The aim is to compare and contrast a few of the different formulations that are commercially available for one route of administration only. This piece of work will explore the different types of pharmaceutical formulations that are commercially available for the oral route of administration.
Tablets are often the desired outcome for via the oral route. Approximately 78% of all pharmaceutical formulations are taken via the oral route. This has been illustrated in the table below;
Table 1: Frequency of oral dosage forms taken via the oral route (implemented from (Aulton, M.E (2007).
As the most popular route of administration is the oral route, an in-depth comparative analysis of the advantages and disadvantages of varying dosage forms comparing and contrasting with would be:
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There are many dosage forms available for drug delivery. The chosen dosage from regularly used in the U.K is tablets, as they tend to be easily accessible and convenient to carry (Wells, J. 2009). Table 1 illustrates this well; the most popular route of administration for drugs is the oral route (78%), of which tablets contribute the vast majority (48%) of it.
In general terms, the formation of a tablet requires a mixture of active substances and excipients which are compacted together to help formulate it into the shape of a tablet. The effectiveness of the tablet is largely dependent on the various excipients added in order to make it into a suitable oral dosage form. The definition of a tablet in the Pharmacopeia (PhEur, 2002) states that a tablet is a "Solid preparation with each containing a single dose of one or more than one active ingredients which is usually obtained via compression of a uniform volume of particles.
Tablets have been around for centuries and mainly originate from the 19th century; where the Royal Pharmaceutical Society explain using their fact sheet, how they saw a progress of increased plant use via extracting the active ingredients from the plant roots and leaves to formulate it, into a much more convenient, easy and compressible dosage form i.e. a tablet (Homan, P. 2002).
There are 2 ways of tableting namely; direct compression and wet granulation. Each way is dependent on the amount of drug required for each dosage form. Low dose tablets are mostly manufactured via a method known as Direct Compression whereas the manufacturing of a high dose tablet requires a process known as Wet granulation (Wet massing). An example of a low dose tablet is e.g. Levothyroxine 25 mcg tablet. An example of a high dose tablet is e.g. Metformin 850mg tablet.
Direct compression is mainly used for low dose tablets. The advantages of using direct compression is that less material is lost, due to direct compression requiring fewer steps in comparison to Wet granulation. No heat or water involved also therefore the stability of the drug is also not affected. Some disadvantages of using direct compression may be that difference in particle size and bulk density of the diluent and the active substance may result in stratification and variation in drug content. Static charges can also develop during mixing and is limited to certain materials (Shoyele, S. 2009).
The manufacturing of tablets via the method of Direct Compression is best described by analysing the flow chart below. There are only two stages to direct compression; powder blending and power compression. The excipients used in Direct compression include; the active pharmaceutical ingredient, a filler, a disintegrant, lubricant and a glidant (Shoyele, S. 2009).
Generally low dose tablets are formulated using the direct compression method. These drugs are very potent and less than 50mg in weight per unit dose. This method is therefore preferred in order to avoid loss in the numerous steps required in wet granulation.
Filler is required in low dose tablets to increase the bulk volume of the tablet. The properties of good filler are that it should be inert and should meet some requirements such as being chemically inert, non-hygroscopic, have good biopharmaceutical properties, good taste and be cost effective. Examples of fillers include lactose, sucrose, microcrystalline cellulose, calcium phosphate. The most common filler used in industry is Lactose (Shoyele, S. & Wells, J. 2009). It fulfils all characteristics of a good filler e.g. dissolves in water, good taste, is non-hygroscopic and inert.
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Disintegrants are used in tablet formulation so that when the tablet comes into contact with a liquid, it breaks into small fragments which would result in rapid drug dissolution. Some examples of such disintegrants used in tableting would be; Starch, Cellulose, Cross linked polyvinyl pyrrolidone, sodium starch glycolate and Sodium carboxymethyl cellulose (Aulton, M.E (2007).
The addition of a lubricant in tableting is to ensure that the tablet formation and ejection can occur with low friction between the solid and the die wall (Wells, J. 2008). Examples of lubricants are magnesium stearate, stearic acid and polyethylene glycol (Wells, J. 2008).
