble lubricant is preferable in order to avoid a film of a hydrophobic lubricant on the surface of the water after tablet dissolution. A binder is normally not included in the composition.

Effervescent tablets are prepared by both direct compaction and by compaction via granulation. In the latter case, traditional wet granulation is seldom used; instead, granules are formed by the fusion of particles as a result of their partial dissolution during wet massing of a moistened powder.

Effervescent tablets should be packaged in such a way that they are protected against moisture. This is accomplished with waterproof containers, often including a dessicant, or with blister packs or aluminium foils.

Compressed lozenges

Compressed lozenges are tablets that dissolve slowly in the mouth and so release the drug dissolved in the saliva. Lozenges are used for systemic drug uptake or for local medication in the mouth or throat, e.g. with local anaesthetic, antiseptic and antibiotic drugs. The latter type of tablets can thus be described as slow-release tablets for local drug treatment.

Disintegrants are not used in the formulation but otherwise such tablets are similar in composition to conventional tablets. In addition, lozenges are often coloured and include a flavour. The choice of filler and binder is of particular importance in the formulation of lozenges, as these excipients should contribute to a pleasant taste or feeling during tablet dissolution. The filler and binder should therefore be water soluble and have a good taste. Common examples of fillers are glucose, sorbitol and mannitol. A common binder in lozenges is gelatin.

Lozenges are normally prepared by compaction at high applied pressures in order to obtain a tablet of high mechanical strength and low porosity which can dissolve slowly in the mouth.

Sublingual tablets and buccal tablets

Sublingual tablets and buccal tablets are used for drug release in the mouth followed by systemic uptake of the drug. A rapid systemic drug effect can thus be obtained without first-pass liver metabolism. Sublingual tablets are placed under the tongue and buccal tablets are placed in the side of the cheek or high up between the inside of the upper lip and gum.

Sublingual and buccal tablets are often small and porous, the latter facilitating fast disintegration and drug release. Other designs, comprising high molecular weight hydrophilic polymers and/or gums, adhere in place by forming a gel. They remain in position, releasing drug, for 1–2 hours (e.g. prochlorperazine maleate for nausea).

Prolonged-release and pulsatile-release tablets

Test methods

In tablet formulation development and during manufacturing of tablets, a number of procedures are used to assess the quality of the tablets. Some test methods are described in pharmacopoeias and these tests are traditionally concerned with the content and the in vitro release of the active ingredient. Test methods not described in pharmacopoeias are sometimes referred to as non-compendial and concern a variety of quality attributes that need to be evaluated, such as the porosity of tablets. Below, some of the tests used in the quality evaluation of tablets are briefly described.

Uniformity of content of active ingredient

A fundamental quality attribute for all pharmaceutical preparations is the requirement for a constant dose of drug between individual tablets. In practice, small variations between individual preparations are accepted and the limits for this variation appear as standards in pharmacopoeias. Traditionally, uniformity of dose or dose variation between tablets is tested in two separate tests: uniformity of weight (mass) and uniformity of active ingredient.

The test for uniformity of weight is carried out by collecting a sample of tablets from a batch and determining their individual weights. The average weight of the tablets is then calculated. The sample complies with the standard if the individual weights do not deviate from the mean more than is permitted in terms of percentage.

If the drug substance forms the greater part of the tablet mass, any weight variation obviously indicates a variation in the content of active ingredient. Compliance with the standard thus helps to ensure that uniformity of dosage is achieved. However, in the case of potent drugs which are administered in low doses, the excipients form the greater part of the tablet weight and the correlation between tablet weight and amount of active ingredient can be poor (Fig. 30.18). Thus, the test for weight variation must be combined with a test for variation in content of the drug substance. Nevertheless, the test for uniformity of weight is a simple way to assess variation in drug dose, which makes the test useful as a quality control procedure during tablet production.

The test for uniformity of drug content is carried out by collecting a sample of tablets followed by a determination of the amount of drug in each. The average drug content is calculated and the content of the individual tablets should fall within specified limits.

Disintegration

As discussed above, the drug release process from tablets often includes a step at which the tablet disintegrates into smaller fragments. In order to assess this, disintegration test methods have been developed and examples of these can be found in pharmacopoeias.

