TABLET DOSAGE FORMS

TABLET:

It is a solid dosage form each containing a unit dose of one or more medicament/s. Tablets are solid, flat or biconvex discs prepared by compressing a drug or a mixture of drugs with or without suitable excipients.

Tablets may be swallowed whole or being chewed. Some are dissolved or dispersed in water before administration. Some are put in oral cavity, where the active ingredient is liberated at a predetermined rate. Implants or passeries may also be presented in form of tablet.

Tablet may vary in shape and differ greatly in size and weight depending on the amount of medicinal substance and the intended mode of administration.

Advantages and disadvantages of tablet as a dosage form:

The advantages are listed below:

I.Large scale manufacturing is feasible in comparison to other dosage forms. Therefore,economy can be achieved.

II.Accuracy of dose is maintained since tablet is a solid unit dosage form.

III. Tailor made release profile can be achieved.

IV. Longer expiry period and minimum microbial spillageowing to lower moisture content.

V. As tablet is not a sterile dosage form, stringent environmental conditions are not required in the tablet department.

VI. Ease of packaging (blister or strip) and easy handling over liquid dosage form.

VII. Easy to transport in bulk. Emergency supply supplies can be carried by patients.

VIII.Organoleptic properties (taste, appearance and odour) are best improved by coating oftablet.

IX. Product identification is easy and markings done with the help of grooved punches and printing with edible ink.

X. Different types of tablets are available like buccal, floating, colon targeting, effervescent, dispersible, soluble, and chewable, etc.

XI. In composition to parenterals dosage form, a doctor or a nurse is not required for administration. I.e. self administration is possible.

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XII. In comparison to capsules, tablets are more tamperproof.

The disadvantages are listed below:

I.It is difficult to convert a high dose poorly compressible API into a tablet of suitable size for human use.

II.Difficult to formulate a drug with poor wettability, slow dissolution into a tablet.

III. Slow onset of action as compared to parenterals, liquid orals and capsules.

IV. The amount of liquid drug (e.g. Vitamin E, Simethicone) that can be trapped into a tablet is very less.

V. Difficult to swallow for kids, terminally ill and geriatric patients.

VI. Patients undergoing radiotherapy cannot swallow tablet.

Various Types Of Tablets

1.1 ORALTABLETS FOR

INGESTION

1.1.1 Standard compressed tablets

1.1.2 Multiple compressed tablets

I. Compression coated tablet

II. Layered tablet

III. Inlay tablet

1.1.3 Modified Release tablet

1.1.4 Delayed action tablet

1.1.5 Targeted tablet

I. Floating tablet

II. Colon targeting tablet

1.1.6 Chewable tablet

1.1.7 Dispersible tablet

1.2 TABLETSUSED IN THE ORAL

CAVITY

1.2.1 Lozenges and troches

1.2.2 Sublingual tablet

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1.2.3 Buccal tablet

1.2.4 Dental cones

1.2.5 Mouth dissolved tablet

1.3 TABLETSADMINISTERED BY

OTHER ROUTES

1.3.1 Vaginal tablet

1.3.2 Implants

1.4 TABLETSUSED TO PREPARE

SOLUTION

1.4.1 Effervescent tablet

1.4.2 Hypodermic tablet

1.4.3 Soluble tablet

1.1 ORAL TABLETS FOR INGESTION

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..

1.1.1 Standard compressed tablets

These are the standard uncoated tablets made by either direct compression or wet granulation or dry granulation or double compaction.

Standard Compressed Tablet

They may be used for local action in gastro-intestinal tract or systemic action

e.g., antacids and adsorbents.

1.1.2 Multiple compressed tablets

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.

There are three categories under this class:

I.Multi Layered tablets – two to three component system.

II.Compression coated tablets – tablet within a tablet.

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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.

I. Multilayered tablets

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..

For example,

admixture containing Phenylephedrin HCL and Ascorbic Acid with Paracetamol.

Paracetamol + phenylephedrine Hydrochloride → one layer

Paracetamol + ascorbic acid → another layer.

Multilayered Tablet

II. Compression coated tablets

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.

Compression Coated Tablet

III. Inlay 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

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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.

Inlay Tablets

1.1.3 Modified Release 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.

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.

1.1.4 Delayed action tablets

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.

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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 acetatephthalate,Eudragit®, 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.

1.1.5 Targeted tablets

When we need to release the API at a specific site in the elementary tract, targeted drug delivery is a preferred option.

we have two types of tablet:

I. Gastro retentive Tablet

This type of dosage form is to be opted when APIrelease is desired in stomach (Antacids, APIs used against H.pylori infection)or site of absorption is either stomach or upper part of small intestine.

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 swellingformulation leaves stomach before it swells it’s ineffective.

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Drugs like Diazepam, Levodopa, Benserazide, and Ciprofloxacin are successfully marketed in this formulation.

II. Colonic tablets

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®S100, Eudragit® 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.

1.1.6 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.

1.1.7 Dispersible tablet

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.

1.2 Tablets used in the oral cavity

The tablets under this group are aimed release API in oral cavity or to provide local action in this region. The tablets under this category avoids first-pass metabolism, decomposition in gastric environment, nauseatic sensations and gives rapid onset of action. The tablets formulated for this region are designed to fit in proper region of oral cavity.

1.2.1 Lozenges and troches

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The tablet is a flat faced at least about 18mm in diameter and meant to suck and dissolves in the mouth. The compressed tablet is called troches and the tablets produced by fusion or candy molding process are called lozenges. Flavours and sweeteners are added to make tablets palatable. The tablet generally contains sucrose or lactose and gelatin solution to impart smooth taste. Lozenges for local action in mouth/ throat are: antiseptics, antibiotics, demulcents, antitussive agents or astringents.

1.2.2 Sublingual tablets

They are to be placed under the tongue and produce immediate systemic effect by enabling the drug absorbed directly through mucosal lining of the mouth beneath the tongue.

Sublingual Tablets

For example, Glyceryl trinitrate (vasodilator) and Isoprinosine sulphate (bronchodilator).

