TABLETS. CHARACTERISTIC. METHODS TABLETS PRODUCTION BY DIRECT COMPRESSING AND PREVIOUS GRANULATION.

TABLETS. CHARACTERISTIC. METHODS TABLETS PRODUCTION BY DIRECT COMPRESSING AND PREVIOUS GRANULATION.

The compressed tablet is by far the most widely used dosage form, having advantages for both producer and user. However, the manufacture of tablets can be a complex process, since only a few raw materials inherently possess those properties which are necessary for the production of tablets of satisfactory quality. Hence some preliminary treatment and/or incorporation of excipients in the formulation is usually needed. Tablet manufacture is a paradox. Considerable ingenuity and formulation expertise are required to transform a mass of particles into a low porosity mass. Yet, after the tablet has been ingested, the requirement then is usually for the tablet to release its active ingredient as rapidly as possible, and further ingenuity is needed to bring this about.

Tablets are solid preparations each of which contains a single dose of one or more active ingredients. They are obtained by compressing uniform volumes of particles, and are almost always intended for oral administration.

The earliest reference to a dosage form resembling the tablet is to be found in tenth century Arabic medical literature. Drug particles were compressed between the ends of engraved ebony rods, force being applied by means of a hammer. Details of the tabletting process, as it is now known, were first published in 1843 when William Brockedon was granted British Patent 9977 for ‘‘manufacturing pills and medicinal lozenges by causing materials when in a state of granulation, dust or powder, to be made into form and solidified by pressure in dies.’’ In this case, too, force was applied by a hammer. Potassium bicarbonate was the first pharmaceutical substance to be so treated.

The use of compressed pills, as they were then known, increased rapidly. It is likely that the term ‘‘tablet’’ for this dosage form was first used in the United States in the 1870s. Power-driven presses replaced Brockedon’s hammer, and by 1874 there existed both rotary and excentric presses, which in their mode of operation were fundamentally similar to those in use at the present time. The tablet lent itself to mass manufacture by mechanical means, in contrast to the slower labour-intensive production of older solid dosage forms such as the pill. It is impractical for individual pharmacists to produce small quantities of tablets on a commercial scale, and this led to the concentration of pharmaceutical manufacture in relatively few industrial sites.

A monograph for Glyceryl Trinitrate Tablets was included in the British Pharmacopoeia of 1885, but no other tablet monograph appeared there until 1945. This was not due to lack of popularity of the dosage form itself, but rather the absence of suitable methods of quality control that were applicable to tablets.

The tablet did not meet with universal approval. In 1895 an editorial in the Pharmaceutical Journal in the United Kingdom described the tablet as ‘‘one of the evils suffered by legitimate pharmacy,’’ and predicted that tablets ‘‘have had their day.’’[1] Not withstanding such a prediction, the usage of tablets has continued to increase. The 2000 edition of the British Pharmacopoeia contains 320 monographs for tablets, far in excess of any other dosage form.

The tablet is the most popular dosage form because it provides advantages for all concerned in the production and consumption of medicinal products. Though the initial capital outlay for the manufacturer of tablets is considerable, they can be produced at a much higher rate than any other dosage form, tablet presses capable of producing about one million tablets per hour being available. Furthermore, the fact that the tablet is a dry dosage form promotes stability, and in general, tablets have shelf lives measured in years. They are also convenient to transport in bulk, since they contain relatively small proportions of excipients unlike, for example, oral liquids.

From the viewpoint of the pharmacist, tablets are easy to dispense, while the patient receives a concentrated and readily transportable and consumed dosage form. Furthermore, if properly prepared, tablets provide a uniformity of dosage greater than that of most other medicines, and appropriate coating can mask unpleasant tastes and improve patient acceptance.

The tablet also provides a versatile drug delivery system. Though most tablets are intended to be swallowed intact, the same basic manufacturing process, associated with appropriate formulation, provides medicines for sublingual, buccal, rectal, and vaginal administration, together with lozenges, soluble, dispersible, and effervescent tablets. In addition, techniques that can delay or otherwise modify the release of the active ingredient from the tablet are available.

Naturally tablets only possess these advantages if they are properly formulated and manufactured. A wellprepared tablet should possess the following qualities:

1. It should, within permitted limits, contain the stated dose of drug.

2. It should be sufficiently strong to withstand the stresses of manufacture, transport, and handling so as to reach the patient intact.

3. It should deliver its dose of drug at the site and at the speed required.

4. Its size, taste, and appearance should not detract from its acceptability by the patient.

Common disk-shaped tablets

A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose. The excipients can include diluents, binders or granulating agents, glidants (flow aids) and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment (extending its shelf life), or to enhance the tablet’s appearance.

The compressed tablet is the most popular dosage form in use today. About two-thirds of all prescriptions are dispensed as solid dosage forms, and half of these are compressed tablets. A tablet can be formulated to deliver an accurate dosage to a specific site; it is usually taken orally, but can be administered sublingually, buccally, rectally or intravaginally. The tablet is just one of the many forms that an oral drug can take such as syrups, elixirs, suspensions, and emulsions. Medicinal tablets were originally made in the shape of a disk of whatever color their components determined, but are now made in many shapes and colors to help distinguish different medicines. Tablets are often stamped with symbols, letters, and numbers, which enable them to be identified. Sizes of tablets to be swallowed range from a few millimeters to about a centimeter. Some tablets are in the shape of capsules, and are called “caplets”. Medicinal tablets and capsules are often called pills. This is technically incorrect, since tablets are made by compression, whereas pills are ancient solid dose forms prepared by rolling a soft mass into a round shape. Other products are manufactured in the form of tablets which are designed to dissolve or disintegrate; e.g. cleaning and deodorizing products.Contents [hide]

Tabletting formulations

In the tablet-pressing process, it is important that all ingredients be fairly dry, powdered or granular, somewhat uniform in particle size, and freely flowing. Mixed particle sized powders can segregate during manufacturing operations due to different densities, which can result in tablets with poor drug or active pharmaceutical ingredient (API) content uniformity but granulation should prevent this. Content uniformity ensures that the same API dose is delivered with each tablet.

Some APIs may be tableted as pure substances, but this is rarely the case; most formulations include excipients. Normally, an pharmacologically inactive ingredient (excipient) termed a binder is added to help hold the tablet together and give it strength. A wide variety of binders may be used, some common ones including lactose, dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose, povidone polyvinylpyrrolidone and modified cellulose (for example hydroxypropyl methylcellulose and hydroxyethylcellulose).

Often, an ingredient is also needed to act as a disintegrant to aid tablet dispersion once swallowed, releasing the API for absorption. Some binders, such as starch and cellulose, are also excellent disintegrants.

Small amounts of lubricants are usually added, as well. The most common of these is magnesium stearate and calcium stearate.

Advantages and disadvantages

 Variations on a common tablet design, which can be distinguished by both color and shapeTablets are simple and convenient to use. They provide an accurately measured dosage of the active ingredient in a convenient portable package, and can be designed to protect unstable medications or disguise unpalatable ingredients. Colored coatings, embossed markings and printing can be used to aid tablet recognition. Manufacturing processes and techniques can provide tablets special properties, for example, sustained release or fast dissolving formulations.

Some drugs may be unsuitable for administration by the oral route. For example, protein drugs such as insulin may be denatured by stomach acids. Such drugs cannot be made into tablets. Some drugs may be deactivated by the liver when they are carried there from the gastrointestinal tract by the hepatic portal vein (the “first pass effect”), making them unsuitable for oral use. Drugs which can be taken sublingually are absorbed through the oral mucosae, so that they bypass the liver and are less susceptible to the first pass effect. The oral bioavailability of some drugs may be low due to poor absorption from the gastrointestinal tract. Such drugs may need to be given in very high doses or by injection. For drugs that need to have rapid onset, or that have severe side effects, the oral route may not be suitable. For example salbutamol, used to treat problems in the pulmonary system, can have effects on the heart and circulation if taken orally; these effects are greatly reduced by inhaling smaller doses direct to the required site of action.

Tablet properties

Tablets can be made in virtually any shape, although requirements of patients and tableting machines mean that most are round, oval or capsule shaped. More unusual shapes have been manufactured but patients find these harder to swallow, and they are more vulnerable to chipping or manufacturing problems.

Tablet diameter and shape are determined by the machine tooling used to produce them – a die plus an upper and a lower punch are required. This is called a station of tooling. The thickness is determined by the amount of tablet material and the position of the punches in relation to each other during compression. Once this is done, we can measure the corresponding pressure applied during compression. The shorter the distance between the punches, thickness, the greater the pressure applied during compression, and sometimes the harder the tablet. Tablets need to be hard enough that they don’t break up in the bottle, yet friable enough that they disintegrate in the gastric tract.

Tablets need to be strong enough to resist the stresses of packaging, shipping and handling by the pharmacist and patient. The mechanical strength of tablets is assessed using a combination of (i) simple failure and erosion tests, and (ii) more sophisticated engineering tests. The simpler tests are often used for quality control purposes, whereas the more complex tests are used during the design of the formulation and manufacturing process in the research and development phase. Standards for tablet properties are published in the various international pharmacopeias (USP/NF, EP, JP, etc.). The hardness of tablets is the principle measure of mechanical strength. Hardness is tested using a hardness tester. The units for hardness have evolved since the 1930s.

Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall.

Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid are the most frequently used lubricants in tablets or hard gelatin capsules.[citatioeeded]

Manufacturing

Manufacture of the tableting blend

In the tablet pressing process, the main guideline is to ensure that the appropriate amount of active ingredient is in each tablet. Hence, all the ingredients should be well-mixed. If a sufficiently homogenous mix of the components cannot be obtained with simple blending processes, the ingredients must be granulated prior to compression to assure an even distribution of the active compound in the final tablet. Two basic techniques are used to granulate powders for compression into a tablet: wet granulation and dry granulation. Powders that can be mixed well do not require granulation and can be compressed into tablets through direct compression.

Wet granulation

Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture. The amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvent-based systems but may not be suitable for drugs which are degraded by hydrolysis.

Procedure

Step 1: The active ingredient and excipients are weighed and mixed.

Step 2: The wet granulate is prepared by adding the liquid binder–adhesive to the powder blend and mixing thoroughly. Examples of binders/adhesives include aqueous preparations of cornstarch, natural gums such as acacia, cellulose derivatives such as methyl cellulose, gelatin, and povidone.

Step 3: Screening the damp mass through a mesh to form pellets or granules.

Step 4: Drying the granulation. A conventional tray-dryer or fluid-bed dryer are most commonly used.

Step 5: After the granules are dried, they are passed through a screen of smaller size than the one used for the wet mass to create granules of uniform size.

Low shear wet granulation processes use very simple mixing equipment, and can take a considerable time to achieve a uniformly mixed state. High shear wet granulation processes use equipment that mixes the powder and liquid at a very fast rate, and thus speeds up the manufacturing process. Fluid bed granulation is a multiple-step wet granulation process performed in the same vessel to pre-heat, granulate, and dry the powders. It is used because it allows close control of the granulation process.

Dry granulation

Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates). This process is often used when the product to be granulated is sensitive to moisture and heat. Dry granulation can be conducted on a tablet press using slugging tooling or on a roll press called a roller compactor. Dry granulation equipment offers a wide range of pressures to attain proper densification and granule formation. Dry granulation is simpler than wet granulation, therefore the cost is reduced. However, dry granulation often produces a higher percentage of fine granules, which can compromise the quality or create yield problems for the tablet. Dry granulation requires drugs or excipients with cohesive properties, and a ‘dry binder’ may need to be added to the formulation to facilitate the formation of granules.

