TABLET

Advantages:

The major advantages of tablets over capsules, which has recently proved significant, is that the tablet is an essentially tamperproof dosage forms.

Disadvantages:

• Some patient particularly children and the seriously ill – persons may not be able to swallow tablets.
• Some drugs resist compression into dense compacts, owing to their amorphous nature or flocculent, low – density character.
• Drugs with poor wetting, slow dissolution properties, intermediate to large dosage, and optimum absorption in gastrointestinal tract or any combination of these features may be difficult or impossible to formulate or manufacture as a tablet that will still provide adequate or full drug bioavailability.
• Bitter tasting drugs, drugs with an objectionable odour or drugs that are sensitive to oxygen or atmospheric moisture may require encapsulation or entrapment prior to compression or the tablets may require coating. In such case, the capsule may offer the best and lowest cost approach.

Essential quality of a good tablet:

• They should be accurate and uniform in weight.
• The drugs should be uniform distributed through the tablets.
• The size and shape should be reasonable for easy administration. (range 3/16” to ½”)
• The tablets should not be too hard that it may not be disintegrate in the stomach.
• There should not be any incompatibilities.
• They should be chemically, physically and microbiologically stable during storage.
• They should not be broken during transportation or crumble in the hands of the patient.
• They should be attractive in appearance.
• They should not be any manufacturing defects like cracking, capping or discoloration.
• After administration it should disintegrate readily.
• They should be easy and economic in production.

Types of tablets:

Tablets are classified:--

By their route of administration and function.

By the type of drug delivery system – they represent within that route. And

By their form and method of manufacture.

Classifications of tablets on the basis of the route of administration or function are as follows: ---

• Oral Tablets for ingestion:--
• Compressed Tablets or standard compressed Tablets(C.T.)
• Multiple compressed tablets. (MCT).
• layer Tablets
• compression coated Tablets
• Repeated action Tablets
• Delayed action and enteric – coated Tablets
• Sugar – coated or chocolate coated Tablets
• Film – coated Tablets
• Chewable Tablets
• Tablets used in the oral cavity:
• Buccal Tablets
• Sublingual Tablets
• Troches and lozenges
• Dental cones

Tablets administered by the other routes:

Implantation Tablets

Vaginal Tablets

Tablets used to prepare solutions:

Effervescent Tablets

Dispensing Tablets

Hypodermic Tablets (H.T.)

Tablet triturates (T.T.)

Compressed Tablets (C.T.):

These Tablets are formed by compression and contain no special coating. They are made from powdered, crystalline or granular materials, alone or in combination with binders, disintegrants, lubricants, diluents and in many cases colorants. This type of tablets are manufactured usually by the following three basic methods—

Wet granulation.

Double compaction. &

Direct compression.                                          

Action flow Diagram:-                                  

                                                         

Most compressed tablets are employed for oral administration of drugs, but some may be used for the sublingual, buccal or vaginal administration of drugs.

Nature:

Rapid disintegration and drug release.

Produce local effect in G.I. tract.

Local effect producing drugs are water insoluble e.g. antacid and adsorbents.

Other systemic effect producing drugs have some aqueous solubility.

Multiple compression tablets (MCT):

There are two or three component system: two or three layer tablets are made by more than one compression cycle to produce a tablet within a tablet or a tablet within a tablet within a tablet.

           

Cause of necessity:

• To separate physically or chemically incompatible ingredients.
• To produce repeat or prolonged action product.

Type: Multiple compression tablets may be divided into two parts due to their formulation process. One is layered tablets and the other is compression – coated tablets.

Layered tablets: are prepared by the initial compaction of a portion of fill material to the same die. Each addition fill being compressed to form a two or three layered tablets, depending upon the number of separate fills. Usually each portion of fill material contains a different medicinal agent separated from the others and sometimes it is significant by multiple colors as well as multiple layers.

On other hand compressible coated tablets are: prepared by feeding previously compressed tablets in to a special tableting machine and compressing another granular layer around the preformed tablets. They possess the advantages of slotting, monogramming, speed of disintegration etc. while retaining the attributes of sugar – coated tablets in masking the taste of the drug substance in the core tablets.

Repeat action tablets:

These are the tablets where different layers are present and the core tablet is usually coated with shellac or an enteric polymer so that it will not release its drug load in the stomach. The multiple layered tablets as well as the sugar coated tablets are also employed for this effect.

These products have the limitation based on unpredictable and uncontrolled gastric emptying which can offer the tablet various blood level to give proper action.

Delayed action and enteric coated tablets:

The delayed action tablet dosage form is intended to release a drug after sometime delay or after the tablet has passed through one part of the G.I.T. in to another.

All enteric – coated tablets (which remain intact in the stomach but quickly release in the upper intestine) are a type of delayed – action tablets. Not all delayed – action tablets are enteric or are intended to produce the enteric effect.

E.g. Erythromycin (enteric coated to protect drug)

       Ibuprofen, Aspirin (enteric coated to protect biological organ).

In case of enteric coated we use cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxy  propyl methyl cellulose phthalate (HPMCP), acrylate polymers (Dicarboxillic acid and phthalic acid in esteric form, which are insoluble in gastric media and there are common substances and the esterase in intestine is responsible for breaking the ester bond).

Sugar and chocolate – coated tablets:

Compressed tablets may be coated with a colored or an uncolored sugar. The coating is water soluble and is quickly dissolved after swallowing. It serves the various purposes of protecting the drug from the air and humidity and providing a taste or a small barrier to objectionable tasting or smelling drugs. Further it enhances the appearance of many compressed tablets. Disadvantage to sugar coated tablets need time and expertise for the processing purposes and the increase in the size and weight of the compressed tablets. Coated tablets may be 50% larger and heavier than the original uncoated tablets.

