Drug products usually contain inactive, non-medicinal substances other than the therapeutic agent(s). These substances are called excipients, and they are intentionally included in a drug product to serve different pharmaceutical purposes, thus ensuring product acceptability in terms of manufacturability, appearance and performance.
In tablet formulation, excipients are usually combined at various quantities with the active drug substance(s) to produce tablets that are of standard quality. The type and quantities of each excipient used depend on the type of tablet desired and the process employed.
- 1 Classes of excipients used in the manufacture of tablets
- 2 Excipients used in the formulation of tablets
- 3 Conclusion
Classes of excipients used in the manufacture of tablets
Excipients used in tablet formulation may be classified into two groups:
- Those that help to impart satisfactory processing and compression characteristics to the formulation e.g. bulking agents/diluents, binders, glidants, and lubricants.
- Those that help to give additional desirable physical characteristics to the compressed tablets e.g., disintegrants, surface acting agents/ surfactants, colours, flavours and sweetening agents (as in the case of chewable tablets), polymers or hydrophobic materials (as in the case of controlled-release tablets).
Excipients used in the formulation of tablets
Typically the following excipients/ ingredients are used in the manufacture of conventional tablets
Binders also referred to as granulators or granulating fluid, are polymeric, natural or synthetic materials that impart cohesive qualities to powdered materials used in tablet manufacture. They ensure the tablets remain intact after compression, as well as improve the free-flowing qualities of the powdered materials without retarding disintegration or dissolution.
Binders are used alone or in combination with one another. They are added as dry powders (e.g., cellulose and polyvinyl pyrrolidone) or in the form of their solution that is, by dissolving it in a suitable and appropriate solvent. The quantity used has considerable influence on the properties of the compressed tablets. The use of excessive binder will make a hard tablet that will not disintegrate easily when the tablet comes in contact with moisture and will also cause excessive wear of punches and dies.
Binders must be non-toxic and must have a good compatibility profile. Materials commonly used as binders include acacia gum, hydroxypropylmethylcellulose, tragacanth, polyvinyl pyrrollidone (PVP), corn starch, microcrystalline cellulose, etc.
Examples and concentrations of binders commonly used in tablet formulation
ii. Bulking Agents/ Diluents/ Fillers
These are approved excipients added to any tablet formular when the quantity of active pharmaceutical ingredient is very small. They are added to increase the size of the tablets to get a significant tablet weight that can be handled or compressed, thereby rendering the manufacturing process more reliable and reproducible. The quantity of bulking agent that appears in a formula is normally determined by the quantity of the drug, the nature and amount of other ingredients in the formulation.
Bulking agents must be approved like all other raw materials used in tablet formulation. They should be chemically inert, non-hygroscopic, hydrophilic and must exhibit good compression properties. The compatibility of the bulking agent with the drug substance must be considered as studies have shown that some interfere with the absorption of drug substances from the gastrointestinal tract e.g., calcium salts used as bulking agent for the broad-spectrum antibiotic tetracycline.
Lactose is a common bulking agent used in both tablet and capsule formulations as it fulfils most of the ideal characteristics of bulking agents. It is unsuitable for patients who are lactose intolerant. Other examples of bulking agents used in tablet manufacture include mannitol, dicalcium phosphate, calcium sulfate, dry starch, cellulose, kaolin, sodium chloride, anhydrous lactose, sorbitol, sucrose etc.
Disintegrants or disintegrating agents are raw materials that appear in some tablets. They are added to formulations to overcome the cohesive strength imparted during compression, thus facilitating the breakdown of the tablet into granules for ready drug availability once they come in contact with moisture. There is still a lack of understanding with respect to the mechanisms by which disintegrants elicit their functions. Disintegrants such as starch, sodium starch glycolate and microcrystalline cellulose may enable tablet disintegration by increasing the porosity and wettability of the compressed tablet matrix. Croscarmellose sodium, crospovidone, sodium starch glycolate and pregelatinised starch swell in the presence of aqueous fluids, thereby facilitating tablet disintegration due to the increase in the internal pressure within the tablet matrix. Tablet disruption following gas production (carbon dioxide) as seen in effervescent tablets is another mechanism used to enhance tablet disintegration.
Disintegrants may be added intragranularly, extragranularly or both (which may be varied to achieve the best result). It does not always mean that the higher the concentration of disintegrants the faster the rate of disintegration. The concentration may have a direct relationship with the rate of disintegration until it gets to maximum after which disintegration rate decreases with increase in concentration of disintegrants.