Granule lubrication

After granulation, a final lubrication step is used to ensure that the tableting blend does not stick to the equipment during the tableting process. This usually involves low shear blending of the granules with a powdered lubricant, such as magnesium stearate or stearic acid.

Manufacture of the tablets

Whatever process is used to make the tableting blend, the process of making a tablet by powder compaction is very similar. First, the powder is filled into the die from above. The mass of powder is determined by the position of the lower punch in the die, the cross-sectional area of the die, and the powder density. At this stage, adjustments to the tablet weight are normally made by repositioning the lower punch. After die filling, the upper punch is lowered into the die and the powder is uniaxially compressed to a porosity of between 5 and 20%. The compression can take place in one or two stages (main compression, and, sometimes, pre-compression or tamping) and for commercial production occurs very fast (500–50 msec per tablet). Finally, the upper punch is pulled up and out of the die (decompression), and the tablet is ejected from the die by lifting the lower punch until its upper surface is flush with the top face of the die. This process is simply repeated many times to manufacture multiple tablets.

Common problems encountered during tablet manufacturing operations include:

poor (low) weight uniformity, usually caused by uneven powder flow into the die poor (low) content uniformity, caused by uneven distribution of the API in the tableting blend sticking of the powder blend to the tablet tooling, due to inadequate lubrication, worn or dirty tooling, and sub-optimal material properties capping, lamination or chipping. Such mechanical failure is due to improper formulation design or faulty equipment operation.

TABLET COMPRESSION

All tablets are made by a process of compression. Solid, in the form of relatively small particles, is contained in a die and a compressing force of several tonnes is applied to it by means of punches. The shape of the die governs the cross-sectional shape of the tablet, and the distance between the punch tips at the point of maximum compression governs its thickness. The conformation of the tablet faces, usually flat or convex, is a reflection of those of the punches.

The tip of the lower punch moves up and down within the die, but never actually leaves it. The upper punch descends to penetrate the die and apply the compressive force. It is then withdrawn to permit ejection of the tablet, brought about by an upward movement of the lower punch.

There are two types of tablet press. The excentric press has one die and one pair of punches. The rotary press has a larger number of dies which are fitted, with their corresponding punches, into a rotating turret.

Irrespective of the type of press that is used, the process of tablet compression can be divided into three stages, as shown in Fig. 1.

Stage 1. Filling

The lower punch falls within the die, leaving a cavity into which particulate matter flows under the influence of gravity from a hopper. Though tablets are usually described in terms of weight, the die is filled by a volumetric process. The volume is determined by the depth to which the lower punch descends in the die. Unless this volume is filled reproducibly on each occasion, then the mass of the tablet will vary, and with it the drug content of each tablet. Therefore, uniform filling is essential. However, it must be borne in mind that the die cavity has a cross-section of only a few millimetres, and only a fraction of a second is available for filling each die. It therefore follows that the particles must flow easily and reproducibly.

Stage 2. Compression

The upper punch descends, and its tip enters the die, confining the particles. The distance separating the punch faces decreases, either by movement of the upper punch alone (as in excentric presses) or by movement of both punches (as happens in rotary presses). The porosity of the contents of the die is progressively reduced, and the particles are forced into ever-closer proximity to each other. This process is facilitated by the particles fragmenting and/or deforming. Once the particles are close enough together, interparticulate forces then cause the individual particles to aggregate, forming a tablet. The magnitude of the force is governed by the minimum distance separating the punch faces. Therefore, a second essential property of the particles is that they cohere under the influence of a compressive force. It is also essential that this coherence be maintained when the compressing force is removed.

Stage 3. Ejection

The upper punch is withdrawn from the die, and so the force being applied to the tablet is removed. The effect of this might be to cause the deformed particles to return to their former shape, which would result in a decrease in interparticulate contact and hence tablet strength. It is essential that this does not occur. As the upper punch leaves the die, the lower punch moves upwards, pushing the tablet before it. During the compression stage, the particles are forced into intimate contact with the interior die wall. It follows that attempts to remove the tablet will be opposed by frictional forces and so successful ejection demands lack of adhesion between the tablet and the diewall.

Therefore in summary, for a particulate solid to be successfully transformed into tablets, three key properties need to be present:

1. Good particle flow.

2. The ability of the particles to cohere under the influence of a compressing force.

3. The ability of the tablet to be ejected from the die after the compressing force has been removed.

Few powders possess all these essentials and some possess none of them. Thus, before successful tabletting can take place, some preliminary treatment with the addition of one or more excipients is almost invariably needed.

METHODS OF TABLET PRODUCTION

The pretreatment that is usually necessary takes the form of granulation. The process of granulation is essentially one of size enlargement, and it serves several purposes in the tablet manufacturing process:

1. It improves flow by increasing particle size, since large particles flow more readily than small ones.

2. It improves compression characteristics, adding to the cohesive strength of the tablet.

3. Once a homogeneous mixture has been achieved, segregation is prevented, since particles that are stuck together cannot separate.

4. It reduces dust.

Both wet and dry granulation techniques are available.

Tablet Manufacture by Wet Granulation

This is the traditional method of pretreatment of solids prior to tabletting. Despite its complexity and inherent disadvantages, eveow about half the tablets produced worldwide are manufactured by this process. Its essence is that particles of active ingredient, with a diluent if necessary, are stuck together using an adhesive, the latter usually being water-based. The result is a granular product which flows more readily and has an improved ability to cohere during compression.

A flow diagram of the wet granulation process together with appropriate excipients is shown in Fig. 2.

The diluent

The first stage in the wet granulation process is often a dry mixing stage in which the active component is mixed with a diluent. Many drugs need to be administered in doses of only a few milligrams or even less, yet a tablet that weighs less than about 50 mg is difficult for the patient to handle conveniently. It is therefore necessary to increase the bulk of such a tablet with a diluent. Some commonly used diluents are listed in Table 1.

The ideal diluent would be both chemically and physiologically inert, and would not interfere with the bioavailability of the active ingredient. It should also be inexpensive and be easily tabletted since, if the proportion of active ingredient is small, the overall tabletting properties of the mixture are largely governed by those of the diluent.

Lactose is by far the most frequently used diluent for solid dosage forms. An inexpensive disaccharide obtained as a by-product of the cheese industry; it is available in a number of forms, though a-Lactose monohydrate is the variety that is normally used as the diluent in tablets made by wet granulation. It is freely albeit slowly soluble in water and as such it is a suitable diluent for active ingredients of low water solubility. Lactose is a non-reducing sugar, and is reasonably inert. It can take part in the Maillard reaction when mixed with substances containing primary amine groups, giving highly colored products, and thus its use is contraindicated in such formulations.[2]

Probably the second most commonly used diluent in the wet granulation process is dibasic calcium phosphate. This substance is virtually insoluble in water and hence is always used in conjunction with a disintegrating agent. Its properties have been reviewed by Carstensen and Ertell.[3]

Mixing

The purpose of the mixing stage is to ensure that the powder blend and hence the resulting tablets are homogeneous in content. A random mixture is defined as one where the probability of sampling a given type of particle is proportional to the number of such particles in the total mixture. Thus, the aim is to produce a

Table 1 Tablet diluents

Diluent	Comments
Calcium carbonate	Insoluble in water (Cal-Carb_, Millicarb_, Pharma-Carb_, Sturcal_)
Calcium phosphate, dibasic	Insoluble in water, good flow properties, available in dihydrate and anhydrous forms (Cyfos_, Calstar_, Calipharm_, Emcompress_)
Calcium phosphate, tribasic	Insoluble in water (Tricafos_, Tri-Cal_, Tri-Tab_)
Calcium sulfate	Insoluble in water (Cal-Tab_, Compactrol_)
Cellulose, microcrystalline	Good compression properties, may not need lubricant, can act as disintegrant (Avicel_, Emcocel_, Vivacel_)
Cellulose, microcrystalline silicified	Combination of microcrystalline cellulose and silica (Prosolv_)
Cellulose, powdered	(Elcema_, Solka-Floc_)
Dextrates	(Emdex_)
Dextrose	Hygroscopic, reducing sugar (Tabfine_)
Fructose	(Fructofin_)
Lactitol	(Finlac_)
Lactose monohydrate	The most commonly used diluent. Inexpensive, takes part in Maillard reaction (Fast-Flo_, Lactochem_, Microtose_, Pharmatose_, Tablettose_, Zeparox_)
Magnesium carbonate
Maltitol	(Maltisorb_, Maltit_)
Maltodextrin	(Glycidex_, Lycatab_, Maltrin_)
Maltose	(Advantose_)
Mannitol	Freely soluble in water, negative heat of solution and therefore cool taste, popular for chewable tablets, non-cariogenic (Pearlitol_)
Sodium chloride	Freely soluble in water, used in solution tablets
Sorbitol
Starch	Also acts as disintegrating agent, may give soft tablets
Starch, pregelatinized	Also acts as disintegrating agent. (Lycatab_, Pharma-Gel_, Pre-Jel_, Sepistab_, Starch 1500_, Starx 1500_)
Sucrose	Freely soluble in water, sweet taste, hygroscopic, used in lozenges in conjunction with lactose
Sugar, compressible	(Dipac_, Nutab_)
Sugar, confectioner’s
Sugar spheres	(Nu-Core_, Nu-Pareil_)
Talc
Xylitol	Negative heat of solution, cool taste (Xylifin_, Xylitab_)

ablet–Tablet

mixture such that when a sample is removed, the relative proportions of the components of that sample are the same as in the mixture as a whole.

Unlike molecules in a fluid, which in time will mix spontaneously by a diffusion mechanism, powder particles do not mix spontaneously but remain in their relative positions. Therefore before mixing can occur, energy must be put into the system. This causes the powder bed to dilate or expand, the particles separate from one another and this leads to relative motion among them.

It might be intuitively expected that the randomness of a mixture will progressively increase with time, but this is not always the case. Under certain conditions, an optimum mixing time occurs, beyond which the mixture shows a tendency to separate back into its components. This process is known as segregation. Segregation is particularly likely to occur in mixtures where the components differ markedly in size, with differences in shape and density as secondary factors. It is especially likely to occur if regular patterns of movement are set up in the mixing device, and for this reason, mixers are designed so that an irregular mixing motion occurs.[4]

Although in general a size difference between components can lead to segregation, a situation where there is a large difference in sizes between components may be beneficial. In such circumstances, small particles of one component can become trapped in irregularities in the surface of the larger component. These are not random mixtures, as the particles of the two components cannot behave independently. This concept is called ‘‘ordered mixing’’ and it has found applicability in the manufacture of solid dosage forms containing small quantities of highly potent active ingredients[5] (see the article on Blenders and Blending in this encyclopedia).

Granulation

The underlying process of size enlargement in wet granulation is achieved by either one or both of two different mechanisms. Firstly, adjacent solid particles may be stuck together using an adhesive. Such substances are known as binders or granulating agents. Secondly, dissolution of the solid in the granulating liquid can occur, followed by evaporation of the liquid phase of the latter. This will result in the deposition of dissolved material on particle surfaces, forming so-called crystal bridges. The occurrence of this mechanism will depend on the solubility of the solids in the liquid phase. Thus, sucrose will form crystal bridges with an aqueous granulating fluid, whereas calcium phosphate will not.

The process and underlying mechanisms of granulation have been fully described by Sherrington and Oliver.[6] Details of commonly used binders are given in Table 2. They are ofteatural or synthetic polymers and are usually added as aqueous solutions or

dispersions. Alternatively, they can be mixed with the other solids in the formulation in the dry state, water then being added.