The test is carried out by agitating a given number of tablets in an aqueous medium at a defined temperature and the time to reach the endpoint of the test is recorded. The preparation complies with the test if the time to reach this endpoint is below a given limit. The endpoint of the test is the point at which all visible parts of the tablets have been eliminated from a set of tubes in which the tablets have been held during agitation. The tubes are closed at the lower end by a screen and the tablet fragments formed during the disintegration are eliminated from the tubes by passing the screen openings, i.e. disintegration is considered to be achieved when no tablet fragments remain on the screen (fragments of coating may however remain).

A disintegration instrument (Fig. 30.19) consists normally of six chambers, i.e. tubes open at the upper end and closed by a screen at the lower. Before disintegration testing, one tablet is placed in each tube and normally a plastic disc is placed over the tablet. The tubes are placed in a water bath and raised and lowered at a constant frequency in the water in such a way that at the highest position of the tubes, the screen (and thus the tablet held down by the plastic disc) remains below the surface of the water.

Tests for disintegration do not normally seek to establish a correlation with in vivo behaviour. Thus, compliance with the specification is no guarantee of an acceptable release and uptake of the drug in vivo and hence an acceptable clinical effect. However, it is reasonable to assume that a preparation which fails to comply with the test is unlikely to be efficacious. Disintegration tests are, however, useful for assessing the potential importance of formulation and process variables on the biopharmaceutical properties of the tablet, and as a control procedure to evaluate the quality reproducibility of the tablet during production.

Dissolution

Dissolution testing is the most important way to study, under in vitro conditions, the release of a drug from a solid dosage form and thus represents an important tool to assess factors that affect the bioavailability of a drug from a solid preparation. During a dissolution test, the cumulative amount of drug that passes into solution is measured as a function of time. The test thus describes the overall rate of all the processes involved in the release of the drug into a bioavailable form. The reasons for and the procedures to enable the dissolution testing of solid dosage forms is discussed in detail in Chapter 35 but will be covered here briefly in the context of this present chapter.

Dissolution is accomplished by locating the tablet in a chamber containing a flowing dissolution medium. So that the method is reproducible, all factors that can affect the dissolution process are standardized. This includes factors that affect the solubility of the substance (i.e. the composition and temperature of the dissolution medium) and others that affect the dissolution process (such as the concentration of dissolved substance in, and the flow conditions of, the fluid in the dissolution chamber).

A number of compendial and non-compendial methods exist for dissolution testing, which can be applied to both drug substances and formulated preparations. With respect to preparations, the main test methods are based on forced convection of the dissolution medium and can be classified into two groups: stirred-vessel methods and continuous-flow methods.

The composition of the dissolution medium might vary between different test situations. Pure water or water mixed with acids or bases to adjust pH are frequently used. In addition, liquids showing a closer resemblance to physiological conditions are also used. These are often referred to as simulated gastric or intestinal fluids or bio-relevant fluids (see Chapter 35). Also, other dissolution media might be used, such as solvent mixtures, if the water solubility of the drug is very low. Finally, dissolution studies may be carried out in water-ethanol solutions in order to assess the potential effect of intake of alcohol drinks close to the administration of a tablet.

Mechanical strength

The mechanical strength of a tablet is associated with the resistance of the solid specimen to fracturing and attrition. An acceptable tablet must remain intact during handling at all stages, i.e. during production, packaging, warehousing, distribution, dispensing and administration by the patient. Thus, an integral part of the formulation and production of tablets is the determination of their mechanical strength. Such testing is carried out to:

A number of methods is available for measuring mechanical strength and they give different results. Also, the hardness of a tablet is sometimes measured by indentation testing. The hardness of a specimen is associated with its resistance to local permanent deformation and is thus not a measure of the resistance of the tablet to fracturing.

The most commonly used methods for strength testing can be subcategorized into two main groups: attrition resistance methods (friability tests) and fracture resistance methods.