Chocolate colored tablets are mainly of historic importance since chocolate was one used to coat and color the compressed tablets. Today chocolate has been replaced by other colorants such as iron oxides which are used stimulate the chocolate color.

Film coated tablets:

These are compressed tablets coated with a thin layer of a water insoluble or water soluble plasticizer for the polymer and possibly a surfactant to facilitate spreading, film coated is used for taste masking, to increase elegancy etc.

The used polymers are such as -----

Hydroxy propyl cellulose, Hydroxy propyl methyl cellulose, methyl hydroxy ethyl cellulose, ethyl cellulose, providone, Na – carboxy ethyl cellulose, polyethylene glycols, acrylate polymers etc.

Advantages of film coated tablets over sugar coated tablets:

• Better mechanical strength of the coating based on the elasticity and flexibility of the polymer coating.
• Little increase in tablet weight.
• The ability to retain debased marking on a tablet through the thin film coating
• The avoidance of sugar which is contraindicated in the diets of a significant segment of the population. And the employment of a process that may be continuous or that readily lends itself to automation.
• Film coated tablets are basically tasteless, so offer the advantage over sugar coated tablets of being less likely to be mistaken for candy.
• Film coated is less expensive than sugar coating.

Disadvantage of film coated tablets over sugar coated tablets:

It is difficult to produce film coated tablets that match the physical appearance and elegance of the sugar coated products.

Chewable tablets:

Chewable tablets are intended to be chewed in the mouth prior to swallowing and are not intended to be swallowed intact. The purpose of a chewable tablet is to provide a unit dose of drug to infants and children or to the elderly, who may have difficulty in swallowing, a tablet intact. E.g. the chewable aspirin for children, antacid for all, antacid for all, vit.C tablet etc.

Advantage of chewable tablets:

• These tablets have very acceptable taste and flavor.
• They disintegrate in a short time and produce cool sweet taste.
• Chewable tablets can be taken at any place even if water is not available.
• The dose of most antacids is large, so typically tablets would be too large to swallow.
• The activity of an antacid is related with particle size. If the tablet is chewed prior swallowing, better acid neutralization may be possible from a give antacid dose.

Buccal and sublingual tablates:

These tablets are required to be placed below the tongue (sublingual) or in the side of the cheek (buccal) for the slow release of the medicament.

Generally these types of tablets contain those drugs which are destroyed, inactivated or not absorbed in the G.I.T. but are directly absorbed through the mucosal tissues of the oral cavity and mix into the blood stream leads directly to the general circulation.

Advantages:

Buccal and sublingual tablets have the following advantages for some drugs----

• Gastric environment may be avoided to serve extensive decomposition of some drugs. E.g. some steroids, hormones etc.
• Some drugs are well absorbed by the mouth.
• More rapid onset of drug action occurs than for tablets that are swallowed. E.g. some vasodilators
• First – pass effect may be avoided.
• Nausea producing drugs may give pleasant effect, E.g. testosterone.

Troches and lozenges:

These tablets are used in the oral cavity where they are intended to exert a local effect in the mouth or throat. These tablets are commonly used to treat sore throat or to control coughing in the common cold. As for example some local anesthetics, antiseptics, and antibacterial agents, demulcents, astringent and antitussives etc.

Lozenges may be named by compression but are usually formed by fusion or by a candy – molding process. Troches, on the other hand, are manufactured by compression.

Dental cones:

Dental cones are designed to be placed in the empty socket remaining following a tooth extraction. Their usual purpose is to prevent the multiplication of bacteria in the socket following such extraction by employing a slow releasing antibacterial compound or to reduce bleeding by containing an astringent or coagulant. The usual vehicle of these tablets is NaHCO3, NaCl, or an amino acid.

Implantation tablets:

Implantation or depot tablets are designed for subcutaneous implantation in animals or man. Their purpose is to provide prolonged drug effects, ranging from one month to a year. Their drug delivery rate is nearly constant.

Since there are two major safety problems with this form of drug administration, this class of dosage form has achieved little use in humans. The safety problems include the need for a surgical technique to discontinue therapy and tissue toxicity problems in the area of the implantation site.

The drugs used in the preparation of implants are water insoluble. These tablets are more commonly used in the veterinary medicine than human medicine. They can also be used for birth control on human beings. Generally steroidal hormones like testosterone, stilbesterol etc are formulated as implants.     

Vaginal tablets (Inserts):

Vaginal tablets or inserts are designed to undergo slow dissolution and drug release in the vaginal cavity. The tablets are typically ovoid or pear – shaped to facilitate retention in the vagina. This tablets form is used to release antibacterial agent, antiseptics or astringent to treat vaginal infections or possibly to release steroids for systemic absorption.

The tablets are often buffered to promote a PH favorable to the action of a given antiseptic agent. The vehicle of these tablets is typically a slowly soluble material (similar to the agent of buccal or sublingual tablets).

Plastic tube inserters can also be used for placing these tablets in vaginal tracts.

Rectal tablets:

Some laxative suppositories are also formulated as compressed tablets. The active medicaments are mixed with such disintegrating agent whom either swells up after absorbing moisture or produce effervescence thus facilitate disintegration. These rectal tablets are covered with layer of polyethylene glycol which acts as protecting covering and also facilitate the insertion of these tablets in the rectum.

Effervescent tablets:

Effervescent tablets are prepared by compressing granular effervescent salts or other materials having the capacity to release gas (Co2) when in contact with water. Here the active ingredients are mixed with organic acids, such as citric acid or tartaric acid and NaHCo3

Reaction mechanism:

Tablets + water or moisture ( Reaction proceeds

Organic acid + NaHCo3 ( Sodium salt of the acid + Co2 ( + H2O

H2O + active ingredient ( solution

Advantages:

Such tablets in their final solution produce a pleasant flavored carbonated drink, which assists in masking the taste of certain drugs.