1.2.3 Buccal tablets

Completeness of drug absorption is desired but fast drug absorption is not intended. The tablets are designed not to disintegrate. They are flat elliptical or capsule shaped tablets as it can be easily held between gum and cheek. It’s placed near the opening of parotid duct to provide the medium to dissolve the tablet.

Since this tablet is to be kept for 30-60 minutes in oral cavity, care should be taken to see that all the ingredients are finely divided to avoid gritty or irritating sensation. This tablet is most often used when replacement hormonal therapy is to be administered. Antifungal drugs are preferred to be administered by this route.

e.g., Miconazole – under preclinical trial – still not in market.

1.2.4 Dental cones

These tables are designed to be loosely packed in the empty socket remaining following a tooth extraction.

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Dental Cones

Main purpose behind the use of this tablet is either to prevent multiplication of bacteria in the socket by employing a slow releasing antibacterial compound or to reduce bleeding by an astringent or coagulant containing tablet. It’s formulated to dissolve or erode slowly in presence of a small volume of serum or fluid over 20-40 minutes period.

1.2.5 Mouth Dissolved tablets/ Rapidly Dissolving tablets

.These kinds of tablets are preferred when fast action or relief is desired. Most commonly used drugs under this formulation are the agents active against Migraine. The tablets are designed to disintegrate as well as dissolve within one minute or some within 10 seconds of oral administration in limited quantity of saliva. They liquefy on tongue and patient swallows the liquid, without the need of water.. Urea, urethane, ammonium carbonate, ammonium bicarbonate, hexamethylene, benzoic acid, naphthalene and camphor are commonly used for sublimation processing as they they volatize rapidly. After removal by sublimation, these inert volatile substances leave the matrices with a high porosity.These dosage forms have become a delivery system of choice for most patients as they provide comfort for administration throughout the day. Pharmaceutical companies, on the other hand, benefit from value addition in terms of product life-cycle management in today’s market.

1 .3 TABLETS ADMINISTERED BY OTHER ROUTES

These tablets are administered by other route except for the oral cavity and so the drugs are avoided from passing through gastro intestinal tract. These tablets may be inserted into other body cavities or directly placed below the skin to be absorbed into systemic circulation from the site of application.

1.3.1 Vaginal tablets

This tablet undergoes slow dissolution and drug release in vaginal cavity of women. The shape is kept ovoid or pear shaped to facilitate retention in vagina. The tablet should be made compatible with plastic tube inserters which are designed to place the tablet in the upper region of vaginal tract. These tablets generally release antibacterial, antiseptics or astringents to treat vaginal infections or release steroids for systemic absorption.

1.3.2 Implants

These tablets are inserted into subcutaneous tissue by surgical procedures where they are very slowly absorbed over a period of a month or a year. A special injector with a hollow needle and plunger is used to administer the rod shaped tablet for other shapes, surgery is required. The tablets may be pellet, cylindrical or rosette shaped with diameter not more than 8mm. Mainly, these tablets are prepared to deliver growth hormones to food producing animals and ear is the preferred site for administration of the drug.

1.4 Tablets used to prepare solution

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The tablets under this category are required to be dissolved first in water or other solvents before administration or application. This solution may be for ingestion or parenteral application or for topical use depending upon type of medicament used.

1.4.1 Effervescent tablets

The oral dosage forms are the most popular way of taking medication despite having some disadvantages like slow absorption and thus onset of action is prolong. This can be overcome by administrating the drug in liquid from but, many APIs have limited level of stability in liquid form. So, effervescent tablets acts as an alternative dosage form. The tablet is added into a glass of water just before administration and the drug solution or dispersion is to be drunk immediately. The tablet is quickly broken apart by internal liberation of CO2 in water due to interaction between tartaric acid and citric acid with alkali metal carbonates or bicarbonates in presence of water.

Effervescent Tablets

Due to liberation in CO2 gas, the dissolution of API in water as well as taste masking effect is enhanced. The advantages of effervescent tablets compared with other oral dosage forms includes an opportunity for formulator to improve taste, a more gentle action on patient’s stomach and marketing aspects.The manufacturing shall be done under controlled climatic condition to avoid effervescent reaction The most commonly used effervescent tablet today is aspirin tablet.

1.4.2 Hypodermic tablets

These tablets contain one or more readily water soluble ingredients and are intended to be added in water for injection of sterile water to form a clear solution which is to be injected parenterally. They were widely used by rural physician due to its portability. One bottle of sterile water was carried by the doctor to prepare many types of injectables. It can be used for medicaments whose stability in water is very poor.

1.4.3 Soluble tablets

Tablets are pre-formed solids of uniform shape and dimensions, usually circular, with either flat or convex faces, the distance between faces being less than the diameter. Water soluble tablets are intended for application after dissolution in water and contain an active ingredient should be totally soluble in water at used concentrations.

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Soluble Tablets

PHARMACEUTICAL EXCIPIENTS FOR TABLET FORMULATION

Pharmaceutical excipient means any component other than the pharmacologically active drug which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form.

While selecting excipients for any formulation following things should be considered wherever possible: keep the excipients to a minimum in number minimize the quantity of each excipients and multifunctional excipients may be given preference over unifunctional excipients.

Fewer ingredients in the formulation are better for the following reasons: Excipients are not completely inert. Even commonly used excipients that are deemed

to be pharmaceutically inactive and nontoxic may cause adverse reactions; Less ingredient variability to influence process and product consistency;

Better economic efficiency in product manufacturing;

Less probability of chemical or physical interaction between API and excipients and among excipients.

Excipients play a crucial role in design of the delivery system, determining its quality and performance. Excipients though usually regarded as nontoxic there are examples of known excipient induced toxicities which include renal failure and death from diethylene glycol, osmotic diarrhoea caused by ingested mannitol, hypersensitivity reactions from lanolin and cardiotoxicity induced by propylene glycol.

Excipients may also be important for keeping the drug from being released too early in the assimilation process in places where it could damage tender tissue and create gastric discomfort or stomach upset.

Excipient Grades.