If the active ingredient is unstable in the presence of water, then a granulation process using non-aqueous liquids can be used. The usual granulating system in such cases is povidone dissolved in isopropanol. The extra costs and environmental problems posed by the use of a volatile and flammable liquid are disincentives to the use of non-aqueous granulation.

The traditional piece of granulating apparatus is the shear granulator. Its function is to homogeneously incorporate an adhesive and viscous liquid such as starch paste into a mass of dry powder to form agglomerates. It follows that a considerable shearing force needs to be exerted. The mixed solids are loaded into the bowl of the mixer, and the liquid added with agitation. The damp solid is then forced through a relatively coarse screen (about 1–2 mm), often by means of oscillating bars, to give discrete granules. The progression of the granulation process can be monitored by measuring the electrical power consumption by the granulator, and hence optimum granulation times can be established. Ertell et al. have shown that the size of the granulator and the mixing time can be major influences on the physical properties and dissolution rate of the resulting tablets.[7]

As described above, the wet granulation process is a long and hence expensive procedure, which has been improved by the introduction of high-speed mixer granulators. These have agitator and chopping blades, which enable mixing, wet massing, and granulation to take place in the same piece of apparatus. In such devices, the granulation process takes place extremely rapidly, and hence the establishment of optimum granulation times is even more important.

A further technique is fluid-bed granulation. Air is passed into the powder bed from below. This causes the particle, of powder to form a suspension in the air and gives effective mixing. The granulating fluid is then sprayed over the particles, which adhere on collision and they are then dried in the heated air stream.

The wet granulation process, apparatus, and pharmaceutical applications have been comprehensively reviewed by Kristensen and Schaefer[8] (see the article on Tablet Granulation in this encyclopedia).

Drying

After the process of granulation, the product exists as a wet mass from which the liquid must be removed, since the presence of water leads to the impairment of flow properties, and perhaps to chemical instability. Water is usually removed by evaporation for which energy is needed. This is normally provided as heat, though microwave energy is being increasingly used for drying in tablet manufacture.

The essential constituents of an effective piece ofdrying equipment are a heat  supply to increase the temperature and thereby reduce relative humidity, a device for removal of evaporated water and a means of minimizing the distance that water molecules must diffuse before they can be evaporated.

The fluidized bed drier is the most commonly used device for drying tablet granules. The solid is fluidized from below by a jet of hot air, and so each granule becomes separated from its neighbors. The air provides an effective means of heat transfer, as well as of removing water vapor. The speed of the drying process is governed by the distance that water molecules must diffuse before they arrive at the evaporative surface. Since the wet granules are present as individual units, the maximum distance over which diffusion occurs is equal to the radius of a granule. Hence, fluidized bed drying is a rapid process.

The temperature of the bed can be precisely controlled, and a free-flowing product results. The resemblance to fluid-bed granulation will be apparent, and apparatus based on the fluidized bed principle is

Table 2 Binders used in the wet granulation process

Binder	Concentration in the granulating fluid (% w/v)	Comments
Acacia mucilage	Up to 20	Yields very hard granules
Alginic acid	1–5
Carbomer	5–10	(Carbopol_)
Carboxymethylcellulose calcium	5–15	(Nymcel_)
Carboxymethylcellulose sodium	5–15	(Nymcel_)
Cellulose, microcrystalline		(Avicel_, Emcocel_, Vivacel_)
Powdered cellulose		(Elcema_, Solka Floc_)
Ethyl cellulose	1–3	(Aquacoat_)
Gelatin	5–20	Forms gel in cold water, therefore warm solution used, strong adhesive
Glucose, liquid	Up to 50	Strong adhesive, hygroscopic
Guar gum	1–10
Hydroxyethyl cellulose	2–6	(Cellosize_)
Hydroxypropyl cellulose	2–6	(Klucel_, Methocel_)
Hydroxypropyl cellulose—low-substituted	5–25
Hydroxypropylmethyl cellulose	2–5	(Methocel_, Pharmacoat_)
Magnesium aluminum silicate	2–10	(Pharmasorb_, Veegum_)
Maltodextrin	2–10	(Glucidex_, Lycatab_, Maltrin_)
Methylcellulose	1–5	(Celacol_, Methocel_)
Polydextrose		(Litesse_)
Polyethylene oxide	5	(Polyox_)
Povidone	0.5–5	Also known as PVP or polyvinylpyrrolidone. Soluble in water and some organic solvents, can be used for non-aqueous granulation, very commonly used, synthetic material (Kollidon_, Plasdone_)
Sodium alginate	1–3	(Manucol_)
Starch paste	5–25	Very commonly used
Starch, pregelatinized	5–10	(Lycatab_, Pharma-Gel_, Pre-Jel_, Sepistab_, Starch 1500_, Starx 1500_)
Sucrose (syrup)	Up to 70	Hygroscopic, tablets may harden on storage
Water		Suitable for solids that are freely soluble in water

ablet–Tablet

available in which mixing, granulation, and drying take place in the same chamber.

Although the apparent turbulence of the air stream may give rise to interparticulate collisions and hence attrition, this is not usually a severe problem. However, the rapid movement of particles in a hot, dry atmosphere can lead to the development of static electrical discharges. Suitable precautions must therefore be taken, especially if flammable liquids have been used in the granulation process.

A more traditional means of drying is the tray drier. Hot air flows over a series of shelves on which the wet material is spread. Compared to the fluidized bed drier, the solid–air interface is smaller, and water molecules may have to diffuse through the whole thickness of the solid layer before the evaporative surface is reached. Thinner layers give quicker evaporation, but this would reduce the overall capacity of the drier. Thus, the drying process is slower in a tray drier than in a fluidized bed drier.

As water diffuses through the bed of solid, it will carry with it any components of the formulation that are soluble in it. This will lead to a non-uniform distribution of these components in the solid. This is not usually a problem with fluidized bed drying, but with tray drying, significant differences in composition can occur between the upper and lower surfaces of the solid bed. This can give rise to non-uniform drug content and, if the migrating species is colored, variation in the appearance of the product.[9,10]

Microwaves are being increasingly employed in the pharmaceutical industry for drying purposes. The incident microwave radiation (frequencies of 2450 and 960MHz are used) causes electrons in substances such as water to resonate, which in turn generates heat and causes the water to evaporate. The water vapor is removed under vacuum, and hence the product dries rapidly at a relatively low temperature. As the bed of solid is stationary, particle attrition does not occur, and dust formation is minimized.

Second mixing stage

When the drying process is complete, it is likely that the product will have cohered into relatively large masses, especially if tray drying has been used. The dried material is therefore passed through a sieve (usually 250–700 mm) to break up aggregates and to give a relatively uniformly sized granule. A second mixing stage now follows in which several important ingredients of the formulation are added.

The glidant

The formation of granules from the original powder particles may have improved flow sufficiently for uniform die filling to be achieved. However, if flow is still not good enough, a glidant (also known as an anticaking agent) can be added to improve flow still further.

The most frequently used glidant is colloidal silicon dioxide, which has a mean size of about 20 nm. It is thought to act by lodging in the surface irregularities of the granule, forming a more rounded structure and hence reducing interparticulate friction. Colloidal silica has the added advantage of acting as a moisture scavenger. Residual water in the formulation is bound to the silica, thereby providing a drier environment for the other ingredients.

Methods of assessing glidant action have been reviewed by Augsburger and Shangraw.[11] Lerk et al. showed that a concentration of 0.2% colloidal silica in a tablet formulation had no effect on tablet crushing strength. However, higher concentrations reduced crushing strength especially when associated with prolonged mixing times.[12] Some commonly used glidants are shown in Table 3.

The lubricant

When the tablet formulation is compressed, the sides of the tablet are brought into intimate contact with the die wall. The tablet must then be ejected from the die, involving the movement of the side of the tablet relative to the die wall. Therefore, friction between the tablet and the die wall must be overcome. With materials such as lactose, friction resistance can be considerable, and it may be impossible to remove the tablet from the die without damage to the tablet or to the tablet press. Therefore, a lubricant is almost invariably included in a tablet formulation. A lubricant is a substance that deforms easily when sheared between two surfaces, and hence when interposed between the tablet and the die wall, provides a readily deformable film.[13] Details of some tablet lubricants are shown in Table 4.

Inadequate lubrication can often be recognized by vertical scratches on the sides of the tablet. It may also lead to a build-up of solid on the punch faces, which in turn gives a matt, dimpled appearance to the face of the tablet, a phenomenon known as picking.

In practice, magnesium stearate is by far the most frequently used tablet lubricant, and is extremely effective. Its activity, as with other metallic salts of fatty acids, is believed to derive from adhesion of the polar metallic portion of the molecule to the powder particle surface. As a consequence, the hydrocarbon portion of the molecule becomes oriented away from the surface.[14] Thus, a non-polar layer is presented to

Table 3 Tablet glidants

Glidant	Concentration in tablet (%)	Comments
Calcium silicate	0.5–2
Cellulose, powdered	1–2	(Elcema_, Solka Floc_)
Magnesium carbonate	1–3
Magnesium oxide	1–3
Magnesium silicate	0.5–2
Silicon dioxide, colloidal	0.05–0.5	Excellent glidant (Aerosil_, Cab-o-Sil_)
Starch	2–10
Talc	1–10	Insoluble in water but not hydrophobic

Table 4 Tablet lubricants

Lubricant	Concentration in tablet (wt%)	Comments
Calcium stearate	0.5–2	Water insoluble
Fumaric acid	5	Water soluble
Glyceryl behenate	0.5–4	Water insoluble
Glyceryl palmitostearate	0.5–5.0	Water insoluble (Precirol_)
Hydrogenated vegetable oil	1–6	Water insoluble, may be used in conjunction with talc (Lubritab_, Sterotex_)
Magnesium lauryl sulfate	1–2	Soluble in warm water
Magnesium stearate	0.25–5	Water insoluble, excellent lubricant, reduces tablet strength, prolongs disintegration and dissolution times
Polyethylene glycol 4000 or 6000	2–5	Soluble in water, moderately effective, also known as macrogols (Carbowax_)
Sodium lauryl sulfate	1–2	Water soluble, moderate lubricant, but good wetting properties, often employed in conjunction with stearates (Empicol_, Stearowet C_)
Sodium stearyl fumarate	0.5–2.0	Sparingly soluble in cold water, soluble in hot water (Pruv_)
Starch	2–10	Moderate lubricant
Stearic acid	1–3	Water insoluble
Talc	1–10	Insoluble in water but not hydrophobic. A moderate lubricant
Zinc stearate	0.5–2	Water insoluble

Tablet–Tablet

adjacent powder particles and structures such as the press tooling. It is from the formation of this non-polar layer that the advantages and disadvantages of the use of magnesium stearate in a tabletarise.

To act as an effective lubricant in a tablet, the lubricant ust be dispersed over the surface of the powder particles or granules. The more complete this layer, the more effective the lubricant action will be. However, this has two deleterious consequences. The first is that each powder particle presents a hydrophobic and hence water repellent exterior. It is well known that the presence of a lubricant based on fatty acids slows disintegration and dissolution, and has been shown to cause bioavailability problems.