The rapid solubility of these tablets causes rapid activity.

It provides a means of extemporaneously preparing a solution containing an accurate drug dose.

Aspirin as an effervescent tablet produce a favorable PH for biological reaction, a great neutralization power of gastric content, a less irritation in the stomach etc.

Disadvantages:

The product is less stable because in contact with moisture the acid and NHCO3 react promptly to solubilize the product.

The humidity should be kept at 40% to avoid this problem. For many years, various saline, cathartics were prepared as effervescent mixtures and powders. The most widely produced effervescent tablet today is one that contains aspirin. A number of investigators have looked at alternative effervescent compounds in recent years in attempt to produce a mere chemically stable system. Such studies have included investigation in maleic acid, fumaric acid and various acid anhydrites in combination with newer carbonate sources such as Na-glycerin carbonate and various sesquicarbonates.   

Dispensing tablets:

Dispensing tablets are no longer in general use. In retrospect they might better have been termed compounding tablets since they were used by the pharmacist in compounding and not dispensed as such to the patient. The tablets containing relatively large amounts of highly potent drug substances were produced as a convenience to the pharmacist enabling him to obtain quickly accurately measured amount of potent drugs in preparing other solid or liquid dosage forms. The base of the tablets was usually water soluble to permit the preparation of clear aqueous solution. Dispensing tablets were prepared by either molding or compression. Dispensing agents, water insoluble lubricants, colorants, flavorants and coating were not used in these tablets. Materials that have been commonly incorporated in dispensing tablets include mild silver proteinate, bichloride of mercury, merbromine and quarternary compounds.

Disadvantages:

They cannot be employed on a routine basis with water of known quantity to produce sterile solutions.

Some components previously used in this dosage from are highly toxic and are extremely hazardous and even lethal, if mistakenly swallowed.

Hypodermic tablets:

Hypodermic tablets are composed of one or more drugs with other readily water – soluble ingredients and are intended to be added to sterile water or water for injection. Such extemporaneous preparation of an injectable solution was once widely used in medicine, because the physician, specially the rural physician, could carry many vials of such tablets in his bag with only one bottle of sterile water for injection, to prepare a great many types of injectable medications as the need arose. However, the difficulty in achieving sterility and the current availability of a large number of drugs in injectable form, some disposable syringes, have reduced the use of dispensing tablets now a day. These are also called dampened tablets because dampened powders used under the pressure into die cavity.

Tablet triturates:

Tablet triturates are small, usually cylindric, molded or compressed tablets. The drugs employed in such products were usually quite potent and were mixed with lactose and possibly a blinder, such as powdered acacia. A combination of sucrose and lactose is usually the diluent and any water insoluble material is avoided in the formulation.

Some tablets triturates are used for oral administration of drugs and some for sublingual use (as nitroglycerine tablets). Pharmacist may employ tablet triturates in compounding procedures in the preparation of other solid or liquid dosage forms.

Pharmacist use these tablets rarely today because------

The alcohol used to wet the powdered mass makes the tablet triturates soft and friable.

The drug migration occurred sometimes with alcohol evaporation leads the uniformity of medication.

Formulation of tablets:

Compressed tablets usually consist of active medicaments mixed with a number of inert substances known as excipient or additives. i.e. all non – drug components of a formula are termed excipients or additives. Although these additives are termed as inert but they have a great influence on stability, bioavailability and the process by which the dosage forms are prepared.

According to the functions which these additives play in the preparation of tablets may be classified as follows: ---

Diluent

Binder

Granulation agent

Disintegrating agent

Lubricants

Coloring agent

Flavoring agents

Sweetening agents

Criteria of good excipients:

All tablet excipients must meet certain criteria in the formulation. These include the following: -----

• They must be nontoxic and acceptable to the regulatory agencies in all countries where the product is to be marketed.
• They must be available in acceptable grade in all countries where the product is to be manufactured.
• Their cost must be acceptably low.
• They must not be contraindicated by themselves (e.g. sucrose) or because of a component (e.g. sodium) in any segment of the population.
• They must be physiologically inert.
• They must be physically and chemically stable by themselves and in combination with the drugs and other tablets components.
• They must be free of any unacceptable microbiological “load”.
• They must be color compatible.
• If the drug product is also classified as food (certain vitamin products) the diluent and other excipients must be approved direct food additives.
• They must have no deleterious effect on the bioavailability of the drugs in the product.

Diluents:

Diluents are fillers designed to make up the required bulk of the tablet when the drug dosage itself is inadequate to produce this bulk. The dose of some drugs is sufficiently high that no filler is required (e.g. aspirin and certain antibiotics) second reasons for countering diluents in formulation is to provide better compression manufacturing or to promote flow.

Round tablets for ingestion are usually in a size range of 3/16 to 1/2 inch. This provides a tablets weight range of perhaps 120 – 700 mg for standard density organic material. Oval tablet which is easier to swallow may contain 800 mg or more content.

Example of diluents: Lactose, starch, microcellulose, dibasic and tribasic calcium dehydrate, manitol, sorbitol, sucrose, dextrose, calcium carbonate, calcium sulfate etc. or their combination.

Something about various diluents:

Lactose is used in the hydrous and anhydrous form. Anhydrous lactose does not undergo the Maillard reaction which can lead to browning and discoloration with certain amide containing drugs. But as the anhydrous lactose picks up moisture from elevated humidity such tablets should be packaged carefully. When a wet granulation process is employed, the hydrous form of lactose should generally be used. Two grades of lactose are commercially available; a 60 – 80 mesh (coarse) and an 80 – 100 mesh (regular) grade.

Spray – dried lactose is one of several diluents now available for direct compression following mixing with the active ingredient and possibly a disintegrant and a lubricant. Spray dried lactose has also good flow characteristics. It can usually be combined with as much as 20 – 25% of active ingredient without losing these advantageous features.        