Many excipients for pharmaceutical use are available in different grades. These grades are differentiated frequently by means of physical and chemical characteristics.

The reason for grades is to change the performance characteristics of excipients.

Excipients are chosen in tablet formulation to perform a variety of functions like 1. For providing essential manufacturing technology functions (binders, glidants,

lubricants may be added),

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2. For enhancing patient acceptance (flavors, colourants may be added),

3. For providing aid in product identification (colourants may be added),

4. For Optimizing or modifying drug release (disintegrants, hydrophilic polymers, wetting agents, biodegradable polymers may be added),

5. For enhancing stability (antioxidant, UV absorbers may be added)

EXCIPIENT WITH THEIR FUNCTIONS IN TABLET FORMULATION

EXCIPIENT FUNCTION

Diluents or Fillers

Diluents make the required bulk of the tablet when the drug dosage itself is inadequate to produce tablets of adequate weight and size.

Binders or Granulatingagents or Adhesives

Binders add cohesiveness to powders, thus providing the necessary bonding to form granules, which under compaction form a cohesive mass or a compact which is referred to as a tablet.

DisintegrantsDisintegrant is added to facilitate a breakup or disintegration of the tablet when placed in an aqueous environment.

Antifrictional Agents

LubricantsLubricants are intended to reduce the friction during tablet formation in a die and also during ejection from die cavity.

AntiadherentsAntiadherents reduce sticking or adhesion of any of the tablet granulation or powder to the faces of the punches or to the die wall.

GlidantsGlidants promote the flow of tablet granulation or powder mixture from hopper to the die cavity by reducing friction between the particles.

MISCELLANEOUS

Wetting agentsWetting agents are added to tablet formulation to aid water uptake duringdisintegration and assist drug dissolution.

Dissolution retardants

Dissolution retardants as the name suggest, retards the dissolution of activepharmaceutical ingredient(s).

Dissolution enhancers

Dissolution enhancers as the name suggest, enhance the dissolution rate of active pharmaceutical ingredient(s).

AdsorbentsAdsorbents are capable of retaining large quantities of liquids without becoming wet; this property of absorbent allows many oils, fluid extracts and eutectic melts to be incorporated into tablets.

BuffersBuffers are added to provide suitable micro environmental pH to get improved stability and / or bioavailability.

AntioxidantsAntioxidants are added to maintain product stability, they act by being preferentially oxidized and gradually consumed over shelf life of the product.

Chelating agents Chelating agents are added to protect against autoxidation; they act by

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forming complexes with the heavy metal ions which are often required to initiate oxidative reactions.

PreservativesPreservatives are added to tablet formulation in order to prevent the growth of micro-organisms.

ColoursColours are added to tablet formulation for following purposes: to disguise off colour drugs, product identification and for production of more elegantproduct.

FlavoursFlavours are added to tablet formulation in order to make them palatable enough in case of chewable tablet by improving the taste.

SweetenersSweeteners are added to tablet formulation to improve the taste of chewable tablets.

1.Diluents (Fillers)

In order to facilitate tablet handling during manufacture and to achieve targeted content uniformity, the tablet size should be kept above 2-3 mm and weight of tablet above 50 mg. Usually the range of diluent may vary from 5-80%.

Diluents are also synonymously known as fillers. Diluents are often added to tablet formulations for secondary reasons like to provide better tablet properties such as:

i)To provide improved cohesion

ii)To allow direct compression manufacturing

iii)To enhance flow

iv)To adjust weight of tablet as per die capacity

Classification of diluents

Tablet diluents or fillers can be divided into following categories:

i)Organic materials - Carbohydrate and modified carbohydrates.

Examples:

Powdered cellulose, Microcrystalline cellulose (MCC), Starch, Starch 1500 (Pregelatinized Starch),Lactose, Sucrose, Mannitol, Sorbitol

ii)Inorganic materials – Calcium phosphates and others.

iii)Co-processed Diluents

Tablet diluent or filler may also be classified on the basis of their solubility in water as soluble and insoluble.

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INSOLUBLE TABLET DILUENTS SOLUBLE TABLET DILUENTS

Starch

Powderedcellulose

Microcrystallinecellulose

Calcium phosphates, etc.

Lactose

Sucrose

Mannitol

Sorbitol,etc.

Selection of diluent should be done after considering properties of diluent such as:

Compactibility, flowability, solubility, disintegration qualities, hygroscopicity, lubricityand stability.

Co-processed diluents:

Co-processing means combining two or more materials by an appropriate process. The products so formed are physically modified in such a special way that they do not loose their chemical structure and stability. Now a days direct compression technique has been one of the well-accepted methods of tablet manufacture.

2.Binders

Binder is one of an important excipient to be added in tablet formulation. In simpler words, binders or adhesives are the substances that promote cohesiveness. It is utilized for converting powder into granules through a process known as Granulation. Granulation is the unit operation by which small powdery particles are agglomerated into larger entities called granules.

Classification of Binders

Sugaras Natural Binders Synthetic/Semisybthetic Polymer

Sucrose Acacia Methyl Cellulose

Liquid glucose Tragacanth Ethyl Cellulose

Gelatin Hydroxy Propyl Methyl Cellulose ( HPMC)

Starch Paste Hydroxy Propyl Cellulose

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Pregelatinized Starch Sodium Carboxy Methyl Cellulose

Alginic Acid Polyvinyl Pyrrolidone (PVP)

Cellulose Polyethylene Glycol (PEG)

Polyvinyl Alcohols

Polymethacrylates

Characteristics of Commonly Used Binder

BINDERSPECIFIED

CONCENTRATION COMMENTS

Starch Paste 5-25%w/w - Freshly prepared starch paste is used as a binder.

Pregelatinized Starch 

(PGS)[Partially and Fully PGS

5-10%w/w(Direct Compression)

5-75%w/w(Wet Granulation )

- It is starch that have been processed chemically and/or mechanically to ruptureall or part of the granules in the presence of water and subsequently dried.- It contains 5% free amylose, 15% free amylopectin and 80% unmodified starch.- used as tablet binder, diluent, disintegrant and flow aid.- They enhance both flow and compressibility andcan be used as binders in Direct Compression aswell as Wet Granulation.- High purity PGS allow simplified processing as they swell in cold water and therefore reduce time/costs compared with traditional starch pastepreparation.