The second consequence is that direct contact between powder particles is, at least in part, replaced by contact between adjacent hydrocarbon layers. Since these by definition have low shear strength, it is not surprising that interparticulate bonding is reduced and hence the tablet structure is weakened. Reduction in tablet strength is particularly marked with substances such as microcrystalline cellulose that undergo deformation on compression, since although the particles may change shape, the hydrocarbon layer remains intact. Substances which fragment on compression suffer a smaller reduction in strength, since new surface, uncontaminated by lubricant, is created as the particles break up. This new surface can then take part in interparticulate bonding.[15]

All these factors, both positive and negative, are consequences of the attrition of particles of lubricant and their spreading around the exterior surface of the other components of the tablet. Therefore, any processing factor that can affect lubricant attrition or the completeness of the film might be expected to influence tablet disintegration, dissolution, bioavailability, and physical strength. The mixing process is extremely important here, and mixing time, mixer type, and batch size[16] have all been shown to influence tablet properties. Thus, there is a need to establish a minimum lubricant concentration and an optimum mixing time within which adequate lubrication is achieved without the development of undesirable tablet characteristics. To ensure batch-to-batch uniformity, the parameters of the mixing process such as type of mixer, batch size, and mixing time must be kept as constant as possible. A mixing time of 2–5 min usually suffices to give adequate lubrication.[17]

The water repellent properties of hydrocarbon based lubricants can be countered to a certain extent by the inclusion of a wetting agent such as sodium lauryl sulfate into the formulation. Such materials themselves can have a limited lubricant action. Mixtures of stearates and lauryl sulfates are commercially available.

Sodium stearyl fumarate has been used as an alternative for magnesium stearate. It has about the same lubricating effect, and causes similar tablet strength reduction and prolongation of disintegration time.[18]

Lubricants based on fatty acids, because of their low water solubility, are unsuitable for tablets which must be dissolved in water before use. Polyethylene glycol 6000 (macrogol 6000) is soluble in water, but its lubricant activity is limited. Magnesium lauryl sulfate has been suggested as a water-soluble substitute for magnesium stearate. In addition to its lubricant action, this substance, like sodium lauryl sulfate, is an effective wetting agent.[19]

It must be stressed that the functions of a glidant and lubricant in a tablet formulation are totally different. A few materials, e.g. talc, can act as both glidant and lubricant, but usually two different excipients are needed. Thus, although colloidal silicon dioxide is an excellent glidant, it has no lubricant activity. Conversely, magnesium stearate, despite its popularity as a lubricant, can hinder rather than promote flow.

The disintegrating agent

Strongly coherent particles are essential for the production of robust tablets, which will have high physical strength and low porosity. However, before it can be absorbed in the gastrointestinal tract, the active ingredient must dissolve, and a physically strong tablet is an impediment to dissolution. Therefore, tablet formulations often include a disintegrating agent, which when it comes into contact with water, disrupts the tablet structure and leads to fragmentation. A larger surface area is thus exposed to the dissolving fluid and dissolution is facilitated. Tablets which contain a large proportion of solids that are freely soluble in water have less need of a disintegrating agent, since such tablets tend to erode from their exterior surfaces rather than disintegrate. Details of some tablet disintegrating agents are given in Table 5.

For many years, starch was the disintegrating agent of choice. Recently, however, so-called ‘‘super disintegrants’’ have been introduced, which markedly reduce tablet disintegration time. Such substances include croscarmellose, crospovidone, polacrilin potassium, and sodium starch glycolate.[20]

The disintegrating agent may be mixed with other powders prior to wetting with the granulating fluid (intragranular) or at the second mixing stage (extragranular), or both. Shotton and Leonard found that while extragranular disintegrating agents caused the tablet to disintegrate quicker, intragranular disintegrants not only broke down the tablet but also the constituent granules, giving a finer product.[21]

The mechanism of action of disintegrating agents has been the subject of some debate.[22] Some substances such as starch swell when they come into contact with water, and disruption of the tablet structure has been attributed to this. However, other effective disintegrants do not swell in this way, and are believed to act by providing a network of hydrophilic pathways inside the tablet through which water can diffuse. Irrespective of the precise mechanism of disintegration, it is clear that water uptake into the tablet must be the first step in the disintegration process.[23]

Addition of wetting agents such as sodium lauryl sulfate or sodium docusate can assist this water penetration by lowering the surface tension, and they are often used in conjunction with hydrophobic lubricants such as magnesium stearate (see the article on Tablet Disintegrants and Disintegration in this encyclopedia).

Tablet Manufacture by Dry Granulation

Although widely used, the wet granulation method of tablet manufacture suffers from several disadvantages. Water is the usual granulating fluid, and this exposes tablet ingredients to the danger of hydrolysis. Furthermore, the granulating fluid has to be removed, usually by heating. In addition to the energy costs that are incurred, the elevated temperature will accelerate any hydrolytic reaction that might be taking place.

Dry granulation is an alternative method that can be used, and this process is shown in Fig. 3. The components of the formulation are compressed in the dry state. If sufficient bonding strength cannot be achieved by compression alone, a binder is added, also in the dry state.

The initial compression stage can take place by one of two methods. The first uses a conventional tablet press, a process often referred to as ‘‘slugging.’’ Because the components of the formulation will not have the necessary attributes for producing good tablets, the tablets produced at this stage (the slugs) will not be of acceptable quality, especially as regards to appearance and weight uniformity. The slugs are then broken down to form a granular product, which after sieving can then be compressed again to give satisfactory tablets. Malkowska and Khan showed that the ease of compressibility of the formulation at the second compression was inversely proportional to the pressure used at the slugging stage, implying that slugging at high pressure should be avoided.[24]

A second method of compression is to use a roller compactor. The powder mixture is passed between two contra-rotating cylindrical rollers to form a cake,

Table 5 Tablet disintegrating agents

Disintegrating agent	Concentration in tablet (wt%)	Comments
Alginic acid	2–10
Carbon dioxide		Created in situ in effervescent tablets
Carboxymethylcellulose calcium	1–15	(Nymcel_)
Carboxymethylcellulose sodium	1–5	(Nymcel_)
Cellulose, microcrystalline	Up to 10	Directly compressible, some lubricant properties (Avicel_, Emcocel_, Vivacel_)
Cellulose, powdered	5–15	Solka Floc_
Croscarmellose sodium	0.5–5	(Ac–di-Sol_, Solutab_)
Crospovidone	2–5	(Kollidon CL_, Polyplasdone XL_)
Docusate sodium	0.5–1	Acts primarily as a wetting agent
Guar gum	2–8
Hydroxypropyl cellulose—low-substituted	5–25
Magnesium aluminum silicate	2–10	(Veegum_)
Methylcellulose	2–10
Polacrilin potassium	2–10	Cation exchange resin (Amberlite IRP88_)
Poloxamer	5–10
Povidone	0.5–5	(Kollidon_, Plasdone_)
Sodium alginate	2.5–10	(Manucol_)
Sodium glycine carbonate		Source of carbon dioxide for effervescent tablets
Sodium lauryl sulfate	0.5–2	Primarily a wetting agent but aids disintegration (Empicol_)
Sodium starch glycolate	2–8	(Explotab_, Primojel_)
Starch	2–10	Potato and maize starches are most frequently used
Starch, pregelatinized	5–10	(Lycatab_, Pharma-Gel_, Pre-Jel_, Sepistab_, Starch 1500_, Starx 1500_)

                                                                                             Tablet–Tablet

which as before is broken down to a product of granular size and then recompressed. Both methods require the addition of a lubricant prior to the first compression stage, though more lubricant will probably be needed before the second compression.

Tablet Manufacture by

Direct Compression

Both wet and dry granulation methods of tablet manufacture are complex multistage processes, but are necessary to convert the components of the formulation into a state that can be readily compressed into acceptable tablets. If, however, a major component of the formulation already possesses the necessary degree of fluidity and compressibility, granulation would be unnecessary. This is the basis of the direct compression method of tablet manufacture.[25]

The key component here is the diluent. This must not only possess those properties which are necessary for satisfactory tablet formulation, but also retain those properties when mixed with the other constituents of the formulation such as the active ingredient. The process of direct compression is shown in Fig. 4. The ingredients are mixed together and then compressed. Almost invariably a lubricant must be added, and a glidant and a disintegrating agent included wheecessary. The process does not involve the use of a liquid, and hence a drying stage with its attendant energy costs is avoided.

Details of some direct compression diluents are given in Table 6. The majority of these are available from only one supplier, though the two most frequently used—spray-dried lactose and microcrystalline cellulose—are available from several sources.

In view of the apparent simplicity of this method of tablet manufacture and the number of suitable diluents that are commercially available, it is perhaps surprising that techniques of tablet manufacture involving granulation are still so widely used. Direct compression can, of course, only be used when a diluent is required by the formulation, i.e., the active ingredient must be relatively potent. Direct compression can offer significant savings in energy, equipment, and material handling costs. Against this must be set higher ingredient costs, since direct compression diluents are more expensive than other diluents.

There are, however, other factors which must be considered. In wet granulation, the properties of the individual drug and diluent particles are, at least to a certain extent, hidden by the binder, whereas in direct compression, the original particles are still present. Therefore, in the latter technique, a premium is placed on batch-to-batch consistency of particulate properties such as size and shape for both drug and diluent. In a direct compression formulation, the components can behave as individual particles, and therefore there is a danger that these can segregate after mixing and prior to compression. In a granulation process, the particles are bound together and so segregation is less likely to happen. Furthermore, the reduction in dust formation brought about by granulation cannot occur in direct compression.

The true direct compression process as described earlier almost invariably applies to formulations containing potent active ingredients and where the direct compression properties derive from the diluent. A few substances do possess adequate flow and cohesive properties without the need for pretreatment. These are usually crystalline inorganic salts such as sodium chloride and potassium chloride. Direct compression forms of less potent active ingredients are available e.g., paracetamol and ascorbic acid. These can be directly compressed into tablets, perhaps after the addition of a lubricant. However, such substances are more accurately described as ‘‘pre-granulated,’’ in that the granulation process—either wet granulation or precompression—has been carried out by the excipient manufacturer.

THE BEHAVIOR OF PARTICLES UNDER A COMPRESSIVE LOAD

All tablet manufacture can be regarded as the application of pressure to a population of particles enclosed in a confined space. An understanding of particle behavior under such conditions is therefore the key to understanding the formation and properties of tablets.

Application of a Force to Particles in a Die

Attractive forces exist between any two solid bodies. These forces may be non-specific, e.g., van der Waal’s forces, or may be more specific iature, e.g., brought about by molecules exhibiting intermolecular hydrogen bonds. However, irrespective of their nature, it is these forces acting among a large population of particles that enable a coherent tablet to be formed.[26] Their magnitude depends directly on the particle mass and inversely on the square of the distance separating the particles. It follows, therefore, that with small particles of small mass, a tablet will only be formed when adjacent particles are forced into intimate contact with each other. This contact is brought about by the application of force.

A representation of what may happen to an individual particle when a force is applied to it can be obtained by considering what happens to a spring when subjected to a load that is applied and then removed. This is shown in Fig. 5. Although the analogy of a powder under compression to a spring undergoing elongation is not exact, it does provide useful comparisons. The load is termed the stress and the change in length the strain.