Starch which may come from corn, wheat or potatoes, is occasionally used as a tablets diluent. The USP grade of starch, however, has four flow and compression characteristics and possesses high typical moisture content between 11 and 14%. Various directly compressible starches such as Sta – Rx 1500 (Sta – Rx 1500 is also a binder and lubricant) Emdex and Celutab (combination of 90 – 92% dextrose and 3 – 5% maltose) etc. are free flowing and directly compressible.

Dextrose (supply name Cerelose) comes in two forms: as a hydrate and in anhydrate form.

Mannitol is perhaps the most expensive sugar used as a tablet diluent, but because of its negative heat of solution, its slow solubility and its pleasant feeling in the mouth, it is widely used in chewable tablets.

Sorbitol: is an optical isomer of mannitol and is used some times with mannitol to reduce the cost of diluents.

Some sucrose based diluents have such trade name as sugartab (90-93% sucrose +7-10% invert sugar), Dilac, Nutab etc.

Microcrystalline cellulose often referred to by the trade name Avicel, is a direct compression material. Two tablet grades exist: PH101 (powder) and PH 102 (granules)

Binders and adhesives:

These materials are added either dry or in liquid form during wet granulation to form granules or to promote cohesive compacts for directly compressed tablets. After the mixing of these substances, their wet granulation masses should be quickly dried at a temperature above 370C to reduce microbial proliferation.

Example: Acacia, tragacanth, gelatin with acacia, povidone (polyvinyl pyrolidone), alginates, starch paste (most common), liquid glucose, (50% solution in H2O), methylcellulose, hydroxypropyl methylcellulose, Hydroxypropyl cellulose etc. are used as binders.

Starch paste: Starch + H2O ( heat ( Dextrin + Glucose (starch paste)

Disintegrants:

A disintegrant is added to most tablet formulations to facilitate a break up of disintegration of the tablet when it contacts water in the GIT. Disintegrants may function by drawing water into the tablet, swelling and causing the tablet to burst apart. Such tablet formulation may be critical to the subsequent dissolution of the drug and to the attainment of satisfactory drug bioavailability.

Example: starch (conc. range 5-20% of the tablet weight), modified starch as primogel and explotab (1-5%, most by 4%), clays such as veegam HV and bentonite, alginic acid, cross linked polyvinyl pyrolidine (PVP), cross kinked sodium carboxy methylcellulose (CMC), Ac-Di-sol (trade name) etc are used as disintegrants.

Types: The dsintegrant is divided into two groups such as

Substances which swell up when they come in contact with water or moisture. Example: starches or modified starches.

Substances which react with effervescence when they come in contact with moisture, eg. Clays such as veegum HV and bentonite, cross linked PVP etc.

The second type of disintegrating agents includes a combination of NaHCO3, citric acid, or tartaric acid. When this combination comes in contact with water present in the GIT produces effervescence thus disintegrating the tablet.

Generally disintegrating agents are added in two portions, the major part is incorporated to the powders befor granulation and the other mixed with the dried granules along with lubricants. Disintegrants added in this manner serve two purposes. The disintegrant added after granulation breaks the tablet apart into granules into fine particles thus facilitating the dissolution of the drugs. 

Lubricants, anti-adherants and glidants:

A material that is primarily described as an antiadherant is typically also a lubricant with some glidant properties as well. The differentiation between these terms is as follows: -----

Lubricants are intended to reduce the friction during tablet ejection between the walls of the tablet and the walls of the die cavity in which the tablet was formed.

Antiadherents have the purpose of reducing sticking or adhesion of any of the tablet granulation or powder of the faces of the punches or to the die wall.

Glidants are intended to promote flow of the tablet granulation or powder materials by reducing friction between the particles.

Example: lubricants and antiadherents are talc, (hydrous Mg silicate, [3MgO.4SiO2. H2O] and sometimes Al-silicate), Ca-, Mg-, Zn- stearate, mineral oil, vegetable oil, polyethylene glycol (PEG) etc. On the otherhand, the glidants are talc (5% concentrated), corn starch (5-10%), colloidal silicates cab-O-sil (5nm size), syloid or Aerosil (2-10(m) in 0.25-3%, colloidal silicon dioxide (15nm)

Colors:

Coloring agents are used for three purposes:

Disguising of off color drug

Product identification and

Production of a more elegant product.

Two forms of color have typically been used in tablet preparation, these are the FD & C and D & C dyes-usually as solution form and also lake form in tablet production.

These colors may be added either in the mixed powders before granulation or they may be dissolved in the vehicles used for making the granules. The letter procedure gives more uniform color.  

Flavor:

Generally, flavors are added to all lozengens, chewable tablets and effervescence tablets. Volatile oils, volatile substances and fruit flavors are used for this purpose. Flavor oils are used in the granulating agent. But water soluble flavors are not used because of their lower stability.

Sweeteners:

            The use of sweeteners is primarily limited to chewable tablets. Mannitol, the natural sweetener is 72% as sweet as sucrose. Saccharine the artificial sweetener is about 500 times sweeter than sucrose. Another artificial sweetener aspartame is used by replacing saccharine but as it is moisture absorbent its stability is lower. So it has restricted use. 

Granulation

            Granulation is the process in which powder particles are made to adhere to form larger particles called granules. In the majority of cases, this will be under taken in the production of tablets or capsules, but granules may also be used as a dosage form.

Reasons for granulation:

There are three primary reasons and also other reasons which are included as follows: -----

To prevent segregation of the constituents in the powder mix: segregation occurs due to differences in the size or density of the components, smaller particles concentrating at the base of a container with the large particles above them. An ideal granulation will contain all the constituents of the mix in each granulation and segregation of the ingredients will not occur.