Factors that influence the actions of disintegrants
Various factors have been identified to influence the actions of disintegrants and they include:
- The amount/ concentration of the disintegrant in the formular.
- The type of disintegrant used.
- The influence of co-excipients (binder, lubricants etc).
- Presence of surfactants/ surface acting agents.
- The nature of the drug substance itself.
- Particle size and particle shape.
- Mixing type, size and time.
- Compressional pressure used during tablet manufacture/ Tablet hardness.
Example of disintegrants used in the manufacture of tablets include corn and potato starches, cation-exchange resins, Veegum HV, alginic acid, agar, bentonite, natural sponge, guar gum, citrus pulp, methylcellulose, carboxymethylcellulose etc.
A group of materials known as “super disintegrants” have gained popularity as disintegrating agents. Compared to the more traditional disintegrants, super disintegrants act extraordinarily fast in exploding tablets in seconds. Their likely mechanism of action is a combination of proposed theories including water wicking, swelling, deformation recovery, repulsion and heat of wetting.
Super disintegrants comprise three groups namely:
- Modified starches
- Modified cellulose
- Cross-linked povidone
Examples of super disintegrants include croscarmellose, locust bean gum (at 10% w/w), crospovidone, sodium starch glycolate (Primojel, Explotab) etc.
Examples and concentrations of disintegrants commonly used in tablet formulation
Lubricants as the name suggest, reduce friction between the powder mix and the die walls during compression and ejection. They also prevent the mixed powders/ granules from sticking to the processing zone of the tablet press especially the punches and die. In some cases, lubricants reduce inter-particulate friction and thus, improve flow rates of powders or granules. The best lubricants are those with low shear strength but strong cohesive tendencies perpendicular to the line of shear.
Lubricants can be classified based on their solubility characteristics into
- Soluble lubricants e.g., Polyethylene glycol (PEG), Polyoxyethylene stearates, and Lauryl sulphate salts.
- Insoluble lubricants e.g., Magnesium stearate, glyceryl behenate, stearic acid, glyceryl palmitostearate etc.
Inadequate lubrication during tablet manufacture results in the production of tablets with a pitted surface. Conversely, excessive use of lubricants yields tablets with reduced rates of disintegration and dissolution. The appearance of the tablet is an important pharmacopoeial (and consumer) requirement and, therefore, inadequate or excessive lubrication will lead to rejection of the tablet batch.
Lubricants should be added after disintegrants to avoid coating it or preferably at the final stage prior to compression to ensure mixing time is kept to a minimum. The hydrophobic stearic acid and stearic acid salts e.g., magnesium stearate, are the most widely used lubricants in tablet formulation. They are included at concentrations less than 1% w/w in order to minimize any deleterious effect on tablet disintegration or dissolution. Other examples of lubricants used in tablet technology include Polyethylene glycol (PEG), polyoxyethylene stearates, lauryl sulphate salts, talc, magnesium stearate, glyceryl behenate, stearic acid, glyceryl palmitostearate, calcium stearate, hydrogenated vegetable oils etc.
Like lubricants, glidants are fine powders that enhance the movement of powders or granules within the hopper and into the die cavity prior to compaction, compression, or encapsulation. By enhacing flow rates of powders or granules, there is less weight variability of the tablets manufactured, resulting in more consistent dosing of the drug substance(s). It has been suggested that the ability of glidants to enhance the movement of the powder or granules within the hopper and into the tablet die in the tablet press is due to the ability of particles of the glidants to locate within the spaces between the powder particles/ granules.
Glidants are typically hydrophobic and therefore care should be taken to ensure that the concentration of glidants used in the formulation does not (in a similar fashion to lubricants) adversely affect tablet disintegration and drug dissolution. Examples of glidants used in tablet manufacture include colloidal silicon dioxide, talc, corn starch etc.
In addition to the drug substance(s), compressed tablets also contain adsorbents. They are used whenever there is need to include a liquid or semisolid drug substance(s) or excipients (e.g., flavour) within the tablet formulation. Adsorbents adsorb moisture that may attack tablets or cause cohesiveness of tablet powder/ granules from these liquid or semi-solid components thus, allowing proper tablet compression during tablet formulation. As the production of tablets requires solid components, the liquid/semisolid constituent is adsorbed on to a solid component which, in many cases, may be one of the other components in the tablet formulation (e.g. diluent) during mixing. If this approach is not possible, an adsorbent is specifically included in the formulation. Examples of adsorbents used in the manufacture of tablets include magnesium oxide/carbonate, kaolin/bentonite etc.