Initially there is a rectilinear relationship between stress and strain, and if the stress is removed, the spring returns to its original length. This is elastic behavior

Table 6 Direct compression tablet diluents

Diluent	Proprietary name	Comments
Calcium phosphate, dibasic	Emcompress_, Di-Tab_	Good flow properties, high density, insoluble in water
Calcium phosphate, tribasic	Tri-Tab_	Insoluble in water
Calcium sulfate	Compactrol_	Insoluble in water
Cellulose, microcrystalline	Avicel_, Emcocel_, Vivacel_	Highly compressible, low bulk density, acts as disintegrant
Cellulose, powdered	Elcema_
Dextrates	Emdex_
Lactitol	Finlac_ DC
Lactose
Anhydrous alpha	Pharmatose DCL30_	Good flow properties
Anhydrous beta	Pharmatose DCL21_
Spray-dried	Fast-Flo_, Zeparox_, Pharmatose DCL11_
Lactose-cellulose coprocessed mixture	Cellactose_
Maltodextrin	Lycatab_, Maltrin_	Fairly soluble in water, slight lubricant effect
Mannitol	Pearlitol_	Freely soluble in water, negative heat of solution
Sorbitol	Neosorb_
Starch, pregelatinized starch	Starch 1500_, Starx 1500_	Disintegrant
Sucrose–maltodextrin coprecipitate	Des-Tab_, Dipac_, Nu-Tab_	Good flow properties, moisture sensitive
Xylitol	Xylitab_	Freely soluble in water, negative heat of solution

Tablet–Tablet

and is completely reversible. The spring is said to obey Hooke’s law and the reciprocal of the slope of this portion of the curve is Young’s Modulus for the spring.

If the stress is further increased, eventually a point is reached when the straight-line relationship is lost. This is termed the elastic limit. If stresses in excess of the elastic limit are applied and then removed, the spring will not return to its original length. Thus, a fraction of the change in length is permanent or irreversible, and this is termed plastic behavior. Further increase in load will result in more and more plastic deformation until eventually the load is so great that the breaking point of the spring is reached and it snaps. Now, consider now a number of particles constrained in the die of a tablet press and to which a progressively increasing force is applied. A series of events can then occur, perhaps sequentially but there is a greater likelihood that some overlap will occur.

The particles will undergo rearrangement to form a less porous structure. This will take place at very low forces, the particles sliding past each other. This stage will usually be associated with some fragmentation, as the rough surfaces move relatively to one another and asperities are abraded away.

The particles have now reached the stage where relative movement becomes impossible, although the porosity of the powder bed may still be considerable. A further increase in applied force can then induce elastic deformation, plastic deformation, or fragmentation. Which of these alternatives predominates will depend on the properties of the material involved, but the net result will be a further decrease in porosity, and an increase in interparticulate contact.

If only elastic deformation has occurred, then when the compressing force is removed, the particles will return to their former shape. The additional interparticulate contact caused by compression will be lost and a coherent tablet will not be formed Fig. 6.

If, however, the elastic limit has been passed, then as the force is removed, not all the increased interparticulate contact will be lost, cohesion will be retained and a tablet will be formed. Thus, from the point of view of forming a robust tablet, substances with low elastic limits, which undergo plastic deformation at low compressive forces, are preferable to more elastic bodies.

If consolidation of the powder mass is brought about by fragmentation, then a large number of points of interparticulate contact are created, from which the strength of the tablet derives. In this case, removal of the compressing force should have no effect on tablet strength, since there is no way the fragments can recombine into the original particles. However, purely fragmentary consolidation is unlikely to have occurred, and so the effect of removal of the force on deformed particles must still be considered.

Force Transmission through a Powder Bed

Consider as before a group of particles in the die of an excentric tablet press. Force is applied by means of the descending upper punch and because the lower punch is passive, the force will be transmitted to it through the powder bed. The distribution of force within the powder bed was investigated by Train, who embedded force transducers (q.v.) in a relatively large mass of powder.[27] He found that the diminution of force did not proceed uniformly on descent through the bed, but formed a much more complex pattern. This was caused by the forces being transmitted to and reflected from the die wall. Significant features are zones of high force at the periphery near the moving punch, and much lower in the powder mass on its vertical axis. On the other hand, low force zones occur on the same axis but much nearer to the moving punch Fig. 7. Train’s findings were later confirmed by Charlton and Newton using gamma-ray attenuation.[28]

The consequences of such a force distribution on tablet strength can be profound. Particle deformation, whether elastic or plastic, will be proportional to the force applied, and as has been discussed, this deformation is an essential preliminary to the formation of the interparticulate bonds on which tablet integrity depends. Thus, the porosity of the tablet, and hence its strength, will vary within the tablet. The weakest points in the tablet structure will be those that receive the lowest force i.e., on the face of the tablet adjacent to the stationary punch and on the central axis near to the moving punch. Thus, because of its non-uniform density, some parts of a tablet are stronger than others.

It should be noted that this discussion assumes that only one punch is actively applying the force to the powder mass while the other is stationary and passive. This is true in the case of an excentric press, but with a rotary tablet press, both punches move and hence both exert forces on the powder bed. The force distribution so obtained is thus different from that shown in Fig. 7, and results in two low density zones near the faces of the tablet and a high density zone in approximately the centre of the powder mass.

The effect of the removal of the compressing force must now be considered. Elastic recovery will occur to a greater or lesser extent, which will result in a reduction in the strength of interparticulate bonds and an overall weakening of the tablet. It therefore follows that if a tablet is to be disrupted by elastic recovery, this is most likely to occur at its weakest point. This is just below the top surface, and is the phenomenon often encountered in tablet manufacture known as lamination or capping. With this explanation in mind, some effects associated with capping, and some causes and pragmatic solutions to the problem caow be explained.

Capping was for many years considered to be due to the entrapment of air in the tablet, and even the production of tablets in vacuo which still capped did little to dispel this theory. Neither did this suggestion explain why air should cause the fracture just below the face of the tablet. However, by considering the non-uniform density distribution in the tablet, it can be seen that the weakness is not caused by the presence of air per se, but rather the relative absence of solid in those parts of the tablet that have high porosity.[29] As compression proceeds, it follows that the pores in the tablet structure are filled with air at a progressively elevated pressure, and this will obviously assist disruption of the tablet when the compressing force is removed. Thus, any factor which obstructs the expulsion of air from the powder mass during compression will exacerbate capping, though it is not the fundamental cause. Such factors include the clearance between punch and die, the speed at which the force is applied, and the presence of small particles, which makes passage of air through the tablet more tortuous.[30]

Any applied stress that exceeds the breaking strength of the tablet will also cause the tablet to break at its weakest point. A number of stresses occur when the tablet is removed from the die after compression. The die may become worn at the point in the die where the tablet is compressed, i.e., the die is fractionally wider at this point than elsewhere. Thus, when the tablet is ejected, it is forced through an aperture, the diameter of which is slightly less than that of the tablet itself. This will obviously stress the tablet, and the interparticulate bonds may be overcome at their weakest point. Also as the tablet is extruded from the die, elastic expansion will occur not just in an axial but in a radial direction. The latter occurs progressively, i.e., one segment of tablet is free to expand while the one below is still constrained by the die. Bond disruption will be an inevitable

Tablet Manufacture by Direct Compression

All tablets are made by compressing a particulate solid between two punches in a die of a tablet press. For an active ingredient to be transformed into tablets of satisfactory quality, the formulation must have three essential attributes.

First, the formulation must flow into the die space of the tablet press sufficiently rapidly and in a reproducible manner. Otherwise, unacceptable variation in tablet weight and content of active ingredient will ensue.

Second, the particles in the formulation must cohere when subject to a compressing force, and that coherence should remain after the compressive force has been removed.

Third, after the compression event is complete, it must be possible for the tablet to be removed from the press without damage to either the tablet or the press.

Very few active ingredients possess all three of these essentials and some possess none of them. Hence some preliminary treatment is almost invariably necessary.

METHODS OF TABLET MANUFACTURES

There are three methods of tablet manufacture designed to confer these essential attributes to a tablet formulation. Wet granulation and direct compression are the most important, with dry granulation (also known as precompression or slugging) used in some circumstances. Fig. 1 shows the processes of wet granulation and direct compression broken down into their constituent stages.

The relative simplicity of the direct compression process is immediately apparent.

Ease of removal of the tablet from the press is, in theory at least, readily achieved. Friction occurs between the tablet and the die and punches of the press, which can be overcome by including a lubricant in the formulation. Hence every formulation, irrespective of the method of manufacture, will include a lubricant. This will usually be a metallic salt of a fatty acid such as magnesium stearate.

The other two prerequisites—flow and cohesion— can only be achieved by more elaborate techniques and are in fact the reasons why the wet and dry granulation processes were devised.

As part of its complexity, wet granulation involves the addition of a liquid (usually water), followed by its removal, normally by evaporation. In addition to the energy requirements of this drying process, the presence of water might bring about hydrolysis of the active ingredient, which will be exacerbated at the elevated temperatures used for drying.

If a major component of the formulation such as the diluent were to possess the necessary degrees of fluidity and compressibility, granulation would be unnecessary. This is the basis of the direct compression method of tablet manufacture.

Prior to the early 1960s, there were very few materials which possessed these properties. Little and Mitchell[1] in their text Tablet Making, cite sodium chloride and bromide, potassium chlorate, bicarbonate and iodide, ammonium chloride, and hexamine as having properties which permit tabletting without some form of prior treatment. No reference is made by name to the process of direct compression.

At about the same time, two materials were introduced that were specifically designed to act as tablet diluents and would not require preliminary treatment. These were spray-dried lactose and microcrystalline cellulose, introduced in 1962 and 1964, respectively. These two substances can be said to have initiated the ‘‘direct compression revolution.’’ Since that time, a wide range of direct compression tablet diluents has become available. The properties of some of these materials will be reviewed later in this article.

It is important to distinguish between true direct compression diluents (i.e., excipients) and active ingredients which are available in a direct compression form. These are usually high dose materials such as aspirin, paracetamol, and ascorbic acid. They can be directly compressed into tablets, the only pretreatment being mixing with a lubricant and perhaps a disintegrating agent. However, such substances are more accurately described as ‘‘pregranulated’’ since the granulation process, either wet or dry, will have been carried out by the excipient manufacturer. It is likely that such materials will contain a binder. For example, ascorbic acid pregranulated with either starch or hydroxypropyl cellulose is commercially available.[2]

The perceived advantages of the direct compression process of tablet manufacture have given rise to a considerable body of literature. Between 1970 and the end of 2000, there were 598 references to ‘‘direct compression’’ in the index of International Pharmaceutical Abstracts. It has been estimated that today, some 40 years after the introduction of diluents specifically designed for direct compression, about 50% of worldwide tablet production is made by this method.[2] The question must be asked why a process which has so many apparent advantages and for which suitable materials seem to be plentifully available has not made a greater impact. An innate conservatism in the pharmaceutical industry is perhaps a factor, but cannot be the complete answer. It is interesting to consider as an analogy that the process of film coating of tablets, coincidentally introduced at about the same time as direct compression, has practically totally replaced the sugar-coating technique. This shows that a new process can achieve significant and relatively speedy penetration into an industrial environment if it represents a major step forward.

Wet Granulation Process: Advantages and Disadvantages

The wet granulation process is the traditional method of manufacture and is frequently used in the pharmaceutical industry. Expertise in wet granulation is widely available, as is the required equipment. The process improves flow and cohesion, reduces dust and crosscontamination, and permits the handling of powder blends without loss of homogeneity.

Though it has been practiced for many years and therefore may be perceived as an ‘‘old-fashioned’’ process, it must be borne in mind that the wet granulation process has itself undergone a transformation in recent decades. High-speed mixer–granulators, fluidized bed granulation and drying, and an ever-increasing use of automation have served to make wet granulation a much more efficient and economic process than it once was.[3]

Nevertheless, the wet granulation process still retains many inherent disadvantages. Problems include choice and method of addition of the binder, and the effect of drying time and temperature on drug stability and its distribution within the solid mass.