  

To improve the flow properties of the mix: Many powder because of their small size or surface characteristics, are cohesive and do not flow well. Poor flow will often result in a wide weight variation within the final product due to variable fill of tablet dies. Etc. granules produced from such a cohesive system will be larger and more isodiametric, both factors contributing to improved flow properties.

To improve the compression characteristics of the mix: Some powders are difficult to compress even if a readily compressed adhesive is included in the mix because of uneven distribution of adhesives but granules of the some formulation are often more easily compressed and produce stronger tablets.

Other reasons:

The granulation of toxic materials will reduce the hazard of the generation of toxic dust which may arise when handling powders. Suitable precautions must be taken to ensure that such dust is not a hazard during the granulation process. .

Materials which are slightly hygroscopic may adhere and form a cake if stored as a powder. Granulation may reduce this hazard as the granules will be able to absorb some moisture and yet retain their flowability because of their size.

Granules being denser than the parent powder mix occupy less volume per unit weight. They are therefore more convenient for storage and shipment.

Effects of bonds in granules formation:

To form granules bonds must be formed between powder particles so that they adhere and these bonds must be sufficiently strong to prevent breakdown of the granules to powder in subsequent handling operations. Rumpf (1962) distinguished five primary bonding mechanisms between particles: ------

Adhesion and cohesion forces in immobile liquid films: In wet granulation sufficient liquid or highly viscous solution can form immobile thin layer in which the particles of mixture and liquids are attached with each other by cohesion and adhesion forces and thus they keep final granule strength. In case of dry granulation the compactness achieved by compression given the cohesion and adhesion forces between the particles.

Interfacial forces in mobile liquid films: When enough liquid is applied to exceed immobile film to mobile film, the liquid distribution between and around the particles follows, some states which were distinguished by Newitt and Conway-Jones (1958). Those states are as follows: ------

From the above picture it has been shown that the readily increasing liquid increases the closeness of the particles by its interfacial tension and thus develops a stronger granule.

Solid bridges:  These can be formed by:---

                                       

Particle melting

Hardening binders and

Crystallization of dissolved substances.

( Sometimes the high pressure applied in dry granulation causes melting of low melting point materials which on crystallization after pressure – release give stronger bind.

( In wet granulation the granulating solvent form liquid bridges and the used adhesive will harden or crystallize on drying to solid bridges to the particles.

( The solvent used to mass powder during wet granulation may dissolve one of the powdered ingredients. When the granules are dried, crystallization of this material will take place and the dissolved substance then acts as a hardening binder.

Attractive forces between solid particles: Each particle possesses Van der Walls force and also sometimes electrostatic force both of which contributes to cohesion and adhesion forces between particles.

Interlocking bonds: Interlocking forces exist in granules because of having few particles cause interlocking bonds between granules.

Mechanism of granule formation:

The formation of granules in dry and wet granulation follows different manner. The precise mechanism by which a dry powder is transformed in to a bed of granules is probably different for each type of granulation equipment. But the mechanism discussed below, originally proposed for pan granulation (Barlow, 1968) has divided into three stages: ---

Nucleation: particle contact and adhesion due to liquid bridges forms an intact mass which acts as nuclei for further granule growth. In the presence of liquids, powders go through the following stages to form such nuclei.

Transition: nuclei can grow by two possible mechanisms; either single particle can be added to the nuclei by pendular bridges or two or more nuclei may combine. The combined nuclei will be reshaped by the agitation of the bed.

Ball growth: further granule growth produces large, spherical granules and mean particle size of the granulating system will increase with time. Although ball growth produces granules which may be too large for pharmaceutical purposes, some degrees of ball growth will occur in planetary mixers and it is an essential feature of some spheronizing equipment. The four possible mechanisms of ball growth are as follows: (Sastry and fuerstenau 1973): --------

Methods of preparation of tablets:

The manufacture of granulations for tablets compression may follow one or a combination of three established methods: ---

Direct compression.

Dry granulation or compression granulation, &

Wet granulation.

In the addition to these three basic methods recent technology has permitted the procedure of tablet granulation by the liquid bed process. The fluid bed granulation performs the following with a single piece of equipment.

Preblending the formulation powder (including the active ingredients, diluents & disintegrants etc.).

Granulation by means of a suitable liquid binder (e.g. aqueous solution of acacia, hydroxy propyl cellulose, povidone etc).

Drying the granulated product to the desired moisture content.

Direct compression:

Some crystalline or granuler substances eg NaCl, NaBr, KCl, NH4Cl, methanomine etc. possess free flowing as will as cohesive properties that enable them to be compressed directly in a tablet machine without need of either wet or dry granulation. But the needed other materials are—

Diluent—spray dried lactose, microcrystalline cellulose, dicalcium phosphate etc.

Disintegrants—direct compression starch (sta-Rx-1500), sodium carboxy methyl starch, providone etc.

Lubricants – Mg-stearate, talc, polyethylene, glycol etc.

Advantages:

Low labour imparts.

Few processing steps.

Capping or splitting is reduced due to deacreation.

Disadvantages:

Diluents and other additives may interfere with the compressibility of the active ingredient and thus minimize the usefulness of the method due to difference in particle size and bulk density between the drug and diluent may lead to stratification within the powder. The powder stratification may then result in poor content uniformity of the drug in the compressed tablets especially with low dose drugs.

Most materials cause relatively weak intermolecular action or are covered with films of absorbed gas that tend to hinder compaction. Thus most large dose drugs do not lend themselves of this process. To facilitate compression large amount of diluents ore required. The resultant tablets are costly and difficult to swallow.

Diluents may interact with the drugs e.g. amine drug and lactose.

Because of the dry nature of direct compression, static charge build up can occur on the drug during routine, screening and mixing, which may prevent a uniform distribution of the drug on the mass.

