1.4.1 Oral tablets for ingestion (1-3)
These tablets are meant to be swallowed intact along with a sufficient quantity of potable water. Exception is chewable tablet. Over 90% of the tablets manufactured today are ingested orally. This shows that this class of formulation is the most popular world wide and the major attention of the researcher is towards this direction.
These are the standard uncoated tablets made by either direct compression or wet granulation or dry granulation or double compaction.
1) Figure.1. Standard Compressed Tablet
They may be used for local action in gastro-intestinal tract or systemic action. When the tablet exert local action, they are formulated as more water insoluble by means of selecting slow dissolving excipients and thus provides local action for long time period. e.g., antacids and adsorbents. The drugs that produce systemic action have some aqueous solubility and designed to disintegrate and dissolve quickly so that the drug can be quickly absorbed and produce systemic action. Generally, an API exhibits bioavailability depending upon Biopharmaceutical Class, which is based on water solubility and gastro-intestinal membrane permeability criteria. But, it can be altered by appropriate selection of excipients and processing technology.
The tablets in this category are prepared for two reasons: to separate physically or chemically incompatible ingredients and to produce repeat action/ prolonged action tablet.
The tablet manufacturing machine is generally operated at relatively lower speed than for standard compression tablet. There are three categories under this class:
I.Layered tablets - two to three component system.
II.Compression coated tablets - tablet within a tablet.
III.Inlay tablet - coat partially surrounding the core.
The layered tablet is preferred over compression coated tablet as the surface contact is less and the production is simple and more rapid.
When two or more active pharmaceutical ingredients are needed to be administered simultaneously and they are incompatible, the best option for the formulation pharmacist would be to formulate multilayered tablet. It consists of several different granulations that are compressed to form a single tablet composed of two or more layers and usually each layer is of different colour to produce a distinctive looking tablet. Each layer is fed from separate feed frame with individual weight control. Dust extraction is essential during compression to avoid contamination. Therefore, each layer undergoes light compression as each component is laid down. This avoids granules intermixing if the machine vibrates.
For example, admixture containing Phenylephedrin HCL and Ascorbic Acid with Paracetamol.
Paracetamol + phenylephedrine Hydrochloride - one layer
Paracetamol + ascorbic acid - another layer.
Figure.2. Multilayered Tablet
This type of tablet has two parts, internal core and surrounding coat. The core is small porous tablet and prepared on one turret. For preparing final tablet, a bigger die cavity in another turret is used in which first the coat material is filled to half and then core tablet is mechanically transferred, again the remaining space is filled with coat material and finally compression force is applied. This tablet readily lend itself in to a repeat action tablet as the outer layer provides the initial dose while the inner core release the drug later on. But, when the core quickly releases the drug, entirely different blood level is achieved with the risk of over dose toxicity. To avoid immediate release of both the layers, the core tablet is coated with enteric polymer so that it will not release the drug in stomach while, the first dose is added in outer sugar coating. Even so, coating operation requires interpretation while manufacturing and dawdling the manufacturing process. Sometimes, inner core may be of liquid formulation to provide immediate release of core after the coat gets dissolved.
Figure.3. Compression Coated Tablet
A type of layered tablet in which instead the core tablet being completely surrounded by coating, top surface is completely exposed. While preparation, only the bottom of the die cavity is filled with coating material and core is placed upon it. When compression force is applied, some coating material is displaced to form the sides and compress the whole tablet. It has some advantages over compression coated tablets:
i)Less coating material is required.
ii)Core is visible, so coreless tablets can be easily detected.
iii)Reduction in coating forms a thinner tablet and thus freedom from capping of top coating.
Figure.4. Inlay Tablets
The main aim behind formulation of this dosage form is to release the medicament slowly for long time duration after administration of a single tablet.