Mechanisms of compression of particles

The compressibility of a powder is defined as its propensity, when held within a confined space, to reduce in volume when subjected to a load. The compression of a powder bed is normally described as a sequence of processes. Initially, the particles in the die are rearranged, resulting in a closer packing structure and reduced porosity. At a certain load the reduced space and the increased interparticulate friction will prevent any further interparticulate movement. The subsequent reduction of the tablet volume is therefore associated with changes in the dimensions of the particles.

Particles, either whole or a part, can change their shape temporarily by elastic deformation and permanently by plastic deformation (Fig. 30.24). Particles can also fracture into a number of smaller, discrete particles, i.e. particle fragmentation. The particle fragments can then find new positions, which will further decrease the volume of the powder bed. When the applied pressure is further increased, the smaller particles formed could again undergo deformation. Thus, one single particle may undergo this cycle of events several times during one compression. As a consequence of compression, particle surfaces are brought into close proximity to each other and particle-particle bonds can be formed.

Elastic and plastic deformations of particles are time-independent processes, i.e. the degree of deformation is related to the applied stress and not the time of loading. However, deformation can also be time-dependent, i.e. the degree of deformation is related to the applied stress and the time of loading. This deformation behaviour is referred to as viscoelastic and viscous deformation of a material. The consequence is that the compression behaviour of a material might depend on the loading conditions during the formation of a tablet in terms of the punch displacement-time relationship. Many pharmaceutical substances seem to have a viscous character, i.e. are strain-rate sensitive, and the properties of the tablet are thus dependent on the punch displacement-time relationship for the compression process.

Elastic deformation can be described as a densification of the particle due to a small movement of the cluster of molecules or ions that forms the particle, e.g. a crystal lattice or a cluster of disordered molecules. Plastic deformation is considered to occur by the sliding of molecules along slip planes within the particles. For real crystals, such slip planes are formed at defects in the crystal lattice, especially dislocations.

The majority of powders handled in pharmaceutical production consist not of non-porous primary particles but rather of granules, i.e. porous secondary particles formed from small dense primary particles. For granules, a larger number of processes is involved in their compression. These can be classified into two groups:

The latter concern changes in the dimensions of the primary particles due to elastic and plastic deformation and fragmentation. Such processes may be significant for the strength of tablets. It is, for example, common for a capping-prone substance, when compacted as dense particles, to also be prone to cap or laminate during compaction in the form of granules, such as substrate–binder granules. However, in terms of the evolution of the tablet structure, the physical changes in the granules that occur during compression are of primary importance.

At low compression forces, the reduction in volume of the bed of granules can occur by a rearrangement within the die. However, granules are normally fairly coarse, which means that they spontaneously form a powder bed of relatively low voidage (i.e. the porosity of the inter-granular spaces). Therefore, this initial rearrangement phase is probably of limited importance with respect to the total change in bed volume of the mass. With increased loading, a further reduction in bed volume therefore requires changes in the structure of the granules. The granules can deform, both elastically and permanently, but also densify, i.e. reduce their intragranular porosity. By these processes, granules can still be described as coherent units but their shape and porosity will change.

Granules can also be broken down into smaller units by two different mechanisms:

Studies on the compression properties of granules formed from pharmaceutical substances have indicated that granules are not prone to fracture into smaller units during compression over a normal range of applied pressures. Thus, permanent deformation and densification dominate the compression event although cracking and attrition may occur in parallel, especially for irregular, rough granules.

The dominating compression mechanisms for dense particles and granules are summarized in Table 30.2. The relative occurrence of fragmentation and deformation of solid particles during compression is related to the fundamental mechanical characteristics of the substance, such as its elasticity and plasticity. For granules, both the mechanical properties of the primary particles from which the granules are formed and the physical structure of the granules, such as their porosity and shape, will affect the relative occurrence of each compression mechanism.

Evaluation of compression behaviour

Bonding in tablets

The transformation of a powder into a tablet is fundamentally an interparticulate bonding process, i.e. the increased strength of the assembly of particles is the result of the formation of bonds between them. The nature of these bonds is traditionally subdivided into five types, known as the Rumpf classification:

In the case of compaction of dry powders, two of the suggested types of bond are often considered to dominate the process of interparticulate bond formation, i.e. bonding due to intermolecular forces and bonding due to the formation of solid bridges. Mechanical interlocking between particles is also considered as a possible but less significant bond type in tablets.