Hydroxypropyl Methyl Cellulose (HPMC)

2-5%w/w- Comparable to Methyl Cellulose.- Used as a binder in either wet or dry granulation processes.

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Polyvinyl Pyrrolidone (PVP)

0.5-5%w/w

- Soluble in both water and alcohol.- Used in wet granulation process.- added to powder blends in the dry form and granulated in situ by the addition of water, alcohol or hydroalcoholic solution.- Binder for chewable tablets.- The drug release is not altered on storage.

Polyethylene Glycol (PEG) 6000

10-15%w/w

        Used as a meltable binder.        Anhydrous granulating agent where water or

alcohol cannot be used .         It may prolong disintegration time when

concentration is 5% or higher   - It improves the plasticity of other binders.

3.Disintegrants

.Disintegrants, an important excipient of the tablet formulation, are always added to tablet to induce breakup of tablet when it comes in contact with aqueous fluid and this process of desegregation of constituent particles before the drug dissolution occurs, is known asdisintegration process and excipients which induce this process are known as disintegrants.

The objectives behind addition of disintegrants are to increase surface area of the tablet fragments and to overcome cohesive forces that keep particles together in a tablet.

.List Of Disintegrants

DISINTEGRANTS CONCENTRATIONIN GRANULES (%W/W)

SPECIAL COMMENTS

Starch USP 5-20 Higher amount is required, poorly compressible

Starch 1500 5-15 -

Avicel®(PH 101,PH 102)

10-20 Lubricant properties and directly compressible

Solka floc® 5-15 Purified wood cellulose

Alginic acid 1-5 Acts by swelling

Na alginate 2.5-10 Acts by swelling

Explotab® 2-8 Sodium starch glycolate, superdisintegrant.

Polyplasdone®(XL) 0.5-5 Crosslinked PVP

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Amberlite® (IPR 88) 0.5-5 Ion exchange resin

Methyl cellulose, Na CMC,HPMC

5-10 -

AC-Di-Sol® 1-3 Direct compression

2-4 Wet granulation

Carbon dioxide _ Created insitu in effervescenttablet

Superdisintegrants

As day’s passes, demand for faster disintegrating formulation is increased. So, pharmacist needs to formulate disintegrants i.e. Superdisintegrants which are effective at low concentration and have greater disintegrating efficiency and they are more effective intragranularly. But have one drawback that it is hygroscopic therefore not used with moisture sensitive drugs.

List Of Superdisintegrants

SUPERDISINTEGRANTS EXAMPLE OF MECHANISM OF ACTION

SPECIAL COMMENT

Crosscarmellose®

 

Ac-Di-Sol®

 

Nymce ZSX®

Primellose®

Solutab®

 

Vivasol®

Crosslinked cellulose

-Swells 4-8 folds in < 10 seconds.

-Swelling and wicking both.

-Swells in two dimensions.

-Direct compression or granulation

 

 

 

-Starch free

Crosspovidone

Crosspovidon M®

Kollidon®

Polyplasdone®

Crosslinked PVP -Swells very little and returns to original size after compression butact by capillary action

-Water insoluble and spongy in nature so get porous tablet

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Sodium starch glycolate

Explotab®

Primogel®

Crosslinked starch -Swells 7-12 folds in <30seconds

-Swells in three dimensions and high level serve as sustain releasematrix

Alginic acid NF

Satialgine®

Crosslinked alginic acid

-Rapid swelling in aqueous medium or wicking action

-Promote disintegration in both dryor wet granulation

Soy polysaccharides

Emcosoy®

Natural super disintegrant

  -Does not contain any starch or sugar. Used in nutritional products.

Effect of surfactants on DISINTEGRATION:

Surfactant Remarks

Sodium lauryl sulfate Good-various drugs

Poor - various drugs

Polysorbate 20 Good

Polysorbate 40 & 60 Poor

Polysorbate 80 Good

Tweens Poor

Poly ethylene glycol Poor

(Good – decrease in disintegration time, Poor – increase in disintegration time)

Antifriction Agents :

Lubricants,Antiadherents and Glidants

Lubricants

Lubricants work by reducing friction by interposing an intermediate layer between the tablet constituents and the die wall during compression and ejection and also between particle during compression.

Classification of Lubricants

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Lubricant are classified (based on their water solubility) into two groups :

1. water insoluble 2. water soluble

Insoluble Lubricants Concentration Comments

Stearates(Magnesium Stearate, Calcium Stearate, Sodium stearate)

0.25-1Reduce tablet strength and prolong disintegration

Talc 1-2Insoluble but not hydrophobic, moderately effective.

Sterotex 0.25-1 -

Waxes 1-5 -

Stearowet 1-5 -

Glyceryl behapate (Compritol 888)

1-5 Both lubricant and binder

Liquid paraffin Up to 5 Dispersion problem, inferior to stearates

List Of Soluble Lubricants

Water Soluble Lubricants Concentration range (%w/w)

Boric acid 1

Sodium benzoate 5

Sodium oleate 5

Sodium acetate 5

Sodium lauryl sulfate (SLS) 1-5

Magnesium lauryl sulfate (MLS) 1-2

Antiadherents 

Some material have strong adhesive properties towards the metal of punches and dies or the tablet formulation containing excessive moisture which has tendency to result in picking and sticking problem. Therefore, antiadherents or anti-sticking agents prevent adhesion of the tablet surface to the die walls and the punches. Talc, magnesium stearate and corn starch have excellent antiadherent properties. Vegan had suggested that silicon oil can be used as antiadherent.