Dry granulation or compression granulation:

Dry granulation is formed not by moistering or adding a binding agent to the drug mixture but by compacting large masses of the mixture and subsequently crashing and sizing these pieces into smaller granules. By this method either the active ingredient or the diluent must have cohesive properties in order for the large masses to be formed. This method is specially applicable to materials that cannot be prepared by wet granulation method due to their sensitivity to moisture or to the elevated temperature required for drying, e.g. for aspirin, enzyme etc. 

            Flow diagram of this method: --

Weighing ( blending ( sizing (large form of tablet, range possible 1 inch) ( crashing into smaller pieces ( screening or sieving ( blending with lubricants ( Tableting.

Wet granulation:

This method is widely employed and it is the general methods used in the preparation in manufacture of tablet. This method is popular due to the granulation meets all the qualities required for a good tablet. But the disadvantage is that materials which are destroyed by moisture or heat cannot be prepared by wet granulation. Besides, this method is time consuming and required a number of persons as many different steps are involved in the preparation. So it is costly.

The steps are as follows: --

Weighing and blending: the active ingredient and any diluent and half of the disintegrating agent required in the tablet formulation are weighed in amounts required for the preparation of the number of tablets to be produced and are mixed thoroughly generally in a motor-driven powder blender or mixer.

Preparing the wet granulation: to prepare the powder mixer to free-flowing granules here a liquid binder or adhesive is added and screened through a desired mesh size. Again after the drying of granulation the granules are achieved a further size by passing through a second screen. Coloring or flavoring agent is used at the time of mixing of the binder.

           

Screening the damp mass into pellets or granules: generally the wet granulation is pressed through a No-6 or No-8 mesh screen. This may be done by hand or big special granulation equipment.

Drying: in the most instances, the granules are dried in special drying cabinets that have circulating air system and thermostatically controlled.

Dry screening: after drying the granules are passed through a screen of a smaller mesh than that used to prepared the original granulation. The degree to which the granules are reduced depends upon the size of the punches to be used and tablets to be produced.

Lubrication and blending: after dry screening, a dry lubricant is generally added to the granulation. So that each granule is covered with lubricant, it may be dusted over the spread-out granulation through a fine mesh screen or blended in a powder mixer.

Tableting by compression: tableting means the production of tablets by the compression of the tablet granulation within a steel die cavity by the pressure exerted by the movement of two steel punches, a lower punch and a upper punch.

Drug + Diluent ( Weighing & blending

(Adhesion + Half disintegrant + water

Wet granulation.  

 

Screening of larger mass of granules (mesh No 6-7)

Drying (( 600C)

 

Dry screening (mesh No. 12-20)

(Other half of disintegrants + lubricant (0.1 to 5 %, of wt. of granulation).

Lubrication & blending.

 

Tableting.

Fig: flow diagram of wet granulation.

Tableting:

Tableting means the final stage of tablet formation in which the tablet is produced by compressing a formulation containing a drug or drug with excipients on stamping machine called presses.

Basic component of tablet compression machine: -- tablet compression machines or tablet presses are designed with the following basic components----

• Hopper(s) for holding and feeding granulation to be compressed.
• Dies that define the size and shape pf the tablet.
• Punches for compressing the granulation within the dies.
• Cam tracts for guiding the movements of the punches.
• A feeding mechanism for moving granulation from hopper into the dies.

Various types of machines are used. They are as follows: ----

• Single punch machine.
• Multi punch machine.
• Rotary tablet machine.
• High speed rotary tablet machine.
• Multi layer rotary tablet machine.

Single punch tablet machine has a capacity 100 tablets per minute.

A single rotary press with 16 stations may produce up to 1150 tablets per minute.

Name of the machine and manufacture:

The Schleuniger tablet hardness tester. (courtesy of Vector corporation, Marion, IA).

The Roche type friabilator (courtesy of Vankel Industries, Chatham, NJ).

The Manesty Nova rotary tablet press. (Thomas Engineering, Hoffman Estates, IL).

The Little form lodige mixer (Littleford Brothers, Florence, KY).

The CF granulator (C. of Vector Corporation, Marion, IA).

Accila-Cata system (C. of Thomas Engineering Inc. Hoffman Estates, IL).

Hi-cota system (Vector Corporation, Marion, IA).

Manufacturing Defects:

During the routing production of tablets so many defects arise with the finished tablets may be due to either some faults in tablet formulation or in the tab letting equipment and sometimes due to both reasons.

The defects are as follows: ---

Capping and Lamination.

Picking and Sticking.

Mottling.

Binding in the Die.

Weight variation.

Hardness Variation

Double impression.

Capping and Lamination:

Capping is the partial or complete separation of the top or bottom crowns of a tablet from the main body of the tablet. Lamination is the separation of a tablet into two or more distinct layers. Usually, these processing problems are readily apparent immediately after compression; however, capping and lamination may occur hours or even days later. Subjecting tablets to the friability test is the quickest way of revealing such problems.

Reason

Due to the entrapment of air among the particles or granules during the compression and does not escape until the compression pressure is removed.

Too much pressure on compression.

Presence of either excess of fine powders of granules or less amount of fines in granules.

A granulation that is too dry tends to cap or laminate for lack of cohesion.

Often deep concave punches produce tablets that cap.

The wear and tear of punches and dies is also responsible for capping.

The wrong setting of dies or punches also causes capping and lamination.

Due to moist and soft granulation.

Recover

• Slowing tabulating rate.
• By granulating the material.
• By reducing the pressure adjustments.
• By reducing the speed of the machine.
• By addition of hygroscopic substance. E.g. sorbitol to maintain a proper moisture level.
• By replacing the worn out dies and punches.
• By correcting the level of the top of the lower punch so as to coincide with the level of the upper surface of the die.
• By changing the wear and tear of the punches and dies.
• By using proper granules and required amount of fine powders.