Bonding by intermolecular forces is sometimes also known as adsorption bonding, i.e. the bonds are formed when two solid surfaces are brought into intimate contact and subsequently adsorb to each other. Among the intermolecular forces, dispersion forces are considered to represent the most important bonding mechanism. This force operates in a vacuum and in a gaseous or liquid environment up to a separation distance between the surfaces of approximately 10–100 nm.

The formation of solid bridges, also referred to as the diffusion theory of bonding, occurs when two solids are mixed at their interface and accordingly form a continuous solid phase. Such a mixing process requires that molecules in the solid state are movable, at least temporarily, during compression. An increased molecular mobility can occur due to melting or as a result of a glass-rubber transition of an amorphous solid phase.

Mechanical interlocking is the term used to describe a situation where strength is provided by interparticulate hooking. This phenomenon usually requires that the particles have an atypical shape, such as needle-shaped, or highly irregular and rough particles.

For tablets of a porosity in the range 5–30%, it is normally assumed that bonding by adsorption is the dominant bond type between particles. In tablets formed from amorphous substances or from substances with low melting points, it is possible that solid bridges can be formed across the particle-particle interface. It is also reasonable that if tablets of a very low porosity, i.e. close to zero, are formed, particles can fuse together to a significant degree.

Often granules, i.e. secondary particles formed by the agglomeration of primary particles, are handled in a tableting operation. When granules are compacted, bonds will be formed between adjacent granule surfaces. For granules that do not include a binder, the fusion of adjacent surfaces during compaction is probably not a significant bonding mechanism. Thus, intermolecular bonding forces acting between intergranular surfaces in intimate contact will probably be the dominant bond type in such tablets.

Granules often include a binder. When such binder–substrate granules are compacted it is reasonable to assume that the binder also plays an important role in the formation of intergranular bonds. The binder may fuse together locally and form binder bridges between granule surfaces which cohere the granules to each other. Such bridges may be the result of a softening or melting of binder layers during the compression phase. However, different types of adsorption bonds may be active between granule surfaces. These may be subdivided into three types: binder–binder, binder–substrate and substrate–substrate bonds.

For adsorption bonds between granules in a tablet, the location of the failure during fracturing of the tablet can vary. Fractures occurring predominantly through binder bridges between substrate particles, as well as predominantly at the interface between the binder and the substrate particle, may occur. The location of the failure has been attributed to the relative strength of the cohesive (binder bridge) and adhesive (binder–substrate interface) forces acting within the granules, which can be affected by, for example, the surface geometry of the substrate particles.

The main bond types in tablets formed from dense particles (interparticulate bonds) and from granules (intergranular bonds) are summarized in Table 30.4.

Compactability of powders and the strength of tablets

The compactability of a powder refers to its propensity to form a coherent tablet and thus represents a critical powder property in successful tableting operations. The ability of a powder to cohere is understood in this context in a broad sense, i.e. a powder with a high compactability forms tablets with a high resistance towards fracturing and without tendencies to cap or laminate (Fig. 30.31). In practice, the most common way to assess powder compactability is to study the effect of compaction pressure on the strength of the resulting tablet, as assessed by the force needed to fracture the formed tablet while loaded diametrically, or the tensile strength of the tablet. Such relationships are often nearly linear (Fig. 30.32) above a lower pressure threshold needed to form a tablet, and up to a pressure corresponding to a tablet of a few per cent porosity. At low porosities the relationship between tablet strength and compaction pressure will often level out. This relationship can thus be described simply in terms of a three-region relationship characterized by lower and upper tablet strength thresholds and an intermediate region in which the tablet strength is pressure-dependent in an almost linear way.

Compactability profiles are sometimes also described by sigmoidal curves that can be divided principally into the three regions described above. At low pressures, the tensile strength of tablets increases as a power function with applied pressure, followed by a nearly linear region that finally levels off.

If cracks are formed in the tablet during tableting, e.g. during the ejection phase, this will often affect the assessed strength. Cracking and capping can often be induced at relatively high compaction pressures. This may be reflected as a drop in the tablet strength-compaction pressure profile.