Glidants are used to improve the flow ability of the powder, hence decreasing the angle of repose. Examples of a Glidants used in industry are; Silica, magnesium stearate and talc (Wells, J. 2008).
The method of direct compression firstly requires all the excipients to be weighed. Next the active ingredient is mixed with the filler in a mixer. After mixing, the binder, disintegrant and glidant is added to the mixture and mixed again using a mixer. The resulting powder is then used and mixed with the lubricant. The mixer mostly used in direct compression is diffusive mixing.
Wet granulation is the process at which high dose tablets can be formulated. This process is also known as wet massing. Granulation is the process where primary powder particles are made to adhere to form larger multi-particle entities known as granules. Wet granulation is a technique used routinely in the pharmaceutical industry when formulating a tablet. It is chosen routinely as a method, as granulation prevents segregation of powder mix; improves flow; improves the compaction characteristics of the mix; and provides uniformity in weight of the ingredients used in the powder mix.
Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid. Granulating fluid contains a solvent that is both non-toxic and volatile so that it may be removed by the process of drying. Examples of solvents used include water ethanol and Isopropanol or a combination. The granulating fluid may also contain a binder (examples could be Polyvinyl pyrrolidone/ Polyethylene glycol (Rowe et al (2009) which is an agent that ensures that the particles adhere when the granule is dry. The most commonly used solvent is water. Advantages of this are that it's economical, readily available, and environmentally friendly and doesn't require expensive equipment. The disadvantages are that water can have an effect on the drug stability, if the drug is susceptible to hydrolysis. Water requires an extended drying time in comparison to organic solvents, which may affect the stability due to extended exposure to heat. Ethanol and Isopropanol can be used as an organic solvent. The advantages of using an organic solvent are that it can be used for drugs which are water sensitive and it reduces drying time rapidly. The disadvantages are that expensive equipment and safety apparatus is required.
Wet granulation involves the following stages: blending, wetting, drying, sizing, blending and compression as described in the flow chart below (Shoyele, S. 2009).
Following the blending process, the final step is tableting which involves the use of a tablet press machine. The process of tableting can be split into 3 stages:
Die filling is when the upper punch is raised and the lower punch is dropped. The hopper shoe moves forward over the die and the powder falls into the die.
Tablet formation is where the upper punch moves down and compresses the powder, forming the tablet. The lower punch remains stationary or can also move up.
One die and one pair of punches
Can produce up to 200 tablets per min
Produces small batches of tablets
Number of dies and punches
Can produce up to 10,000 tablets per minute
Produces Large batches of tabletsTablet ejection is where the upper punch moves up and the lower punch rises until its tip reaches the top of the die and the tablet is removed.
(Shoyele, Sunday, (2009). Lecture Notes- Tablet Testing and Tableting, Huddersfield: School of Pharmacy, University of Huddersfield).
As explained above there are many routes by which pharmaceutical dosing can be taken place. The use of capsules is interesting as they are another solid dosage form similarly to tablets that can be taken via the oral route however it has been noted that there are products that have been formulated into a hard gelatin capsule which are not used for oral administration, but used for the administration via the inhaled route therefore counselling patient becomes essential.
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The word capsule is derived from the Latin word "capsula" meaning a small box (Aulton, M.E (2007). There are 2 types of capsules that are commercially available; soft gelatin capsules and hard gelatin capsules. The soft gelatin capsule is often referred to being described as one-piece whereas the hard gelatin capsule is referred to as two-piece incorporating the cap and the shell body as two separate pieces (Aulton, M.E (2007).
Soft gelatin capsules Hard gelatin capsules
Capsules contain certain raw materials that are present in both types of capsules. Both will contain gelatin, water, colorants, some processing aids and preservatives. When considering the soft gel capsules, they have all of the above, plus some various plasticizers (Aulton, M.E (2007).