Sweeteners are incorporated in tablets to impart sweetness to the product and hence the acceptability of tablets. The excipient is of particular importance if the conventional tablet contains a bitter drug substance(s) or, more importantly, if the tablet is a chewable tablet. Sucrose is the standard against which all sweeteners, both natural and artificial, are measured.
In addition to being many more times sweeter than sucrose, artificial sweeteners have the advantage of not impacting blood sugars of diabetic or pre-diabetic patients, and they are considered non-cariogenic. Examples of sweeteners that have found use in tablet manufacture include acesulfame potassium, aspartame, confectioner’s sugar, dextrates, dextrose, fructose, mannitol, saccharin, sorbitol, sucralose, sucrose, xylitol etc.
Flavourants also referred to as falvours, or flavouring agents are pharmaceutical excipients used to impart a pleasant flavour and often odour to pharmaceutical formulations. They may be derived from natural sources (e.g., fruit components) or prepared artificially. Their selected use in pharmaceutical dosage forms is based on the desired flavour, their solubility characteristics, and their physicochemical compatibility with the drug substance/ active pharmaceutical ingredient and other excipients in the formulation. Some favouring materials are more effective than others in masking or disguising the undesirable taste of drug substances. Although individuals’ tastes and flavour preferences differ, cocoa-flavoured vehicles are considered effective for masking the taste of bitter drugs. Fruit or citrus flavours are frequently used to combat sour or acid-tasting drugs, and cinnamon, orange, raspberry, and other flavours have been successfully used to make preparations of salty drugs more palatable.
The age of the intended patient should be considered in the selection of the favouring agent, because certain age groups seem to prefer certain flavours. Children for instant prefer sweet candy-like preparations with fruity flavours, but adults seem to prefer less sweet preparations with a tart rather than a fruit flavour.
Flavourants can degrade as a result of exposure to light, temperature, headspace oxygen, water, enzymes, contaminants, and other product components, so they must be carefully selected and checked for stability.
ix. Colourants/ Colouring Agents
Colourants are generally employed in tablet manufacture either for aesthetics or to uniquely identify finished tablets. A distinction should be made between substances that have inherent colour and those that are used as colourants. Colourants can be divided into water-soluble dyes and water-insoluble pigments. Concerns over the safety of these agents in pharmaceutical formulations generally arise from their adverse effects in food substances. Each country has its own list of approved colourants that may be used in medicinal products, and formulation scientists must consider this in designing pharmaceutical dosage forms for the international market. Any of the approved, certified, water-soluble FD&C dyes, mixtures of the same, or their corresponding lakes may be used to colour tablets. It is important that the colour is uniformly distributed throughout the tablet. Examples of colourants used in the manufacture of tablets include iron oxides, titanium dioxide, and aluminium lakes.
Surfactants are excipients that are addded into tablets to improve the wetting properties of hydrophobic tablets and hence increase the rate of tablet disintegration. They may also increase the aqueous solubility of poorly soluble drug substance in the gastrointestinal tract and, as a result, the rate of dissolution of the active agent will increase. It should be noted that the surfactants should not interact with the drug substance as this may affect the dissolution rate of the drug substance. Example of surfactant include sodium lauryl sulphate (one of the most popular surface-active agent that improves the wetting properties of hydrophobic tablets), Cetylpyridine chloride, glyceryl monooleate etc.
Excipients are essential in the formulation of tablets as it ensures successful manufacturing process and quality of the resultant formulation. Proper selection of excipients and their relative concentrations in the formulation is important in development of a successful pharmaceutical formulation. Although excipient are often categorized as inert, preformulation studies can help determine how these excipient influence the stability, bioavailability, and processability of the dosage forms.
The need for acquiring more information and use standards for excipients has been recognized in a joint venture of the Academy of Pharmaceutical Sciences and the Council of the Pharmaceutical Society of Great Britain. The result is called the Handbook of Pharmaceutical Excipients. This reference work is now distributed widely throughout the world.
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The title of this article is Excipients Used In the Manufacture of Tablets. By reading this article you will get an overview of all the excipients used In the manufacture of tablets.