Direct Compression Process: Advantages and Disadvantages

The most striking feature of the direct compression process is its simplicity and hence economy. Less equipment is required and the number of stages in the process, each of which will require validation, is greatly reduced. There are also lower labor costs, reduced processing time, and lower power consumption.

An important advantage of the direct compression process is that it is a dry procedure with no need for a drying stage. Thus, exposure to water and the elevated temperatures needed to remove that water are avoided, resulting in a decreased risk of deterioration of the active ingredient.

A further advantage of direct compression is that tablets disintegrate into their primary particles rather than granular aggregates. The resultant increase in surface area available for dissolution should result in faster drug release.

The primary limitation on the use of direct compression is that it depends on the fluidity and compressibility of a tablet diluent. Therefore, it cannot be used for low potency, high dose active ingredients where the inclusion of sufficient diluent in the formulation to permit direct compression would lead to unacceptably large tablets. Thus, active ingredients such as paracetamol and aspirin do not lend themselves to the direct compression process. However, as stated earlier, such ingredients are often available in pregranulated form.

Paradoxically, one of the root causes of difficulties in the direct compression process is its simplicity. It must be regarded as a process in its own right, albeit a simple one, rather than a simplified form of the wet granulation process. The key point to grasp is that wet granulation produces what is in effect a new raw material, i.e., the granule. Minor variations in the properties of the constituents of that granule are covered up by ‘‘submerging’’ them in a mass of binder. This is not so with direct compression. The properties of each particle of every constituent remain essentially unchanged. There is thus a greater need for withinbatch and between-batch consistency.

There is also the possibility of segregation of the constituents of the formulation after a homogeneous blend of active ingredient and excipients has been achieved. In a wet granulated product, particles are stuck together by the binder and so there is a much reduced chance of segregation. Because segregation is principally a function of differences in particle size between active ingredients and excipients, it is desirable that the size of the direct compression diluent matches that of the drug. This may not always be feasible.

The simplicity of the direct compression process should obviously bring financial benefits. However, it must be borne in mind that direct compression tablet diluents are considerably more expensive than conventional diluents such as a-lactose monohydrate.

Regulatory considerations also play a part in a decision whether or not to use the direct compression process. Several years may elapse between the finalizing of a tablet formulation and its marketing. During this period, stability testing of the product will have occurred. The formulator must be confident that a chosen direct compression diluent will still be available for a considerable time after product marketing; otherwise reformulation with all its attendant delay and expense will be required. A number of direct compression diluents have been marketed that were withdrawn after only a few years because of lack of market penetration.

Progression of product development will be accompanied by scale-up of the manufacturing process of the active ingredient to commercial proportions. This may bring about changes in the physical properties of the active ingredient. As stated earlier, the wet granulation process can mask minor changes in physical properties, but this masking cannot occur in direct compression.

For these reasons, direct compression has been most widely adopted by manufacturers of generic (i.e., noninnovative) pharmaceuticals. During the time when the active ingredient is covered by patent protection, its optimum manufacturing process will have been achieved, and so subsequent batch-to-batch variation in its physical properties ought then to be minimal.

FACTORS INFLUENCING THE CHOICE OF A DIRECT COMPRESSION TABLET DILUENT

A wide range of substances is or has been marketed as direct compression tablet diluents. In general, these are commonly occurring materials whose properties have been modified in such a way to give the fluidity and compressibility demanded by the direct compression process. Many direct compression diluents are aggregates of primary particles. For example, an aqueous slurry of a-lactose monohydrate is spray-dried to give an agglomerated product that flows better and is more compressible than the parent substance. A second example is the acid hydrolysis of a-wood cellulose to yield particles containing bundles of microcrystals of cellulose. These can cohere by means of hydrogen bonds to give extremely strong tablets of microcrystalline cellulose.

Most direct compression diluents are available from only one source, but a few can be obtained from more than one manufacturer. If multiple sources are available, they will be offered under individual registered names. For example, microcrystalline cellulose is available under a number of brand names such as Avicel_ (FMC Corporation), Emcocel_ (Edward Mendell), and Vivacel_ (J. Rettenmaier). Chemical properties of such materials will be similar if not completely identical, especially if there are pharmacopeial standards for identity and purity. However, it cannot be assumed that products from different manufacturers will have the similar physical properties which will govern their performance in the tabletting process.

Each brand will probably be accompanied by promotional literature to assist the sale of the product. It is customary to describe its properties adjectivally, e.g., ‘‘excellent flow,’’ ‘‘superior compressibility,’’ and to present data referring to that material alone. Hence comparison between different excipients can be sometimes extremely difficult.

Several authors have listed the attributes of the ‘‘ideal’’ direct compression diluent.[2,4] However, it must always be borne in mind that the diluent will invariably form part of a multicomponent mixture. At the very least, the diluent will be mixed with the active ingredient, and almost invariably a lubricant will also be present. The greater the proportion of active ingredient in the formulation, the less influence the diluent will have on the properties of the tablet.

One of the difficulties that beset the product developer is the lack of meaningful tests by which excipients (including direct compression diluents) can be assessed. This has led to the development of the so-called ‘‘functionality tests.’’ Some functionality tests that have been suggested (e.g., particle size, surface area) are in fact physical test methods being carried out under closely defined conditions.[5] The relation of such a test to the actual function of the excipient needs to be established. After this link has been made, a more suitable title for these tests might be ‘‘functionality-related tests.’’[6]

Nevertheless, it is useful to consider some of the desirable properties of a direct compression diluent and how these properties can be appropriately measured.

Properties Required of a Direct Compression Diluent

Fluidity

Good flow is a prerequisite for any tablet formulation to ensure uniformity of tablet weight, which in turn contributes to uniformity of content. Flow can be measured by methods such as angle of repose, flow through an orifice, and by using flow cells, but more meaningful data can be obtained by measuring the uniformity of weight of the tablets themselves. Flow properties can often be improved by the inclusion of a glidant in the formulation.

Ease of mixing and lack of segregation

Achievement of a homogeneous mixture of active ingredient and diluent is essential to obtain tablets with an acceptable uniformity of content of active ingredient. As stated earlier, there is a risk of segregation in a direct compression mixture, because the components are not stuck together as they are in wet granulation. The main cause of segregation is differences in the particle size of components, with differences in shape and density being secondary factors.[7] Hence it is desirable that there should not be differences between the particle sizes of active ingredient and diluent. It is unlikely that the size of the active ingredient particles can be changed to match those of the diluent, so the reverse is desirable. Thus, the ideal direct compression diluent should be available in a range of sizes.

An alternative approach is to use the concept of ordered mixing in which fine particles of the active ingredient are dispersed over the surface of much larger diluent particles.[8] This is only feasible with potent drugs when the diluent will comprise by far the major component of the formulation.

Compression pressure–tablet strength profile

This is the relationship between the compression pressure applied to the formulation and the physical strength of the resulting tablets. It would seem to be a most important piece of information, yet its derivation is by no means straightforward. Also comparison of data derived by different researchers is often difficult.

If such data are presented graphically, either force or pressure can be used as the abscissa. Unless the cross-sectional dimensions of the tablet are known, interconversion between force and pressure is impossible. Furthermore, a wide variety of units of force and pressure have been used (Table 1), which again makes comparisons difficult if not impossible.

The physical strength of the tablet usually forms the ordinate of a graph. The variety of units used for this is also shown in Table 1. Here too interconversion can be extremely difficult. The breaking strength of a tablet is dependent on its physical dimensions. It is therefore logical to use some measure of strength that is independent of tablet size. Therefore the tensile strength of the tablet is often calculated according to Eq. (1).[

Use of this equation presupposes that the tablet is circular in cross-section and of uniform thickness, i.e., it is cylindrical. Pitt et al. have attempted to extend the concept of tensile strength to tablets which are not cylindrical.[11]

Even though comparison is often difficult, it would be rendered considerably easier if the units used conformed to the SI system of weights and measures. Thus, the meter, newton, and pascal should be used as the units of length, force, and pressure, respectively.

Reworking

A faulty batch of tablets can sometimes be recovered by grinding up the tablets and recompressing them, a process which is known as reworking and is analogous to the dry granulation method of tablet manufacture. This can sometimes cause problems with a direct compression formulation. Many direct compression diluent particles are in the form of aggregates, e.g., spray-dried lactose is composed of small crystals of lactose embedded in amorphous lactose. If these aggregates are compressed, their structure may be broken down to such an extent that subsequent recompression will result in impaired tablet quality.

The technique of Malkowska and Khan,[14] used as described before to determine the capacity of a direct compression diluent, was originally developed as a method of expressing the ability of a formulation to be reworked. Referring to Fig. 2, the upper curve represents the strength of tablets prepared without reworking and the lower curve is the strength of reworked tablets. The reworking index is calculated from the ratio of the areas under the curves as described previously.

The mechanism of consolidation

A fundamental property of a solid is the mechanism by which it consolidates under the influence of a compressing force. There are two principal mechanisms—fragmentation and deformation—though most solids will show a mixture of the two with one mechanism predominating. The mechanism can have a major influence on tablet properties.

The effect of compression speed on tablet quality is dependent on the consolidation mechanism. Fragmentation can be regarded as a virtually instantaneous process. Thus, solids which consolidate by fragmentation show little dependence, if any, on the speed at which the consolidation pressure is applied. Deformation on the other hand is time-dependent. It takes a finite time for deformation to occur, and at high rates of punch movement, not enough time may be available for the full effect of the pressure to be exerted. Changes in punch speed can arise by changing the speed of the tablet press or by changing from a relatively slow-speed excentric press to a high-speed rotary. It must be stressed that the key parameter is punch speed rather than production rate.[16] Roberts and Rowe[17] derived a parameter that they called the strain rate sensitivity. This classifies substances according to how tablet strength is affected by changes in punch speed. Details of some of the substances investigated by Roberts and Rowe are shown in Table 3, and many of these are direct compression diluents.

A second area in which consolidation mechanism is important is in the sensitivity of diluents to the effects of lubricants. In general, addition of a lubricant such as magnesium stearate causes a reduction in tablet breaking strength. As the diluent is mixed with the lubricant, each diluent particle becomes coated with a thin film of lubricant which interferes with interparticulate bonding. However, if fragmentation is the primary method of consolidation, new surface that is uncontaminated by lubricant is continually generated, and so bonding is less affected. Thus, factors which affect the distribution of the lubricant over the diluent surface may have an influence on tablet strength, the magnitude of which depends on the predominant consolidation mechanism. Such factors include mixer design and mixing time and speed.[19] It follows that the lubricant, its concentration, and method of incorporation should be stated in any publication relating to direct compression diluents.

TABLET DILUENTS USED IN DIRECT COMPRESSION

A wide variety of materials have been used as direct compression diluents, and this has given rise to a considerable literature. Many research reports originate with organizations marketing a specific diluent, or are derived from work sponsored by that organization. Such publications will obviously report data and results relevant to that one diluent.

However, there are some publications which seek to compare a range of diluents, and these are particularly valuable.[20,21] Perhaps, the most comprehensive review of direct compression diluents has been published by Bolhuis and Chowhan.[2] Monographs of many direct compression diluents are to be found in the Handbook of Pharmaceutical Excipients, which contains details of the physical properties of these substances.[22]

Direct compression diluents are often commonly occurring substances which have been physically modified to give the necessary degree of fluidity and compressibility. They are most conveniently classified according to their source, viz.:

·                   Cellulose and cellulose derivatives.