A series of approaches to quantitatively describe or to model the compactability profile of a powder can be found in the literature. Some modelling approaches aim at describing the microstructure of a tablet in terms of an interparticulate bond structure and are based on the view that bond formation during compaction is significant for the development of coherence, i.e. it is postulated that the tensile strength of a tablet has some proportionality to the interparticulate bonds that act over the fracture area. Such models can thus be described as bond summation approaches and implicit is that all bonds are separated simultaneously during strength assessment. Since this is not consistent with the real mode of failure of a solid, the models are not fundamental approaches to understanding the strength of a tablet (see below).

Examples of equations describing compactability profiles have been given by Leuenberger (1982) and Alderborn and co-workers (Alderborn 2003). In both cases, the bond structure is modelled and related to an endpoint representing the maximum tensile strength (T_max) that can be obtained for tablets of a specific powder. Leuenberger’s approach is based on the concept of effective numbers of interparticulate bonds in a cross-section of the tablet. It is assumed that over a cross-section of a tablet, a number of bonding and non-bonding sites exists. This number depends on the applied pressure during compression (P) and the tablet relative density (r, which is equivalent to 1 minus the tablet porosity, e). In the derivation of the expression, the term compression susceptibility (γ) was introduced, which described the compressibility of the powder and has the unit 1/pressure. The equation takes the following form:

(30.12)

The compactability profile as described by the expression stems from the origin of the tensile strength-compaction pressure axes; the tensile strength will initially increase with compaction pressure and finally level off (compare discussion of compactability profiles above).

Alternatives to tablet strength-compaction pressure relationships for representing the compactability of powders are also used, such as the relationship between tablet strength and tablet porosity and the relationship between tablet strength and the work done by the punches during tablet formation.

Compaction is fundamentally a bonding process, i.e. strength is provided by bonds formed at the interparticulate junctions or contact sites during the compression process. Studies on the structure of fractured tablets indicate that a tablet generally fails by the breakage of interparticulate bonds, i.e. an interparticulate fracture process. However, especially for tablets of low porosity, the tablet can also fracture by breakage of the particles that form the tablet, i.e. a combination of an inter- and an intraparticulate fracture process. In general terms it seems, though, that the interparticulate contacts in a tablet represent the preferred failure path during fracturing. This conclusion is applicable to both tablets formed from solid particles and tablets formed from porous secondary particles (granules and pellets). Consequently, factors that affect the microstructure at the interparticulate junctions have been considered significant for the compactability of a powder.

Our understanding of the mechanical strength of a solid is based on the resistance of a solid body to fracture while loaded. It might seem reasonable that the sum of the bonding forces that cohere the molecules forming the solid will represent the strength of that solid. However, solids fail by a process of crack propagation, i.e. the fracture is initiated at a certain point within the solid and is thereafter propagated across a plane, thereby causing the solid to break. The consequence in terms of the strength of the solid is that the sum of the bonding forces acting over the fracture surface will be higher than the stress required to initiate failure. It is known, for example, that for crystalline solids the theoretical strength due to the summation of intermolecular bonds is much higher than the measured strength of the solid.

In order to understand the strength of solids, the process of fracture has attracted considerable interest in different scientific areas. In this context, important factors associated with the fracturing process and the strength of a specimen are the size of the flaw at which the crack is initiated and the resistance of the solid towards fracturing. The latter property can be described by the critical stress intensity factor, which is an indication of the stress needed to propagate a crack. Another fracture mechanics parameter, which is related to the critical stress intensity factor, is the strain energy release rate, which is a measure of the energy released during crack propagation.

By using the critical stress intensity factor, the tensile strength of the solid (T) is considered to relate to the flaw size (c) and the critical stress intensity factor (K_IC) in the following way:

(30.13)

The critical stress intensity factor varies with tablet porosity. It has therefore been suggested that for compacts, such as tablets, factors such as the size of the particles within the tablet and the surface energy of the material will affect the critical stress intensity factor (Kendall 1988). These factors are also considered to control the interparticulate bond structure in a tablet.