List Of Antiadherents

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AntiadherentConcentration

Range (%w/w)

Comments

Talc 1-5 Lubricant with excellent antiadherents properties

Corn starch 3-10 Lubricant with excellent antiadherents properties

Colloidal silica 0.1-0.5Does not give satisfactory results due to small surface area. Cab-O-Sil® and Syloid®

DL-Leucine 3-10Water soluble lubricant; excellent antiadherents properties

Sodium Lauryl Sulfate  less than 1 Antiadherents with water soluble lubricant

Stearates less than 1 Antiadherents with water insoluble lubricant

Glidants 

Glidants are added to the formulation to improve the flow properties of the material which is to be fed into the die cavity and aid in particle rearrangement within the die during the early stages of compression. If the flow properties are extremely poor then glidants are ineffective and consideration of force free mechanisms may be necessary. The effect of glidants on the flow of the granules depends on the shape and size of the particle of the glidant and the the granule.

Examples:

The commonly used glidants are talcum, starch, colloidal silica silicates, stearates calcium phosphate, etc.

Wetting Agents

Wetting Agents in tablet formulation aid water uptake and thereby enhancing disintegration and assisting in drug dissolution.

Incorporation of anionic surfactant like Sodium Lauryl Sulphate (SLS) is known to enhance the dissolution.It has been established that SLS improves permeation of drug through biological membrane since it destroys the path through which drug has to pass and thus minimizing the path length for the drug to travel.

Wetting agents are mainly added when hydrophobic drug is to be formulated into tablet.

Examples:

SLS, Sodium diisobutyl sulfosuccinate are used as wetting agent in tablet formulation.

Dissolution Retardants

Dissolution Retardants are incorporated into tablet formulation only when controlled release of drug is required.

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Examples:

Waxy materials like stearic acid and their esters can be used as dissolution retardants.

Dissolution Enhancers

They are the agents that alter the molecular forces between ingredients to enhance the dissolution of solute in the solvent.

Examples:Fructose, Povidone, Surfactants are used as dissolution enhancer.

Adsorbents

Adsorbents are the agents that can retain large quantities of liquids. Therefore liquids like Vitamin E can be incorporated into tablets by addition of adsorbents ..

Examples:

Most commonly used adsorbents in pharmaceuticals are anhydrous calcium phosphate, starch, magnesium carbonate, bentonite, kaolin, magnesium silicate, magnesium oxide and silicon dioxide

Buffers

Buffers are added to maintain a required pH since a change in pH may cause significant alteration in stability.

Examples:

Most commonly used buffering agent in tablet formulation includes sodium bicarbonate, calcium carbonate, and sodium citrate.

Antioxidants

Antioxidants are added in tablet formulation to protect drug from undergoing oxidation. Antioxidants undergo oxidation in place of drug or they block the oxidation reaction or they act as synergists to other antioxidants. Chelators may also act as antioxidant.

Examples:

Most commonly used antioxidants include ascorbic acid and their esters , alpha-tocopherol , ethylene diamine tetra acetic acid , sodium metabisulfite , sodium bisulfite , Butylated Hydroxy Toluene (BHT) , Butylated Hydroxy Anisole (BHA) , citric acid , and tartaric acid .

Chelating Agents

Chelating agents tend to form complexes with trace amount of heavy metal ions inactivating their catalytic activity in the oxidation of medicaments.

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Examples:

Ethylenediamine tetracetic acid and its salts, Dihydroxy Ethyl Glycine, Citric Acid and Tartaric Acid are most commonly used chelators.

Preservatives

Preservatives may be a part of tablet formulation in order to prevent the growth of microorganisms in tablet formulation.

Examples:

Parabens like methyl, propyl, benzyl, butyl p-hydroxy benzoate are used as preservatives.

Colourants

Colourants neither contribute to therapeutic activity nor do they improve product bioavailability or stability but are incorporated into tablets for purposes like to facilitate identification of similar looking products with in a product line to avoid mix ups, to facilitate identification of products of similar appearance that exist in the lines of different manufacturers, to overcome colour change on aging, disguising of off-colour drugs, for brand image in the market, to enhance the aesthetic appearance of the product to have better patientacceptance.

Some Commonly Used Pharmaceutical Colourants (Synthetic)

FD &C COLOUR

COMMONNAME

Red 3 Erythrosine

Red 40 Allura red AC

Yellow 5 Tartrazine

Yellow 6 Sunset Yellow

Blue 1 Brilliant Blue

Blue 2 Indigotine

Green 3 Fast Green

Flavours

Flavors are commonly used to improve the taste of chewable tablets as well as mouth dissolved tablets.

Flavors are incorporated either as solids (spray dried flavors) or oils or aqueous (water soluble) flavors.

Sweeteners

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Sweeteners are added primarily to chewable tablets.

Some Of The Sweeteners Used In Tablet Formulation

NATURALSWEETENERS

ARTIFICIALSWEETENERS

Mannitol

Lactose

Sucrose

Saccharin

Cyclamate

Aspartame

GRANULATION TECHNOLOGY ON LARGE SCALE BY VARIOUS TECHNIQUES

Physics of compression : 

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A tablet is formed by reducing tile volume of a set of autonomous particles until they are consolidated into a solid body

Tablet consolidation occurs when the punches and die go between two compression rollers

The complete tablet manufacturing cycle occurs in four steps:

(i) the die is filled,

(ii ) the fill weight is adjusted,

(iii) the tablet is compacted. and

(iv) the tablet ejected from the die .

From a material point of view, a compaction process is normally described by a series of sequential phases

Compression : 

Tableting procedure

Filling

Compression

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Ejection

Compression process: 

Filling By gravitational flow of powder from hopper via the die table into die. The die

is closed at its lower end by the lower punch. Compression

The upper punch descends and enters the die and the powder is compressed until a tablet is formed.

During the compression phase, the lower punch can be stationary or can move upwards in the die.

After maximum applied force is reached, the upper punch leaves the powder i.e. the decompressed phase.

Ejection During this phase, the lower punch rises until its tip reaches the level of the

top of the die. The tablet is subsequently removed from the die and die table by a pushing device.