·                   Inorganic materials.

·                   Polyols.

·                   Starch and starch derivatives.

·                   Sugars.

·                   Mixtures and coprocessed products.

Information on some direct compression diluents is given in Table 5.

When compressed, microcrystalline cellulose particles deform plastically and the surfaces thus brought into contact unite by hydrogen bonding. Because tablets made from microcrystalline cellulose are extremely strong, there is a high dilution potential and they can withstand weakening caused by lubricants.[19] In fact, microcrystalline cellulose tablets exhibit such a low coefficient of friction that they may need no lubricant. Fluidity of microcrystalline cellulose is low and the addition of a glidant may be necessary. Its bulk density is also low. Unlike many direct compression diluents, it is available in a wide range of particle sizes.

Microcrystalline cellulose is available from several different sources. These can exhibit a range of tabletting properties, and so the substitution of one brand of microcrystalline cellulose by another must be approached with caution.[23] Microcrystalline cellulose is quite hygroscopic, and its tabletting properties are dependent on its moisture content, with water causing the interparticulate hydrogen bonds to weaken. Therefore, comparisons between different brands must also take the moisture content into account.[24]

Powdered cellulose has been used as a direct compression diluent. Though it forms hard tablets, fluidity is poor and dilution potential is low. Like microcrystalline cellulose it has some self-lubricating properties, but addition of a lubricant is usually necessary, causing a marked reduction in tablet strength.[25]

Silicified microcrystalline cellulose is a coprocessed mixture of microcrystalline cellulose and 2% colloidal silicon dioxide, which has improved flow and binding properties compared to microcrystalline cellulose itself.[26]

Inorganic Materials

The most widely used inorganic direct compression diluent is calcium phosphate. It is available in several forms, but the unmilled (i.e., coarse) dibasic dihydrate (CaHPO4 _ 2H2O) is the most frequently used. It has good flow and binding properties. Consolidation is principally by fragmentation, so although a lubricant is needed, tablet strength loss is low.[19] It is nonhygroscopic at humidities up to 80%, and due to its hydrophilic nature, dicalcium phosphate dihydrate tablets are rapidly penetrated by water on immersion. Despite this, the tablets do not disintegrate because they are almost insoluble in water.[27] Dicalcium phosphate dihydrate is, however, soluble in acidic media such as gastric juice.

The water of hydration is relatively easily lost from dibasic calcium phosphate dihydrate, and this may have consequences for the stability of products containing it.[28]

Anhydrous dibasic calcium phosphate and calcium triphosphate can also be used for direct compression. The latter is actually a mixture of calcium phosphates including tricalcium orthophosphate [Ca3(PO4)2] and hydroxyapatite [Ca5(OH)(PO4)3]. The preparation and properties of calcium phosphates have been reviewed by Carstensen and Ertell,[29] and their tabletting properties have been studied by Bryan and McAllister.[30]

A direct compression diluent based on calcium sulphate is also available.[31]

Sorbitol can exist in four crystalline forms. Guyot- Hermann, Leblanc, and Draguet-Brugmans[32] compared 11 commercially available varieties of sorbitol, and found three of these four forms to be present. g-Sorbitol was found to be the most useful as a tablet diluent. The method of manufacture has also been shown to affect tabletting properties, differences being attributed to variations in particle shape and surface properties. Spray-dried varieties of sorbitol are available as direct compression diluents which are claimed to have overcome problems associated with the different crystalline forms.[33]

Mannitol

Mannitol is an isomer of sorbitol. Like the latter, it has a negative heat of solution which makes it a useful excipient for chewable tablets and lozenges. It is less hygroscopic than sorbitol and has about one-tenth of the solubility in water. Similarly to sorbitol, several polymorphic forms are available which differ in their ability to form tablets.[34] However, unmodified mannitol cannot be used for direct compression because of poor flow and binding properties. Directly compressible forms are available in a range of particle sizes which are reported to produce excellent tablets.

Lactitol and xylitol

These are both commercially available in forms suitable for direct compression with good flow and binding properties. The former is a water-granulated product of microcrystalline aggregates.[35] A similar form of xylitol is available, and in the case of xylitol, there are also products pregranulated with either polydextrose or carboxymethyl cellulose.[36] Both substances are highly soluble in water with negative heats of solution.

Starch and Starch Derivatives

Starch is a very widely used tablet excipient, but in its natural state, it does not possess the fluidity and binding characteristics needed as a tablet diluent. The major consolidation mechanism of starch is by deformation with a high elastic component.[37] In addition, starch shows a high degree of lubricant sensitivity.[19]

Pregelatinized starch, often referred to as Starch 1500, contains about 80% unmodified starch, 5% free amylose, and 15% free amylopectin. Though it has been described as a direct compression diluent,[38] tablets made from pregelatinized starch show low physical strength. The principal application of pregelatinized starch in tablet formulation is as a disintegrating agent. It retains the disintegrating ability of natural starch without the deleterious effects on flow and tablet strength that natural starch would bring about.

Sugars

Lactose

Lactose is a naturally occurring disaccharide containing one galactose unit and one dextrose unit. It is a constituent of all forms of mammalian milk, but is produced commercially from cow’s milk, usually as a by-product of the cheese industry. Lactose can exist in two isomeric forms, a-lactose and b-lactose, and can be either crystalline or amorphous. Crystalline a-lactose occurs in both monohydrate and anhydrous forms, but b-lactose only exists in the anhydrous form. The temperature of crystallization is the principal determinant of which form is obtained.[39]

Though crystalline a-lactosemonohydrate is the most common tablet diluent, it is usually used in granulated rather than in direct compression formulations. Neither its flow properties nor its binding properties are good enough to form satisfactory tablets without preliminary treatment. Bonding properties are improved by conversion into aggregates of a-lactose monohydrate crystals by fluid bed granulation. This product is virtually free from amorphous lactose.[40]

Spray-dried lactose was the first direct compression diluent to be introduced.[41] It had a major impact on tabletting technology and it is still widely used. Spray drying an aqueous suspension of lactose yields a product that largely consists of crystals of a-lactose monohydrate (about 80%) held together in a glass of amorphous material (about 20%). Spray-dried lactose exhibits excellent flow properties due to the spherical shape of the aggregates. However, its ability to form strong tablets is limited and it has low dilution potential, so it is primarily used in tablets in which it forms the major ingredient. Fragmentation is the major consolidation mechanism, and so tablet strength is not significantly affected by lubricants. Spray-dried lactose can be obtained from several manufacturers whose products differ slightly. A comparative study of spray-dried lactoses from a number of sources has been published by Whiteman and Yarwood.[21]

Anhydrous lactose is primarily anhydrous b-lactose with up to about 25% anhydrous a-lactose. It consists of agglomerates of fine crystals produced by roller drying a solution of a-lactose monohydrate. Flow properties are good, and tablet strength was found to be superior to other lactose products.[21] Anhydrous b-lactose is much more soluble than the a-isomer, and extended disintegration times of tablets made from anhydrous lactose have been attributed to the presence of anhydrous a-lactose in the roller dried product.[42]

Anhydrous a-lactose can be produced by thermal or chemical dehydration of a-lactose monohydrate. During this process, the starting material changes from single crystals to aggregates of anhydrous a-lactose particles. Flowability and binding properties are good, but slow dissolution of tablets made from anhydrous a-lactose has proved a major limitation to its use.[42]

Sucrose

A non-reducing disaccharide obtained from vegetable sources, sucrose is a widely used pharmaceutical excipient. Because it is more hygroscopic than lactose, it is used less in solid dosage forms. The compactability of pure sucrose is poor, but modified forms of sucrose for direct compression are available. These are collectively termed ‘‘compressible sugar,’’ and may contain, depending on source, starch, maltodextrin, or invert sugar, together with a lubricant. Several different types of compressible sugar have been compared.[43] The minor components obviously played a major role in tablet formation, since significant differences were obtained between varieties. Compressible sugar is often used for lozenges and chewable tablets—because of the high solubility of sucrose, tablets tend to dissolve rather than disintegrate.

Dextrose and dextrates

Dextrose does not lend itself to direct compression. However, a spray-crystallized product, the major constituent of which is dextrose, is used in direct compression. This is known as dextrates, and is produced by the partial hydrolysis of starch. It consists of about 90% dextrose, together with about 5% maltose and higher polysaccharides.[44] Though both hydrated and anhydrous forms of dextrates have been described, only the former is commercially available. Dextrose is freely soluble in water and is highly hygroscopic, and hence its use in atmospheres of high humidity may cause problems. Because of its sweet taste and negative heat of solution, it is recommended for use in chewable tablets.

Mixtures and Coprocessed Products

Though numerous direct compression diluents are available, none is ideal. For example, spray-dried lactose flows easily but forms relatively weak tablets, whereas the fluidity of microcrystalline cellulose is poor yet it forms extremely strong tablets. It is understandable, therefore, that the possibilities of combining diluents have been considered, the aim being to combine the advantages of both components without their disadvantages.

The compaction properties of mixtures have been reviewed by Fell,[45] who concluded that the relationship between the tabletting properties of a mixture could only rarely be predicted from knowledge of the same properties of the individual components. Nevertheless, some success has been achieved.[46]

In recent years, a number of coprocessed excipient combinations have been marketed, which undoubtedly possess advantages over physical mixtures of the same components. Such materials include mixtures of lactose and povidone,[47] cellulose and lactose,[48] and anhydrous lactose and anhydrous lactitol. A disadvantage of this approach is that the relative proportions of the components are fixed, and such a combination may not be universally optimal.

Tablet compaction simulator

Tablet formulations are designed and tested using a laboratory machine called a Tablet Compaction Simulator or Powder Compaction Simulator. This is a computer controlled device that can measure the punch positions, punch pressures, friction forces, die wall pressures, and sometimes the tablet internal temperature during the compaction event. Numerous experiments with small quantities of different mixtures can be performed to optimise a formulation. Mathematically corrected punch motions can be programmed to simulate any type and model of production tablet press. Initial quantities of active pharmaceutical ingredients are very expensive to produce, and using a Compaction Simulator reduces the amount of powder required for product development.

Tablet presses

The tablet pressing operation

An old Cadmach rotary tablet press

Tablet presses, also called tableting machines, range from small, inexpensive bench-top models that make one tablet at a time (single-station presses), with only around a half-ton pressure, to large, computerized, industrial models (multi-station rotary presses) that can make hundreds of thousands to millions of tablets an hour with much greater pressure. The tablet press is an essential piece of machinery for any pharmaceutical and nutraceutical manufacturer. Common manufacturers of tablet presses include Fette, Korsch, Kikusui, Manesty, IMA and Courtoy. Tablet presses must allow the operator to adjust the position of the lower and upper punches accurately, so that the tablet weight, thickness and density can each be controlled. This is achieved using a series of cams, rollers, and/or tracks that act on the tablet tooling (punches). Mechanical systems are also incorporated for die filling, and for ejecting and removing the tablets from the press after compression. Pharmaceutical tablet presses are required to be easy to clean and quick to reconfigure with different tooling, because they are usually used to manufacture many different products.

Tablet coating

Many tablets today are coated after being pressed. Although sugar-coating was popular in the past, the process has many drawbacks. Modern tablet coatings are polymer and polysaccharide based, with plasticizers and pigments included. Tablet coatings must be stable and strong enough to survive the handling of the tablet, must not make tablets stick together during the coating process, and must follow the fine contours of embossed characters or logos on tablets. Coatings are necessary for tablets that have an unpleasant taste, and a smoother finish makes large tablets easier to swallow. Tablet coatings are also useful to extend the shelf-life of components that are sensitive to moisture or oxidation. Special coatings (for example with pearlescent effects) can enhance brand recognition.