Figure.5. Graphical Comparison Of Blood Concentration V/S Time
A widespread use of this type of tablet is seen in present scenario, as well as many researchers have concentrated their attention in this direction. This is mainly because of improvement in patient's compliance as the dosage frequency is reduced, patient can take an undisturbed sleep at night, it's also beneficial for psychiatric patients who forget to take their tablets regularly and the dose related side effects and toxicities are reduced. Any adjuvant that can alter water uptake rate, swelling and gelling characteristics of Matrixing agents can alter the release rate of API e.g., electrolytes in HPMC matrix tablet. It's also possible to achieve pulsed drug release. Weakly basic drugs exhibit good solubility at low pH while less soluble at high pH conditions, which can result in incomplete drug release for sustained release formulations. The drug release can be modified by providing suitable micro environmental pH in the tablet e.g., acidic polymer, succinic acid, etc. Similarly, inclusion of alkaline polymers results in desirable drug release of acidic drugs. On the other hand, formulation of this type of dosage form presents challenge for the formulator: increases the cost of manufacturing, chances of burst drug release and drop in drug release rate in terminal phase and thus incomplete release on API. In case of accidental poisoning, the doctor has to deal with special treatment problems. Due to large size, patient may feel difficulties in swallowing as the matrixing agent to drug ratio is high. Classic approaches are usually based on adaptation of either film coated or multiparticulate technologies or those involving slow release matrices.
Coating technology (6)
It combines semi permeable coatings and osmotic tablet cores to produce "zero order release" technology. Attention is also focused to trigger drug release at critical time point e.g., to achieve drug release 1 -2 hours before the patient awakens. Alza's prolific research activities have yielded a technology called "Ringcap" which is based on a tablet, preferentially film coated, partially coated with a series of rings whose respective thickness provides the means of moderating the rate at which the drug is released from final dosage form.
Figure.6. Ringcap (Coated) Tablet
Classically matrix products exhibit first order (or perhaps square-root-of-time) drug release characteristics. In order to achieve zero order release characteristics, it's necessary to employ specially designed materials or strategies that seek to manipulate tablet structure or geometry. Combination of conventional HPMC matrix technology with upper and lower layer. This helps to moderate drug release by increase in surface area with concomitant reduction in drug concentration within the device.
Figure.7. Matrix Tablet
Release of medicament can follow various mechanisms (2)
i) Diffusion is rate limiting
Diffusion is driving force where the movement of drug molecules occurs from high concentration in the tablet to lower concentration in gastro intestinal fluids. This movement depends on surface area exposed to gastric fluid, diffusion pathway, drug concentration gradient and diffusion coefficient of the system.
Figure.8. Diffusion Release Pattern
In practice, we can follow either of the two methods,
1.The drug is formulated in an insoluble matrix; the gastric fluid penetrates the dosage form and dissolves the medicament and release the drug through diffusion.
2.The drug particles are coated with polymer of defined thickness so as the portion of drug slowly diffuse through the polymer to maintain constant drug level in blood.
ii) Dissolution is rate limiting
The drugs with poor water solubility (BCS class 2 and 4) are inherently sustained release forms. While for water soluble drugs, it's possible to incorporate a water insoluble carrier to reduce dissolution of the drug particles are coated with this type of materials e.g. Polyethylene Glycol. One may skip the use of disintegrating agent to promote delayed release.
iii) Osmotic pressure is rate limiting
Osmosis is a phenomenon in which the flow of liquid occurs from lower concentration to higher concentration through a semi permeable membrane which allows transfer of liquid only. The whole drug is coated with a semi permeable membrane with a hole on one end of tablet made by a laser beam. The gastric fluid penetrates through the membrane, solubilizes the drug and increases the internal pressure which pumps the drug solution out of the aperture and releases the drug in gastric environment. The delivery rate is constant provided that the excess of drug present inside the tablet. But, it declines to zero once the concentration drops below saturation.
Figure.9. Osmotic Release Pattern
iv) Release is controlled by ion exchange
Ion exchangers are water insoluble resinous materials containing salt forming anionic or cationic groups. While manufacturing, the drug solution is mixed with resin and dried to form beads which are tableted. The drug release depends upon high concentration of charged ions in gastro intestinal tract where, the drug molecules are exchanged and diffused out of the resin into the surrounding fluid. This mechanism relies upon the ionic environment of resin and not pH or enzyme on absorption site.