Common stages occurring during compression

Stage 1: Top punch is withdrawn from the die by the upper cam. Bottom punch is low in the die so powder falls in through the hole and fills the die

Stage 2: Bottom punch moves up to adjust the powder weight-it raises and expels some powder

Stage 3: Top punch is driven into the die by upper cam. Bottom punch is raised by lower cam. Both punch heads pass between heavy rollers to compress the powder

Stage 4: Top punch is withdraw by the upper cam. Lower punch is pushed up and expels the tablet. Tablet is removed from the die surface by surface plate

Stage 5: Return to stage 1

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Procedure for compression

Granulation stored in hopper-

Transferred to feed frame Which having several compartments.

Spread granule into the die Pull down cam guides the lower punch.

Allowing dies to overfill Punches pass over a weight control cam.

It reduce fill in die to desired amount

Swipe off blade remove excess granulation.

The lower punches travel over the lower compression roll while simultaneously the upper punches ride beneath the upper compression roll

The upper punches enter a fixed distance into the dies, while the lower punches are raised to squeeze and compact the granulation within the dies

After the moment of compression, the upper punches are withdrawn as they follow the upper punch raising cam

The lower punches ride up the cam which brings the tablets flush with or slightly above the surface of the dies

At the same time, the lower punches re-enter the pull down cam and the cycle is repeated. The tablets strike a sweep off blade affixed to the front of the feed frme and slide down a chute into a receptacle

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TABLET DEFECTS : THE CAUSE AND THE REMEDY

MOTTLING

Unequal distribution of colour on the tablet surface with light and dark areas standing out in an otherwise uniform coloured surface

Cause :• Variation in the colours of ingredients (drug and other additives)• Drugs with degradation nature and have different coloured degraded products• Migration of dye to the surface of granulation during drying. At high temperature dyes are easily migrate to surface and spread to upper surface.• Uneven distribution of colored adhesive gel solutions resulting in precipitationRemedy:• By using bright coloring agent that will mask all the color variationsof the ingredients• Proper drying by reducing the drying temperature• Colored adhesive gel solutions must be added when they are hot too much cooler powder mixtures to avoid precipitation • It is better to incorporate fine powder adhesives like acacia and tragacanth into product before adding the granulating fluid• By changing the solvent system or binder system• Grinding to small particle size

CAPPING and LAMINATINGCAPPING : Capping Continuously high speed of tablet machine and high degree of compression setting makes tablet to separate main surface into individual surface. Avoid defective punches and dies. High temperature adjustment also favor capping. Distance between upper and lower punches will entrap air is bone factor for capping. Fine particles were susceptible than coarse particles will affect ideality of tablets. Capping minimized by keeping the feed material with cohesive nature.

LAMINATION : Lamination It is major problem among of all defects. Occur upon storage period, or soon after compression. Air entrapment between layers of tablet. Low levels of binding agent. It minimized by improving lubricant concentration. Change the method of granulation. By direct compression technique it is prevented to some extent. Use always dry material (feed).

Causes Remedy

Air entrapment in the tablet among granules or amongparticles

By pre-compression, Reducing final compression, Minimizingtableting rate

Deformational properties of formulation during and after compression

Increasing stress relaxation time

Improper/Deep concave punches Better to use flat punches

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Over dried granules (Due to lack of cohesion)By maintaining moisture levels using hygroscopic materialslike MC (Methyl Cellulose), Sorbitol, PEG 4000 (Polyethylene glycol) etc.

Improper tooling: Concave edges of punches turning

claw shaped Greater radius of curvature of punch

face

Dies developing a wear ring shape

Improper adjustment of sweep off blade

Less rise of lower punch during ejection of table

Proper tooling: Checking of punches and replacing

them Proper checking and replacing them

Turning the die over so that compression occurs in anunworn area above ring

Proper setting of sweep off blade & lower punch rise

Poor compressibility observed during direct compression technique

Relative compressibility is to be maintained

PICKING Adherence of the tablet material from the surface of a tablet by a punchCauses:Because of engraving or embossing or debossing on the punch tips like small enclosed areas in the letters like “A”, “B”, “D”, “O”, “Q” etc

Remedy:• Lettering should be designed as large as possible, even the tablet size can be increased by reformulation• Colloidal silica can be added as polishing agent to formula• Using additional binder to increase cohesiveness of granules and thereby causing decreased adherence• Plating of punch faces with a chromium material to obtain smooth face which is non-adherent• Avoid wet granules.

STICKING

Sticking always occurs in low melting point substances, and moisture supports this defects, lower the speed up of upper and lower punch leads to weight variation of tablets. It produces rough and chipping surface tablets. It develops material on both punches. Lack of drying is basis of this one.

Causes:• Presence of low melting point substances in the formula ex. Stearic acid, PEG (Polyethylene glycol) etc , which gets soften due to compressive heat• Excessive moisture in the granules

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Remedy:• Partial or complete substitution of low melting point components with high melting point materials in the formula• Proper drying of the granules to remove excessive moisture• Selection of Binding agent is essential to solve sticking.• Ideal selection of lubricant in desired proportion will minimized this problem.

WEIGHT VARIATION (Granule size and size distribution)

Causes:• Improper blending of granules• Lack of sufficient of lubricant .• Abnormal uniform mixing of all excipients. • Improper tool setting of machine. Hi-speed running of machine. • improper glidant selection. • Improper drying making tablet with different weight. • Proportion of small to large granules influence the die filling capacity and thereby results in weight variation of tablets• If large granules are used to fill small die cavities, even a small difference in granules results in high percent weight variation of tablets

Remedies: • Uniform size distribution (Narrow) and smaller granular size is preferable

POOR FLOW

Causes:• Improper design of hopper• Poor flow of granules• Bridging/arching and rat-holing of granules at the bottom of the hopper• Segregation or stratification of particles due to use of flow promotingdevices like vibrators• Surges of excessive flow above the hopperRemedies:• Flow can be improved by using glidants like talc, colloidal silica etc.• By proper design of the hopper• By using flow enhancing devices like vibrators• By preparing uniform sized and shaped granules

POOR MIXING

Causes:• Improper mixing of ingredients like glidants and lubricants useful forproper flow and punching• Insufficient or inadequate time of mixingRemedy:• Proper mixing by maintaining adequate time and using suitable mixer

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PUNCH VARIATION

Cause:• Unequal lengths of lower punches which results in variations of granularvolume filled in dieRemedy:• Proper tooling by using good and uniform sized punches

HARDNESS VARIATION

Causes:• Due to weight variation in granules filled in die• Space between lower and upper punchesRemedy:• Proper tooling of machine

DOUBLE IMPRESSION

Cause:Uncontrolled movement of punches with engravings on themRemedy:Using anti-turning devices

TABLET COATING:

Coating is performed for the following reasons:

1. Providing controlled, continuous release or reduce the frequency of drug dosing

2. Maintaining physical or chemical drug integrity

3. Enhancing product acceptance and appearance

4. Protects the tablet (or the capsule contents) from stomach acids

 5. Protects the stomach lining from aggressive drugs such as enteric coated aspirin

6. Provides a delayed release of the medication

 7.Maintains shape of the tablet.