Procedures to determine the critical stress intensity factor for a particulate solid have been described. Such a procedure normally involves the formation of a beam-shaped compact in which a notch is formed. When the compact is loaded, the fracture is initiated at the notch. The force needed to fracture the compact is determined and the critical stress intensity factor thereafter calculated. In order to assess a material characteristic, compacts of a series of porosities are formed and the series of values for the critical stress intensity factor subsequently determined is plotted as a function of the compact porosity (Fig. 30.33). The relationship thereafter may sometimes be extrapolated to zero porosity and the value thus derived is sometimes considered a fundamental material characteristic.

In addition to the evaluation of compactability profiles and fracture mechanics studies, indices and expressions have been derived within pharmaceutical science which can be described as indicators of the compactability of a powder. There are several applications of such indicators during pharmaceutical development, such as:

Examples of such indicators which have found industrial use are the indices of tableting performance derived by Hiestand and co-workers (Hiestand 1996). Hiestand derived three indices of tableting performance, among which the bonding index (BI) and the brittle fracture index (BFI) are suggested to reflect the compactability of the powder. These indices are dimensionless ratios between mechanical properties of compacts formed at some porosity. The BI is proposed to reflect the ability of particles to form a tablet of high tensile strength, whereas the BFI is proposed to reflect the ability of a tablet to resist fracturing and lamination during handling. These indices are defined as follows:

(30.14)

and

(30.15)

where T is the tensile strength of a normal compact, T_o is the tensile strength of a compact with a small hole and H is the hardness of the compact.

Post-compaction tablet strength changes

The compactability of a powder is normally understood in terms of the ability of particles to cohere during the compression process and hence to form a porous specimen of defined shape. However, the mechanical strength of tablets can change, increase or decrease, during storage without the application of any external mechanical force. The underlying mechanisms for such changes are often a complex function of the combination of ingredients in the tablet and the storage conditions, such as relative humidity and temperature.

During storage at a fairly high relative humidity, tablets can be softer and their tensile strength reduced. With increased relative humidity, the state of water adsorbed at the solid surface can change from an adsorbed gas to a liquid, i.e. water condenses in the tablet pores. Furthermore, if the solid material is freely soluble in water, it can dissolve. Both the presence of condensed water in the pores and the dissolution of a substance in the condensed water can drastically decrease tablet strength and eventually lead to the collapse of the whole tablet. However, the dissolution of a freely soluble substance in condensed pore water can also give an increase in tablet strength if the water is allowed to evaporate owing to a change in temperature or relative humidity. The result of this evaporation can be crystallization of solid material, with the subsequent formation of solid bridges between particles in the tablet and increased tablet strength.

In addition to the mechanisms involving the presence of condensed pore water, several other mechanisms have been proposed to cause an increase in tablet strength during storage at a relative humidity at which condensation of water is unlikely to occur. One such mechanism is a continuing viscous deformation of particles after the compaction process is completed. This phenomenon is referred to as stress relaxation of tablets. The increase in tablet strength can be significant with no, or minor, detectable changes in its physical structure. However, viscous deformation of small parts of particles might change the microstructure of the tablet in terms of the relative orientation of particle surfaces and the geometry of the interparticle voids and thus affect the resistance to fracturing of a tablet. A characteristic feature for stress relaxation changes is that the tablet strength changes occur for a limited time in connection with the compaction phase. An increase in tablet strength during storage may also be related to a polymorphic transformation, i.e. a change in the crystal structure of particles.

Factors of importance for powder compactability

A number of empirical studies exist in the pharmaceutical literature with the aim of mapping factors that affect the structure of a tablet and its mechanical strength, i.e. tensile strength, resistance towards attrition and capping tendencies. These factors can be classified into three groups: material and formulation factors; processing factors (choice of tablet machine and operation conditions); and environmental factors (relative humidity, etc.).

Of special importance from a formulation perspective are the physical and mechanical properties of the particles used in the formulation, and how these particles are combined in granulation and mixing steps. Relationships for powders consisting of one component; of two components, such as a filler and a lubricant or a dry binder; or of several components have been discussed in this context.