If the active ingredient of a tablet is sensitive to acid, or is irritant to the stomach lining, an enteric coating can be used, which is resistant to stomach acid, and dissolves in the less acidic area of the intestines. Enteric coatings are also used for medicines that can be negatively affected by taking a long time to reach the small intestine, where they are absorbed. Coatings are often chosen to control the rate of dissolution of the drug in the gastrointestinal tract. Some drugs will be absorbed better at different points in the digestive system. If the highest percentage of absorption of a drug takes place in the stomach, a coating that dissolves quickly and easily in acid will be selected. If the rate of absorption is best in the large intestine or colon, then a coating that is acid resistant and dissolves slowly would be used to ensure it reached that point before dispersing.

There are two types of coating machines used in the pharmaceutical industry: coating pans and automatic coaters. Coating pans are used mostly for sugar coating of pellets. Automatic coaters are used for all kinds of coatings; they can be equipped with remote control panel, dehumidifier, dust collectors. The explosion-proof design is required for alcohol containing coatings.

Pill-splitters

It is sometimes necessary to split tablets into halves or quarters. Tablets are easier to break accurately if scored, but there are devices called pill-splitters which cut unscored and scored tablets. Tablets with special coatings (for example enteric coatings or controlled-release coatings) should not be broken before use, as this will expose the tablet core to the digestive juices, short-circuiting the intended delayed-release effect.

Tablets comply with the requirements of the European Pharmacopoeia. These requirements are reproduced below.

The requirements of this monograph do not necessarily apply to preparations that are presented as tablets intended for use other than by oral administration. Requirements for such preparations may be found, where appropriate, in other general monographs; for example Rectal preparations (1145), Vaginal preparations (1164) and Oromucosal preparations (1807). This monograph does not apply to lozenges, oral pastes and oral gums. Where justified and authorised, the requirements of this monograph do not apply to tablets for veterinary use.

Tablets are solid preparations each containing a single dose of one or more active substances. They are obtained by compressing uniform volumes of particles or by another suitable manufacturing technique, such as extrusion, moulding or freeze-drying (lyophilisation) . Tablets are intended for oral administration. Some are swallowed whole, some after being chewed, some are dissolved or dispersed in water before being administered and some are retained in the mouth where the active substance is liberated.

The particles consist of one or more active substances with or without excipients such as diluents, binders, disintegrating agents, glidants, lubricants, substances capable of modifying the behaviour of the preparation in the digestive tract, colouring matter authorised by the competent authority and flavouring substances. Tablets are usually straight, circular solid cylinders, the end surfaces of which are flat or convex and the edges of which may be bevelled. They may have break-marks and may bear a symbol or other markings. Tablets may be coated.

Where applicable, containers for tablets comply with the requirements for materials used for the manufacture of containers (3.1 and subsections) and containers (3.2 and subsections).

Several categories of tablets for oral use may be distinguished:

ı— uncoated tablets;

ı— coated tablets;

ı— effervescent tablets;

ı— soluble tablets;

ı— dispersible tablets;

ı— orodispersible tablets;

ı— gastro-resistant tablets;

ı— modified-release tablets;

ı— tablets for use in the mouth;

ı— oral lyophilisates.

PRODUCTION

Tablets are usually prepared by compressing uniform volumes of particles or particle aggregates produced by granulation methods. In the manufacture of tablets, means are taken to ensure that they possess a suitable mechanical strength to avoid crumbling or breaking on handling or subsequent processing. This may be demonstrated using the tests described in chapters 2.9.7. Friability of uncoated tablets and 2.9.8. Resistance to crushing of tablets.

Chewable tablets are prepared to ensure that they are easily crushed by chewing.

 Subdivision of tabletsıTablets may bear a break-mark or break-marks and may be subdivided in parts, either to ease the intake of the medicinal product or to comply with the posology. In the latter case, subdivision must be assessed and authorised by the competent authority. In order to ensure that the patient will receive the intended dose, the efficacy of the break-mark(s) must be assessed during the development of the product, in respect of uniformity of mass of the subdivided parts. Each authorised dose must be tested using the following test.

Take 30 tablets at random, break them by hand and, from all the parts obtained from 1 tablet, take 1 part for the test and reject the other part(s). Weigh each of the 30 parts individually and calculate the average mass. The tablets comply with the test if not more than 1 individual mass is outside the limits of 85 per cent to 115 per cent of the average mass. The tablets fail to comply with the test if more than 1 individual mass is outside these limits, or if 1 individual mass is outside the limits of 75 per cent to 125 per cent of the average mass.

In the manufacture, packaging, storage and distribution of tablets, suitable means are taken to ensure their microbiological quality; recommendations on this aspect are provided in chapter 5.1.4. Microbiological quality of pharmaceutical preparations.

Uniformity of dosage units (2.9.40)

Tablets comply with the test or, where justified and authorised, with the tests for uniformity of content and/or uniformity of mass shown below. Herbal drugs and herbal drug preparations present in the dosage form are not subject to the provisions of this paragraph.

Uniformity of content (2.9.6)

Unless otherwise prescribed or justified and authorised, tablets with a content of active substance less than 2 mg or less than 2 per cent of the total mass comply with test A. If the preparation has more than 1 active substance, the requirement applies only to those substances that correspond to the above conditions. Unless otherwise justified and authorised, coated tablets other than film-coated tablets

comply with test A irrespective of their content of active substance(s).

Uniformity of mass (2.9.5)

Uncoated tablets and, unless otherwise justified and authorised, film-coated tablets comply with the test. If the test for uniformity of content is prescribed or justified and authorised for all the active substances, the test for uniformity of mass is not required.

Dissolution

A suitable test may be carried out to demonstrate the appropriate release of the active substance(s), for example one of the tests described in chapter 2.9.3. Dissolution test for solid dosage forms.

Where a dissolution test is prescribed, a disintegration test may not be required.

UNCOATED TABLETS

Uncoated tablets include single-layer tablets resulting from a single compression of particles and multi-layer tablets consisting of concentric or parallel layers obtained by successive compression of particles of different composition. The excipients used are not specifically intended to modify the release of the active substance in the digestive fluids. Uncoated tablets conform to the general definition of tablets. A broken section, when examined under a lens, shows either a relatively uniform texture (single-layer tablets) or a stratified texture (multi-layer tablets) but no signs of coating.

Disintegration (2.9.1)

Uncoated tablets comply with the test. Use water R as the liquid. Add a disc to each tube. Operate the apparatus for 15 min, unless otherwise justified and authorised, and examine the state of the tablets. If the tablets fail to comply because of adherence to the discs, the results are invalid. Repeat the test on a further 6 tablets omitting the discs. Chewable tablets are not required to comply with the test.

EFFERVESCENT TABLETS

Effervescent tablets are uncoated tablets generally containing acid substances and carbonates or hydrogen carbonates, which react rapidly in the presence of water to release carbon dioxide. They are intended to be dissolved or dispersed in water before administration.

Disintegration

Place 1 tablet in a beaker containing 200 ml of water R at 15-25 °C; numerous bubbles of gas are evolved. When the evolution of gas around the tablet or its fragments ceases the tablet has disintegrated, being either dissolved or dispersed in the water so that no agglomerates of particles remain. Repeat the operation on 5 other tablets. The tablets comply with the test if each of the 6 tablets used disintegrates in the manner prescribed within 5 min, unless otherwise justified and authorised.

SOLUBLE TABLETS

Soluble tablets are uncoated or film-coated tablets. They are intended to be dissolved in water before administration. The solution produced may be slightly opalescent due to the added excipients used in the manufacture of the tablets.

Disintegration (2.9.1)

Soluble tablets disintegrate within 3 min, using water R at 15-25 °C.

DISPERSIBLE TABLETS

Dispersible tablets are uncoated or film-coated tablets intended to be dispersed in water before dministration, giving a homogeneous dispersion.

Disintegration (2.9.1)

Dispersible tablets disintegrate within 3 min, using water R at 15-25 °C.

Fineness of dispersion

Place 2 tablets in 100 ml of water R and stir until completely dispersed. A smooth dispersion is produced, which passes through a sieve screen with a nominal mesh aperture of 710 μm.

ORODISPERSIBLE TABLETS

Orodispersible tablets are uncoated tablets intended to be placed in the mouth where they disperse rapidly before being swallowed.

Disintegration (2.9.1)

Orodispersible tablets disintegrate within 3 min.

MODIFIED-RELEASE TABLETS

Modified-release tablets are coated or uncoated tablets that contain special excipients or are prepared by special procedures, or both, designed to modify the rate, the place or the time at which the active substance(s) are released. Modified-release tablets include prolonged-release tablets, delayed-release tablets and pulsatile-release tablets.

PRODUCTION

A suitable test is carried out to demonstrate the appropriate release of the active substance(s)

GASTRO-RESISTANT TABLETS

Gastro-resistant tablets are delayed-release tablets that are intended to resist the gastric fluid and to release their active substance(s) in the intestinal fluid. Usually they are prepared from granules or particles already covered with a gastro-resistant coating or in certain cases by covering tablets with a gastro-resistant coating (enteric-coated tablets).

Tablets covered with a gastro-resistant coating conform to the definition of coated tablets.

PRODUCTION

For tablets prepared from granules or particles already covered with a gastro-resistant coating, a suitable test is carried out to demonstrate the appropriate release of the active substance(s).

Disintegration (2.9.1)

For tablets covered with a gastro-resistant coating, carry out the test with the following modifications. Use 0.1 M hydrochloric acid as the liquid. Operate the apparatus for 2 h, or another such time as may be justified and authorised, without the discs and examine the state of the tablets. The time of resistance to the acid medium varies according to the formulation of the tablets to be examined. It is typically 2 h to 3 h but even with authorised deviations is not less than 1 h. No tablet shows signs of either disintegration (apart from fragments of

coating) or cracks that would allow the escape of the contents. Replace the acid by phosphate buffer solution pH 6.8 R and add a disc to each tube. Operate the apparatus for 60 min and examine the state of the tablets. If the tablets fail to comply because of adherence to the discs, the results are invalid. Repeat the test on a further 6 tablets omitting the discs.

Dissolution

For tablets prepared from granules or particles already covered with a gastro-resistant coating, a suitable test is carried out to demonstrate the appropriate release of the active substance(s), for example the test described in chapter 2.9.3. Dissolution test for solid dosage forms.

TABLETS FOR USE IN THE MOUTH

Tablets for use in the mouth are usually uncoated tablets. They are formulated to effect a slow release and local action of the active substance(s) or the release and absorption of the active substance(s) at a defined part of the mouth. They comply with the requirements of the monograph Oromucosal preparations

ORAL LYOPHILISATES

Oral lyophilisates are solid preparations intended either to be placed in the mouth or to be dispersed (or dissolved) in water before administration.

PRODUCTION

Oral lyophilisates are obtained by freeze-drying (lyophilisation), involving division into single doses, freezing, sublimation and drying of usually aqueous, liquid or semi-solid preparations.

Disintegration

Place 1 oral lyophilisate in a beaker containing 200 ml of water R at 15-25 °C. It disintegrates within 3 min. Repeat the test on 5 other oral lyophilisates. They comply with the test if all 6 have disintegrated.

Water (2.5.12)

Oral lyophilisates comply with the test; the limits are approved by the competent authority.Ph Eur