ASPECTS OF TABLET COATING

I.   Therapy

i) Avoid irritation of oesophagus and stomach

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ii) Avoid bad taste

iii) Avoid inactivation of drug in the stomach

iv) Improve drug effectiveness

v) Prolong dosing interval

vi) Improve dosing interval

vii) Improve patient compliance

II.  Technology

i) Reduce influence of moisture

ii) Avoid dust formation

iii) Reduce influence of atmosphere

iv) Improve drug stability

v) Prolong shelve life

III. Marketing

i) Avoid bad taste

ii) Improve product identity

iii) Improve appearance and acceptability

Basic principle of tablet coating

Basic principles involve

i) Insulation which influences the release pattern as little as possible and does not markedlychange the appearance.

ii) Modified release with specific requirement and release mechanism adapted to body function in the digestive tract

iii) Colour coating which provides insulation or is combined with modified release coating.

TYPE OF TABLET COATING PROCESS

Sugar coating

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Compressed tablets may be coated with coloured or uncoloured sugar layer. The coating iswater soluble and quickly dissolves after swallowing. The sugarcoat protects the enclosed drug from the environment and provides a barrier to objectionable taste or order. The sugar coat also enhances the appearance of the compressed tablet and permit imprinting manufacturing’s information. Sugar coating provides a combination of insulation, taste masking, smoothing the tablet core, colouring and modified release. The disadvantages of sugar coating are the time and expertise required in the coating process and thus increases size, weight and shipping costs.

Sugar coating process involves five separate operations:

I. Sealing/Water proofing: provides a moisture barrier and harden the tablet surface.

II. Subcoating: causes a rapid buildup to round off the tablet edges.

III. Grossing/Smoothing: smoothes out the subcoated surface and increases the tablet size topredetermine dimension.

IV. Colouring: gives the tablet its colour and finished size.

V. Polishing: produces the characteristics gloss.

Enteric coating

This type of coating is used to protect tablet core from disintegration in the acid environment of the stomach for one or more of the following reasons:

i) To prevent degradation of acid sensitive API

ii) To prevent irritation of stomach by certain drugs like sodium salicylate

iii) Delivery of API into intestine

iv) To provide a delayed release component for repeat action tablet

Several kinds of enteric layer systems are now available

One layer system - The coating formulation is applied in one homogeneous layer,which can be whites-opaque or coloured. Benefit is only one application needed.

Two layer system - To prepare enteric tablets of high quality and pleasing appearance the enteric formulation is applied first, followed by colouredfilm. Both layers can be of enteric polymer or only the basic layer contains enteric polymer while top layer is fast disintegrating & water-soluble polymer

Controlled release coating

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Polymers like modified acrylates, water insoluble cellulose (ethyl cellulose), etc. used for control release coating.

Specialized coating

Compressed coating

This type of coating requires a specialization tablet machine. Compression coating is not widely used but it has advantages in some cases in which the tablet core cannot tolerate organic solvent or water and yet needs to be coated for taste masking or to provide delayed or enteric properties to the finished product and also to avoid incompatibility by separating incompatible ingredients.

Electrostatic coating

Electrostatic coating is an efficient method of applying coating to conductive substrates. A strong electrostatic charge is applied to the substrate. The coating material containing conductive ionic species of opposite charge is sprayed onto the charged substrate. Complete and uniform coating of corners and adaptability of this method to such relatively nonconductive substrate as pharmaceutical is limited.

Dip coating

Coating is applied to the tablet cores by dipping them into the coating liquid. The wet tablets are dried in a conventional manner in coating pan. Alternative dipping and drying steps may be repeated several times to obtain the desired coating. This process lacks the speed, versatility, and reliability of spray-coating techniques.

Vacuum film coating

Vacuum film coating is a new coating procedure that employs a specially designed baffled pan. The pan is hot water jacketed, and it can be sealed to achieve a vacuum system. The tablets are placed in the sealed pan, and the air in the pan is displaced by nitrogen before the desired vacuum level is obtained. The coating solution is then applied with airless spray system..

Equipments

Three general types of equipments are available

1. Standard coating pan

e.g., Pellegrin pan system

Immersion sword system

Immersion tube system

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2. Perforated pan system

e.g., Accela cota system

Hicoater system

Glattcoater system

Driacoated system

3. Fluidized bed coater

EVALUATION OF TABLET

Before a tablet is released out into the market it has to pass a few quality checks, which is mandatory. Evaluation of tablet includes the assessment of tablets physical, chemical and biological properties. To studies them the following test are formulated

 1)      GENERAL APPEARANCE:

         General appearance is the physical appearance of the tablet it has two aspects to address

         First one is the patient compliance, if the tablet is appearance is legible and good, it improves the patient compliance.

         The second one Is for the manufacturer, it helps him in trouble free manufacturing if there is tablet to tablet, batch to batch and lot to lto uniformity of tablet.

         General appearance would include a number of aspects like, size, shape, odor, taste, texture, legibility, identifying marks.

2)      SIZE AND SHAPE:

         Different shapes and sizes of tablet are available in the market they are manufactured in order to differentiate them based on their purpose of use and quantity of active ingredient, and the age group of the patient who is going to be administered with the drug.