Enteric coated tablet is such an example of delayed action tablet. This formulation is preferred when,
i)The API irritates gastric mucosa e.g., aspirin or strong electrolytes
ii)Drugs that produce nausea and vomiting.
iii)API is sensitive to low pH e.g., erythromycin
iv)When it's necessary to release the drug undiluted. e.g., intestinal antibacterial, antiseptic agents, intestinal vermifuge, etc.
The commonly used coating agents are: Cellulose acetate phthalate, Hydroxy methyl propyl phthalate, polyvinyl acetate phthalate, Eudragit(r), etc. This dosage form is intended to hydrate and begin to dissolve in duodenum (pH 4 to 6) or in small intestine where pH increases to 7 to 8. The presence of esterases or bile salts like surface active agents plays a role in drug release.
18.104.22.168 Targeted tablets
When we need to release the API at a specific site in the elementary tract, targeted drug delivery is a preferred option. Depending upon the composition and release mechanism of a tablet, the drug is delivered to a particular region. Under this category, we have two types of tablet:
I. Gastro retentive Tablet
This type of dosage form is to be opted when API release is desired in stomach (Antacids, APIs used against H.pylori infection) or site of absorption is either stomach or upper part of small intestine.
Figure.10. Floating Tablet
To retain the drug for longer time period in stomach, following approaches can be used:
i) Low density tablet (effervescent or non effervescent)
ii) Tablets that can expand in gastric environment (swelling or by unfolding) and thus increasing the size so that it cannot cross the pyloric sphincter.
iii) Using mucoadhesive polymers that stick to mucosa of stomach and provide slow drug release.
Supine position is to be avoided and also high level of fluid is necessary or if the swelling formulation leaves stomach before it swells it's ineffective. Drugs like Diazepam, Levodopa, Benserazide, and Ciprofloxacin are successfully marketed in this formulation.
II. Colonic tablets (7,8)
When the aim is to deliver the drug into colon without dilution in other regions of gastrointestinal tract or the drug has poor absorption in stomach or small intestine, colonic drug delivery is an answer of choice. The pH in this region varies from 6.4 - 7 and presence of microbial flora plays as important role in drug release especially in this region. Various mechanisms are adopted for drug release in this area are coating with pH sensitive polymer e.g., Eudragit(r)S100, Eudragit(r) L100, biodegradable polymer like polymers which are sensitive to colonic bacteria, bioadhesive polymers which selectively sticks to colonic mucosa e.g., polycarbophils or polyethans, redox sensitive polymers that respond to redox potential in colon which expresses the total metabolic and bacterial action.
22.214.171.124 Chewable tablets
The patients who have difficulty in swallowing tablets whole or for children who have not yet learnt to swallow a tablet, chewable tablet serves as an attractive alternative. The added advantage of this medication is that it can be taken at any time or when water is not available. Mannitol is normally used as a base due to low hygroscopy and more importantly, it gives pleasant, cooling sensation. Antacid tablets are invariably prepared as chewable to obtain quick ingestion relief as well as the antacid dose is too large to swallow and the activity is related to particle size. Another example is multivitamin tablet which a patient can take as a daily dose.
126.96.36.199 Dispersible tablet (9)
These tablets disintegrate either rapidly in water, to form a stabilized suspension, or disperse instantaneously in the mouth to be swallowed without the aid of water. So, it's preferred for pediatric patients who cannot swallow a solid dosage form and the API is unstable if formulated in liquid formulation. Also helpful for patients having prolonged illness who are prone to nauseatic sensations if they have to swallow a tablet. The added advantage of this formulation is faster onset of action as compared to standard compressed tablet. The properties of the water dispersible tablet, such as porosity, hardness, disintegration time and increase in viscosity after dispersion are necessary to investigate during manufacturing which decides the product performance. The common examples of API formulated in this dosage form are analgesics e.g., aspirin, ibuprofen, etc.