Gelatin is a substance which is derived from a natural source; however is not a natural product itself (Aulton, M.E (2007). Gelatin is a protein substance derived from collagen and is prepared via collagen, the main protein constituent of tendons, ligaments of mammals (connective tissues) (Aulton, M.E (2007). The ability of gelatin to form strong digestible films and capsule shell bodies which are also soluble in hot water gives rise to the use of many uses such as food processing, pharmaceuticals, photography, and paper production.
Capsules are available in different sizes and each size is dependent on the fill weight. A table has been constructed where the fill weights are given against the size of the capsule available commercially (Wells, J. 2008.
Size of capsule
Capsules are elegant looking and they achieve this by adding colorants to the gelatin body to give a more attractive feel for the product as well as providing a means of identification for the capsule as well. Mainly non-azo class dyes are used commercially and examples of these would be; indigo carmine (E132), quinoline yellow (E104) and erythrosine (E127) (Aulton, M.E (2007). Two pigments also used widely in the pharmaceutical industry is titanium oxide (E171) which is white itself, but helps opacify the capsule itself i.e. make it opaque and iron oxides (E172) giving black, red and yellow colours (Aulton, M.E (2007).
The use of preservatives in previous years during capsule formulation was to prevent any contamination of microbes during the manufacture process (used as a process aid); however due to the strict guidelines set by the MHRA, it has been noted that the use of preservatives in capsules did have no effect and therefore the use of preservatives in capsules has decreased recently. The use of a plasticizers is only applicable in soft gels with the most commonly used plasticizer to be glycerol, with sorbitol and propylene glycol also frequently used (Aulton, M.E (2007).
Solutions are best described as homogeneous mixtures of two or more components where the one substance known as a solute is dissolved in a solvent. The meaning of homogeneous is derived from the prefix "homo" meaning sameness. A homogenous solution will have the same uniform appearance and composition throughout with the particle sizes distinguishing between a homogeneous and heterogeneous solution (Ophardt, C. 2003). Oral formulations such as solutions are formulated in such a way so that the patient receives the dosage required in a set amount which is easily measurable by the patient (Winfield A.J et al. 2009).
Solutions have a wide variety of uses in the pharmaceutical industry and based on their composition or medical use, they can be formulated into; oral dosage forms, mouthwashes, nasal drops, ear drops and externally as lotions, liniments etc...(Winfield A.J et al. 2009).
The different forms of oral solutions can be sectioned into syrups, elixirs, linctuses, mixtures and oral drops. Syrups are described as aqueous solutions which contain sugar with an example being EpilimÂ® syrup. Elixirs are clear flavoured liquids which contain a high proportion of sucrose or suitable polyhydric alcohol, an example of which is Phenobarbital elixir. Linctuses tend to be formulated to be more viscous as they are usually used for the treatment of cough. Again they contain a high proportion of sucrose, other sugars or alcohols. Simple Linctus BP is a good example of one. Mixtures is another term used to describe pharmaceutical oral solutions and suspensions; a good example of which is Ammonium and Ipecacuanha Mixture BP. Oral drops are solutions or suspensions that are tend to be administered in small volumes. A suitable device is usually used and an example of which would be AbidecÂ® vitamin drops.
The formulation of a solution consists mainly of the active ingredient dissolved in a solvent however many other excipients are added to make the product more palatable and to increase shelf life of the product. Colouring, flavour, sweetness and or stability of the solution can be enhanced by such excipients in the formulation.
Solubility is a key issue during the formulation of a solution. The solubility of a drug will essentially determine whether it can be formulated into a solution or not. The solubilities of each medicinal agent in a given solvent can be found in the British Pharmacopoeia (BP), Martindale or other reference sources such as the Handbook of Pharmaceutical excipients (Winfield A.J et al. 2009).
The term vehicle in pharmaceutics terms is known as the medium in which the ingredients are contained in. The active ingredient will have a key impact on the solubility as well as the choice of vehicle used when formulating the solution. There are many examples of vehicles used with water being the most popular as it is inexpensive, most widely available, non-toxic and non-irritant (Winfield A.J et al. 2009).