Picking and Sticking:

In picking a small surface of the tablet material is removed by the punches and adheres to the surface of punches therefore the resulting tablets show a pitted surface instead of smooth surface. In sticking the tablet material i.e. the granules adhere to the die wall and thereby the lower punch cannot move freely.        

Reason:

For the presence of scratches or engraving or embossing on the punches.

For using wet granulation during compression.

Sticking may be happened due to the use of damp granules or, due to worn out dies and punches.

Excessive moisture may be responsible.

Low melting point substances, either active ingredient or additives may soften from heat compression and thus can cause sticking and picking.

Recover:

• Lettering should be designed as large as possible.
• By using chromium plated punches for producing a smooth non-adherent face.
• By using dry granules and by adding a lubricant to the granules.
• By replacing the worn out dies and punches.
• In some cases colloidal silica added to formula acts a polishing agent and makes the punch faces smooth sometimes-additional binder or a change in binder may make the granules more cohesive and therefore less adherent.
• By using higher melting point materials as diluent.
• In case of excessive moisture further drying of the granules.

Mottling:

This defect occurs in the colored tablets. Mottling is an unequal distribution of color on a tablet, with light or dark areas standing out in an otherwise uniform surface.

    

Causes:

• Due to the difference of colors in the drugs and the added excipients.
• Due to the colored degraded products of the drug.
• Due to the migration of dyes during drying of granules, and
• Due to the use of colorants in direct compression formulation.

Prevention:

• By using a dye, which can mask the color of tablet ingredients.
• By changing the solvent system of the granulation.
• By drying the granules at a low temperature.
• By changing the binder system.
• By grinding to a smaller particle size.

Binding in the die:

During binding in the die the ejection of the tablet is difficult and is often accompanied by a characteristic noise. The edges of the tablets become rough.

Causes:

• Due to poor lubrication of granules.
• Due to dried granules.
• Due to dirty or worn out dies.
• Due to seep downward of the fine powder from granules thus forms a thick layer on the die, which hinders the free movement of the punches.

Recover:

• Lubricating the granules properly
• Using granules of having proper cohesive properly
• Replacing the worn out dies
• Cleaning the dirty dies.

Weight variation: Weight varies beyond the specifications.

Causes: This problem due to the following reasons: --------

• Poor flow of granules to the die
• Size separation of granules i.e. small and large size granules.
• Presence of too fines in the granules.
• Separation of the mixed ingredients of granules
• Less quantity of poor mixing of lubricants.
• Due to automatic change in the adjustment of punches.
• In rotary tablet making machines this defect is due to unequal length of lower punches.

Overcome:

• Making granules of good flow properly.
• Proper granulation
• Removing the too fines from the granulation etc. according to the causative factors.

Hardness variation: The tablet varies greatly in hardness.

Reasons: The reasons for this variation are the same as discussed under weight variation. Apart from these reasons other factors include

Weight of material.

Space between the upper and lower punches at the time of compression.

Inappropriate pressure applied on the upper punches

Excessive proportions of fatty lubricant such as magnesium stearate.

Some times on normal storage of tablets.

Problem: It is important to note that the tablets should not be harder than required. The hard tablets may not disintegrate in the required period of time and to soft tablets may not withstand the hazards of during handling, transporting and dispensing.  

Overcome:

This defect should be made up by obsoleting the causative factors.

Double impression:

This defect occurs in those tablets on which letters are printed. This involves only lower punch, which has a monogram to produce an impression on the tablet during compression. On some machines the punch moves downwards and then travels uncontrolled upward to a short distance to push the tablet out of the die. During its free travel it rotates and makes second impression on the tablet. This impression is generally lighter than the original impression. The new tablet making machines are fitted with devices, which prevent the rotation of the lower punch.

Evaluation of tablets or standardization of tablets or quality control of tablets:

The following standards or quality control tests are carried out on compressed tablets:

Appearance – color, size, odor.

Diameter size and shape.

Uniformity of weight.

Thickness.

Hardness.

Friability.

Percentage of medicament.

Rate of disintegration.

Appearance:

The appearance of the tablet should be examined on the basis of experience. If it is not usual it will be rejected even with the package.

Diameter, size and shape:

The diameter size and shape of tablets depends on the die and punches selected for making the tablets. The tablets of various sizes and shapes are prepared but generally they are circular with either flat or biconvex faces. Diameter size of the tablets can be examined by measuring the diameter of some tablets from a batch (with random selection) and shape is examined by their appearance.

Uniformity of weight:

It is desirable that all the tablets of a particular batch should be uniform in weight. If any weight variation is there, that should fall within the prescribed limits (generally ( 10% for tables weighing 120 mf, or less ( 7.5% for tablets weighing 120mg to 300mg and ( 5% for tablets weighing more than 300mg).

Procedure: For carrying out this test generally 20 tablets at random are taken and weighed. The average weight is calculated, then each tablet is weighed individually and weight noted. The weights of individual tablets are then compared with the average weight already calculated and see that not more than two tablets fall outside the range. This test is repeated after short intervals of time to ensure that tablets of required weight are produced.

Result: The test is considered correct if not more than two tablets fall outside this range if 20 tablets are taken for the test and not more than one tablet falls out side this range if only ten tablets are taken for the test.

Thickness:

The thickness of a tablet can vary without any change in its weight. This is generally due to the difference of density of granules, pressure applied for compression and the speed of compression.

The thickness of a tablet can be determined with the help of micrometer calipers. The thickness variation limits allowed are 15% of the size of the tablet. The variation in thickness leads to counting and packing problems.

Hardness:

The hardness of tablet depends on the weight of the material used, space between the upper and lower punch at the time of compression and pressure applied during compression. The hardness also depends on the nature and quantity of excipient used during formulation.