Compaction of solid particles

As discussed above, it is often assumed that the evolution of the interparticulate structure of a tablet, in terms of bonds between particles and the pores between the particles, will be significant for the mechanical strength of the tablet. Thus, the material-related factors that control the evolution of the microstructure of the tablet have been discussed as important factors for the compactability of a powder. In this context, the compression behaviour and the original dimensions of the particles have received special interest.

As already mentioned, the degree of fragmentation and permanent deformation that particles undergo during compression are significant for tablet structure and strength. It has been suggested that both fragmentation and deformation are strength-producing compression mechanisms. The significance of particle fragmentation has been considered to be related to the formation of small particles which constitute the tablet, with the consequence that a large number of contact sites between particles at which bonds can be formed will be developed and the voids between the particles will be reduced in size. The significance of permanent deformation has been explained in terms of an effect on the area of contact of the interparticulate contact sites, with a subsequent increased bonding force. The relative importance of these mechanisms for the bonding between particles in a tablet and the resistance of a tablet towards fracturing has not, however, been fully clarified. Concerning elastic deformation, which is recoverable, this is considered as a disruptive rather than a bond-forming mechanism. Poor compactability, in terms of low tablet strength and capping/lamination, has been attributed to elastic properties of the solid. A summary of proposed advantages and disadvantages of the different particle compression mechanisms for the ability of the particles to form tablets is given in Table 30.5.

It is sometimes considered that one of the most important properties of particles for the mechanical strength of a tablet is their size before compaction. A number of empirical relationships between particle dimensions before compaction and the mechanical strength of the resultant tablet can thus be found in the literature. As a rule, it is normally assumed that a smaller original particle size increases tablet strength. However, it is also suggested that the effect of original particle size is in relative terms limited for powder compactability, with the possible exception of very small (i.e. micronized) particles. Reported data show, however, that different and sometimes complex relationships between particle size and tablet strength can be obtained, with maximum or minimum tablet strength values. Complex relationships might be associated with a change in the shape, structure (such as the formation of aggregates) or degree of disorder of the particles with particle size. It seems also that increased compaction pressure stresses the relationship between the original particle size and tablet strength in absolute terms.

Some studies have specifically reported on the effect of original particle shape on tablet strength. The results indicate that, for particles that fragment to a limited degree during compression, an increased particle irregularity improved their compactability. However, for particles that fragmented markedly during compression, the original shape of the particles did not affect tablet strength. Moreover, an increased compaction pressure increased the absolute difference in strength of compacts of different original particle shape. Thus, the shape characteristics of particles that fragment markedly during compression seem not to affect the microstructure and the tensile strength of tablets, but the converse applies for particles that showed limited fragmentation.

Compaction of granules

The rationale for granulating a powder mixture before tableting has been discussed above, one reason being to ensure good tableting behaviour, including the compactability. When granules are compacted, the mechanical characteristics of the primary particles and the properties of other excipients will affect the tableting behaviour of the powder. For example, it is a common experience that capping-prone material will show capping tendencies in the granulated form of the substance also. However, the design of the granulation process, such as the method of granulation, will control the physical properties of the granules formed, e.g. in terms of granule size, shape, porosity and strength, which subsequently will affect the evolution in the microstructure of the tablets during compaction. It has, for example, been shown (Fig. 30.34) that tablets formed from granules prepared by roller compaction show a tensile strength that depends on the compaction force used during the dry granulation process. Thus, the evolution of the intergranular tablet microstructure during compression, as well as the evolution in tablet strength, is related to the following two factors:

During compression of granules, the granules tend to keep their integrity and the formed tablet can in physical terms be described as granules bonded together. When subjected to a load, tablets formed from granules often fail because of breakage of these bonds. Hence, the bonding force of the intergranular bonds and the structure of the intergranular pores will be significant for the tensile strength of the tablets.

In terms of the physical properties of granules, their porosity and compression shear strength are significant properties that influence compactability that can be modulated by the granulation process and by the composition. In general terms, increased porosity and decreased compression shear strength will increase the compactability of the granules. As discussed above, pharmaceutical granules seem to fragment to only a limited degree during compression. The importance of these granule properties for compactability has thus been discussed in terms of a sequential relationship between the original physical character of the granules, the degree of deformation they undergo during compression and the area of contact and the geometry of the intergranular pores of the formed tablet. The formation of large intergranular areas of contact and a closed pore system promote a high tablet strength.