There are many occasions however where water isn't used when formulating a solution. Reasons for such may be that the active medicament isn't soluble in water and therefore the use of another vehicle is required. Syrup BP, Glycerol, Alcohol, Propylene glycol, Oils are some examples of many different kinds of vehicles that can be used in the pharmaceutical industry apart from water (Aulton, M.E (2007).
Preservation of a solution can be tricky as most water-containing pharmaceutical solutions facilitate microbial growth. The most widely used preservative in the formulation of a solution is Chloroform at 0.25% v/v (Winfield A.J et al. 2009) however many other preservatives can be used such as Benzoic acid 0.1% w/v as well as ethanol, sorbic acid and hydroxybenzoates. Some preservatives unfortunately have ph dependant activity and should be considered when incorporating it into the solution (Wells, J. 2009) .
Flavouring is essential for solutions as they are added to solutions to make the taste of the medicine more pleasant, therefore increasing patient compliance with the medicine. When formulating extemporaneously for solutions the flavouring is tend to be done via natural components such as tinctures, juices and extracts to help mask the taste of the bitter tasting medicine.
Sweetening agents are incorporated into oral solutions to give a pleasant taste in the mouth. Examples of which could be sucrose, and glucose. Sucrose as well as giving a pleasant texture in the mouth can also increase viscosity of the liquid. Prolonged use of solutions with such sugars used in oral solutions can give rise to dental decay and this can be particularly dominant in children. Sorbitol, mannitol and saccharin are examples of sweetening agents that can be used in replacement of sucrose and glucose, and by doing so also makes the formulation sugar free.
Colouring agents are used widely in solutions as they enhance the appearance of a solution (Winfield A.J et al. 2009) making it look much more elegant in comparison to the addition of the colouring agent. The colour is generally matched to the flavouring used e.g. yellow for banana. The colouring agents used should be non-toxic, and chemically inert. Materials derived from plants exhibit both these characteristics and a good example of this is red beetroot extract or carotenoids.
Stabilizers such as antioxidants are added to preparation which the ingredients are likely to undergo degradation via oxidation. Examples of such stabilizers are citric acid, sodium metasulphite and ascorbic acid (Winfield A.J et al. 2009).
Suspensions can be defined as one or more insoluble active ingredients which have been suspended in a suitable vehicle (Pharmacopeia (PhEur, 2002). Suspended solids may slowly separate on standing but are easily dispersed (Winfield A.J et al. 2009 & Langley, C. et al. 2008). Suspensions when formulated usually contain; the active ingredient, the suspending agent, preservatives, buffers, colouring agents and stabilizers if necessary (Winfield A.J et al. 2009).
Suspensions when formulated must have certain physical properties for them to be classified as a well formulated suspension. Firstly the product must remain sufficiently homogeneous upon shaking the container for accurate dosing to be taken place. Any sedimentation or creaming produced during storage must be easily re-suspended via mild to moderate agitation. The product may require agents to increase viscosity of formulation and in doing so, control the rate of sedimentation. Resulting viscosity must be so that the product can be easily removed from the container as well as the rate of sedimentation is controlled. Suspension must contain particles with a uniform size to exhibit a smooth texture to the product (Aulton, M.E (2007).
The properties of a well formed suspension are determined by the particles natural tendency to aggregate. When formulating a deflocculated suspension the separate particles remain separate in the formulation and settle slowly. Upon settling to the bottom of the container, the sediments harden, making it difficult for the sediments to re-disperse and is known as "caking". A flocculated suspension however the individual particles aggregate into clumps; meaning that sedimentation rate is increased due to increased size when comparing with single particles. The sediments of a flocculated suspension however when reaching the bottom of the contained are easily re-dispersed and do not "cake" at the bottom; therefore an ideal suspension would be a flocculated suspension with an increased viscosity to help slow rate of sedimentation to allow accurate dosing of the liquid formulation.