If the finished tablet is too hard, it may not disintegrate in the required period of time and if the tablet is too soft it may not withstand the handling during packing and transporting. Therefore it is very necessary to check hardness of tablets when they are being compressed and pressure adjusted accordingly on the tablet machine.

Procedure & result: Tablet hardness can roughly be determined by holding the tablet in between the fingers of the hand and through it lightly on the floor, if it does not break it indicates that proper hardness has been obtained. A number of hardness tasters are used for determining the tablet hardness but Monsanto hardness testers and Pfizer tasters are commonly used. Hardness of 4kg is considered suitable for handling the tablets hardness of 6kg or more produce tablet of highly compact nature.

Friability:

Friability test is performed to evaluate the ability of the tablets to withstand abrasion in packing, handling and transporting. The instrument used for this test is known as Friability Test Apparatus or Friabilator.

Procedure & result: Friabilator consists of plastic chamber, which is divided into two parts and revolves at a speed of 25 r.p.m. A number of tablets are weighed and placed in the tusubling chamber, which is rotated for four minutes or for 100 revolutions. During each revolution the tablets fall from a distance of six inches to undergo shock. After 100 revolutions the tablets are again weighed and the loss in weight indicates the friability. The acceptable limits of weight loss should not be more than 0.8%.

Percentage of medicament / content uniformity:

This test is preformed to ensure that every tablet coated or uncoated must contain the stated amount of medicaments within the prescribed limits.

Procedure & result: For this purpose 30 tablets are selected randomly and 10 of them are assayed individually according to the procedure indicated in the monographs of the official books. Nine of the 10 tablets must contain not less than 85% and not more than 115% of the labeled drug content. The 10th tablet may not contain less than 75% or more than 125%. If this step is failed than remaining 20 tablets are assayed individually. They must contain 85 – 115% of drug content.

Content uniformity may be disturbed by 3 factors: ---

Non-uniform distribution of ingredients during granulation.

Segregation of the powder mixture of granulation during the various manufacturing process.

Tablet weight variation (occasionally)

But weight cannot be used as potent indicator except perhaps when the active ingredients are 90-95% of the tablet weight. In tablet with smaller doses weight variation does not ensure content non-uniformity.

Rate of Disintegration:

The disintegration test is performed to find out that within how much time the tablet disintegrates. This test is very important and necessary for all the tablets, coated or uncoated to be swallowed because the dissolution rate depends upon the time of disintegration which ultimately affects the rate of absorption of drugs.

Apparatus: The apparatus used for this test is known as disintegration test apparatus. This apparatus consists of a glass or plastic tube, which is open at one end, and the other end is fitted with a rust proof No. 10 mesh.

Procedure: The tube is suspended in a bath of water or suitable liquid which is thermostically maintained at a temperature of 370C. The tube is allowed to move up and down at a constant rate i.e. 29 – 32 times per minute through a distance of 75 mm. The volume of the liquid and distance of movement adjusted in such a way that at the highest point the mesh screen just breaks the surface of the liquid to give a turbulent movement to the tablets and at the lowest point the mesh screen remains about 25mm above the bottom of the container.

About five tablets are placed in the tube along with a plastic disk over the tablets unless otherwise stated in the monograph. The plastic disk does not allow the tablets to float and imparts a slight pressure on the tablets. The tube is allowed to move up and down and disintegration time noted when all the tablets have passed through the sieve. This time should comply with the time stated in the monograph for that tablet.

Result: The test fails if all the tablets do not pass through the sieve within specified time. Generally the disintegration time for uncoated tablets is 30 min. and for coated tablets one hour. 

Dissolution time:

The rate of dissolution of a solid drug plays an important role in the absorption and physiological availability of the drug in the blood stream. Therefore determination of dissolution rate of any solid drug is very necessary. For this purpose there are a number of tests available in the literature but none is official. This test is performed for tablets and capsules when stated in the individual drug monograph.

Apparatus: The apparatus for dissolution test consists of: -----------

A cylindrical stainless steel basket, which is attached to the end of the stirrer shaft.

A 1000ml vessel made of glass or other inert, transparent material filled with a cover having four holes, one for the shaft of the stirrer second for placing the thermometer and remaining two for removing the samples

A variable speed motor driven stirrer which can rotate at a speed of 25-150 revolutions per minutes by a suitable thermostatically controlled water bath to maintain the temperature of the dissolution medium at a temperature of 370C ( 0.50C.

Procedure: For performing the test a suitable volume of dissolution medium like distilled water, hydrochloric acid or phosphate buffer at a pH of 7.4 or as stated in the individual monograph is filled in the glass vessel which is submerged in the water bath maintained at 370C. The tablet or capsules to be tested is introduced in the basket and fitted in position. The motor is started and its revolutions adjusted according to monograph. The samples are withdrawn at specified intervals and filtered immediately through a suitable filter medium. Generally 5ml sample solution is withdrawn each time which is replaced with 5ml of medium at 370C in order to maintain a constant volume in the vessel. The samples are tested by chemical analysis for proportion of drug dissolved which should meet the requirements as stated in the monograph.

Testing stages: Dissolution test may take the following stages to be completed.

Stage 1: 6 tablets are tested in 6 beakers. Acceptable range ( Q + 5%. Where Q is the monograph tolerance limit.

If this fails: -----

Stage 2: 6 more tablets are taken and tested. Acceptable range 12 tablets ( Q. individually no unit should be ( Q+15%. If fails: ------

Stage 3:12 more tablets are taken and tested. Acceptable range 24 tab. Average ( Q. but not more than 2 tablets should be not less than Q – 15%.

Interpretation: A value for 90% of 30% minutes is considered satisfactory and is an excellent goal.

USP: ---- not less than 75% dissolute in 45 minutes.