Traditionally, the most important means of controlling the compactability of granules has been to add a binder to the powder to be granulated. This is normally done by adding the binder in a dissolved form, thereby creating binder–substrate granules. An increased amount of binder can correspond to an increased compactability but this is not a general rule. The importance of the presence of a binder for the compactability of such granules can be explained in two ways. First, it has been suggested that intergranular bonds that involve binder-coated granule surfaces can be described as comparatively strong, i.e. difficult to break. Second, binders are often comparatively deformable substances, which can reduce the compression shear strength of the whole granule and thus facilitate the deformation of the granules during compression. An increased degree of granule deformation is sometimes proposed to increase the compactability of the granules. Thus, the binder might have a double role in the compactability of granules, i.e. to increase granule deformation and increase bond strength. Except for the presence of a binder in the granules, the combination of fillers in terms of the hardness and dimensions of the particles can affect the compression shear strength and hence the deformation properties of the granules during compression.

In the preparation of binder–substrate granules, the intention is normally to spread out the binder homogeneously within the granules, i.e. all substrate particles are more or less covered with a layer of binder. However, it is possible that the binder will be concentrated at different regions within the granules, e.g. due to solute migration during drying. The question of the importance of a relatively homogeneous distribution versus a peripheral localization of the binder, i.e. concentration at the granule surface, has been addressed in the literature. It has been argued that a peripheral localization of the binder in the granules before compression should be advantageous, as the binder can thereby be used most effectively for the formation of intergranular bonds. However, the opposite has also been suggested, i.e. a homogeneous binder distribution is advantageous for the compactability of granules. This observation was explained by assuming that, owing to extensive deformation and some attrition of granules during compression, new extragranular surfaces will be formed originating from the interior of the granule. When the binder is distributed homogeneously, such compression-formed surfaces will show a high capacity for bonding.

Figure 30.35 gives an overview of the physical granule properties that may affect the compression behaviour and compactability of granules.

Compaction of binary mixtures

Most of the fundamental work on powder compaction has been carried out on one-component powders. It is, however, of obvious interest to derive knowledge that enables the prediction of the tableting behaviour of mixtures of powders from information on the behaviour of the individual components. In this context, powder mixtures of two components, i.e. binary mixtures, have often been the system of choice in pharmaceutical studies. Binary mixtures can be of two types: simple physical mixtures, i.e. nearly randomized mixtures of particles, and interactive (ordered) mixtures. Most of the studies in this context are empirical, although models for the compaction of binary powder mixtures have been derived.

Concerning simple binary mixtures, the importance of the relative proportions of the ingredients has been studied in relation to the compactability, of or compression parameters for, the respective single component. The mixture can show a linear dependence of the properties of the single powders but deviations from such a simple linear relationship, both positively and negatively, have also been reported. Such non-linear behaviour has been explained in terms of differences between the components in their mechanical and adhesive properties.

Interactive mixtures, especially their compactability after the admixture of lubricants and dry binders, have been the subject of study. The tablet strength-reducing effect of a lubricant mixed with solid particles depends on the surface coverage of the lubricant film obtained during mixing, on the compaction properties of the lubricant per se and on the compression behaviour of the substrate particles. Lubricant sensitivity, also referred to as dilution capacity, seems to be strongly related to the fragmentation propensity of the substrate particles, as discussed earlier.

Concerning the tablet strength-increasing effect of a dry binder mixed with solid particles, similar factors seem to control the compactability of the dry binder mixture as for the lubricant mixture, i.e. the degree of surface coverage of the substrate particle, the binding capacity and deformability of the dry binder and the fragmentation propensity of the substrate particles (Fig. 30.36).

The dilution capacity of interactive mixtures between granules and lubricants or dry binders seems to be related to the degree of deformation the granules undergo during compression, i.e. a high degree of deformation will give a lower sensitivity to a lubricant but also a less positive effect of a dry binder.