The use of a suspending agent is simple. It is added to the formulation to provide a well formulated suspension by controlling the rate of sedimentation. This is achieved by suspending the drug inside the suspending agent which increases the viscosity; therefore controls the rate of sedimentation, enabling dosing to be taken place accurately. There are a wide variety of suspending agents available such as: (Winfield A.J et al. 2009).
Natural polysaccharides e.g. Xanthan gum (KeltrolÂ®)
Semi-synthetic polysaccharides e.g. microcrystalline cellulose (AvicelÂ®)
Clays e.g. Magnesium Aluminium Silicate (VeegumÂ®) and
Synthetic thickeners e.g. Carbomer (CarbopolÂ®)
A comparative analysis of the advantages and disadvantages of the oral route formulations discussed above
Tablets can be advantageous as an oral dosage form as they can provide a means of accurate dosing; they are easy to carry, are discrete looking and offer great help to compliance of patients needs. Tablets are also attractive and elegant in appearance. Due to tablets being compressed from powders this give rise to increased stability in comparison to other dosage forms such as solutions and suspensions. The cost for manufacture of tablets is also low, with shipping and packaging done fairly cheap as well. The masking of unpleasant tastes can also be achieved with sugar coating which can make them a suitable dosage form for patients. Colouring and shaping is easily achieved to help aid of identification of tablet. Tablet release mechanisms can be developed so that the tablet can release at a certain rate e.g. standard and modified release tablets.
The disadvantages unfortunately may be that some drugs due to reasons such as poor wetting properties, slow dissolution profiles or being amorphous in nature can be difficult to formulate into tablet dosage form. As well as being cheap to formulate, costs can rise; especially if special packaging is needed for the drug to stay stable before administration of drug. Taste masking requires sugar coating which could also increase manufacturing costs to help mask the taste of the bitter tasting drug. Drugs that are found in nature that are of a liquid state can also be difficult to formulate into a tablet. Swallowing is a big issue with some patients such as the critically ill patients, the children and the elderly which makes tablets an unsuitable form for dosing. Liquid dosage forms seem to be much more appropriate for patients these kinds of patients (Baboota S. 2010).
Advantages of a capsule as an oral dosage form are similar to tablets however if the powder cannot be compressed; instead of formulating into a liquid dosage form, a capsule could be a much suitable option. A patient would prefer a capsule in regards to in comparison to rather than a liquid dosage form due to convenience and discreteness of a capsule in regards to a medicine bottle. There are two main disadvantages however may be that dosing of children and elderly could potentially be difficult and also patient may have objections against the capsule formulation due to religious reasons i.e. the gelatin capsule.
Some advantages of both solutions and suspensions may be that they are much easier to swallow rather than tablets when considering formulating an oral dosage form. This is advantageous when dosing critically ill patients, the elderly and children as all these types of patients will find it difficult to swallow a solid oral dosage form such as a tablet. Another advantage of suspensions and solutions are due to them being liquids, allow more active ingredient to be absorbed more readily in the gastrointestinal tract.
Solutions can be more beneficial than suspensions in some cases as solutions due to being homogeneous; reduces the need of it does not require the shaking of the bottle and therefore ensures consistent dosing is taking place at all times.
Drugs when exhibiting a low solubility can be formulated into a suspension. The drug's unpleasant taste can also be overcome by masking the taste using flavouring agents.
The disadvantages of such may be; when formulating, the cost of manufacture of a suspension or solution is much higher in comparison to formulating a solid oral dosage form. Liquid dosing can be tricky and also inaccuracies can take place giving rise to risk of overdosing. Patient compliance can be an issue also as carrying a bottle is more difficult in comparison with a tablet. Stability issues are a big disadvantage when thinking about liquid dosage forms.
This article provides a quick summary of how each oral dosage form is made and provides a comparative analysis of all the formulations discussed above for example tablets, capsules, solutions and suspensions. This article gives an appreciation of the differences between each formulation putting forward their advantages and disadvantages. Oral formulations need to be both easy to take, provide the correct dose, give a pleasant taste to the mouth, be elegant looking and also be convenient to carry to help aid patient compliance when taking their medicines via the oral route.