         Heart shape tablet signify that they are for the cardiac problems, small toy shape, tablet are manufactured in order to attract children etc.

         The shape and size of a tablet would vary based on tooling used in the tablet manufacturing.

         The prime consideration here would be the crown size, because if the concavity is very high it many lead to capping, or chipping problem.

         The crown size is measured by using micrometer, and sliding caliper scale is used to measure the size of 5 to 10 tablets at a time.

3)      UNIQUE IDENTIFICATION MARK:

         Pharmaceutical manufacturers in order to differentiate their product from the other manufacturers emboss a special marking g on the tablet. The marking can be an embossing, engraving or printing.

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         Apart from the company marking there can be imprints which include product code, product name, product potenct,

         But care must be taken that the letters that are embossed on the tablet are properly printed without double impression.

 

4)      ORGANOLEPTIC PROPERTIES:

         For rapid identification of the tablet and consumer acceptance the tablet are given a specific colour, the colour of the tablet will enable the manufacturer form differentiating the tablet lot.

         The uniformity of the colour is important parameter here, the tablet should be free form mottling.

         The colour uniformity and gloss of the tablet is evaluated by using reflectance spectrophotometer, tristimulus colorimetric measurement, microreflectance photometer.

         The odour of the tablet indicate the stability of the tablet, for example, the smell of acetic acid in aspirin tablet indicates that the tablet is degraded

         The taste of the tablet is also an important factor, every company has a taste panel which enalise the taste of the tablet, machines are yet to be discovered which can provide the report of the taste.

 

TABLET THICKNESS

Tablet thickness is determined by 1) the diameter of die. 2) the amount of fill permitted to enter the die. 3) the compatability of the fill material. 4) the force or pressure applied during compression.

The tableting press affects not only tablet thickness but also tablet hardness.

Tablet thickness may be measured by hand gauge or automated equipment.

Tablet hardness: Force required to break a tablet in diametric compression test. 1) The greater the pressure applied, the harder the tablets. 2) The hardness required by different tablets a) Lozenges and buccal tablets: hard (dissolve slowly) b) The tablets for immediate drug release: soft (dissolve slightly faster) 3) Hardness is function of Die fill a) At constant compression force, hardness increases with increase in die fill

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b) At constant die fill Hardness increases & thickness decreases with Increase in compression force. MEASUREMENT a) Subjective: Breaking the tablet between 2nd & 3rd fingers with thumb as fulcrum: ‘sharp snap’ deemed to have acceptable strength. b) Special dedicated hardness testers (Monsanto, Pfizer, etc) Generally used Hardness testers are: Monsanto Tester Strong-Cobb Tester Pfizer Tester Erweka Tester Schleuniger Tester

Hardness for compressed tablet is 5 to 8 kg

  Pfizer tester Monsanto tester

 

 

Erweka tester Schleunigertester

TABLET FRIABILITY

Friability of a tablet can determine in laboratory by Roche friabilator. This consist of a plastic chamber that revolves at 25 rpm, dropping the tablets through a distance of six inches in the friabilator, which is then operate for 100 revolutions. The tablets are reweighed. Compress tablet that lose less than 0.5 to 1.0 % of the tablet weigh are consider acceptable. If capping is observed on friability testing, the tablets should not be considered for commercial use.

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Roche friabilator

 6)      WEIGHT VARIATION:

         Weight variation test is performed to check that the manufactured tablets have an uniform weight.

         As per USP twenty tablets are weighed individually and an compendia weight is taken, the average weight is obtained by dividing the compendia weight by 20, now the average weight is compared to the individual weight of the tablet,

         For a tablet to pass the test not more than 2 tablets should lie out of the specified percentage and if no tablet differs by more than two times the percentage limit.

Sno Average weight Maximum percentage difference allowed

1 130 or less 10

2 130-324 7.5

3 More than 324 5

7.CONTENT UNIFORMITY TEST

Applies to potent drug of low dose

Method:

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Tablet sample----- 30 A)10 tablets Assayed individually------- at least 9 should be 85-115%, one tablet may 75-125 %------ pass test B)20 tablets Assayed---- All should be 85-115% then pass test If any deviation whole batch fails in test Content non uniformity is due to- Non uniform distribution of drugs in powder or granules -Segregation -weight variation (only gives approx hint of content non uniformity)

8.TABLET DISINTEGRATION TEST

The significance of tablet disintegration : Prerequisite for dissolution and bioavailability It is in-process and finished product QC tool Testing apparatus: USP disintegrating test apparatus:

-6 glass tubes 3 inch long dia=2.15mm -open at top, #10 screen at bottom -1 L beaker, kept at 37 + 2 C -28-32 cycles per second

If the tablets are floating use disc having 1gm wt

Procedure : 6 Tablets placed in each of the tubes, with plastic discs on them. Simulated GF/ IF/ Distilled water/ any sp.medium. Time required for complete disintegration of tablets and fragments to pass # 10 sieve. If any residue remains, it must have a soft mass, not firm core. Normally Time limit is 5 – 30 mins.

Limitation as per IP

Conduct 6 tablets at time note done the average time if any tablet is more than Specified time repeat the tests with 12 tablets. Out of 18 tablet 16 tablets should pass.

The disintegration of enteric-coated tablets:

1) To be tested in simulated gastric fluid (SGF) for one hour after which no sign of disintegration, cracking, or softening must be seen. 2) To be tested in simulated intestinal fluid (SIF) for the time (usually, 1 h) stated in the individual monograph

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9.TABLET DISSOLUTION TEST

The importance of in vitro dissolution test

To guide the formulation and product development process toward product optimization To monitor the performance of manufacturing process To assure bioequivalence from batch to batch As a requirement for regulatory approval for product marketing for products registered with the FDA and regulatory agencies of other countries.

The formulation and manufacturing factors affecting the dissolution of a tablet

The particle size of the drug substance The solubility and hygroscopicity of the formulation The type and concentration of the disintegrant, binder and lubricant used The manufacturing method, particularly, the compactness of the granulation and the compression force

         Different types of apparatus are used to study the dissolution test of the tablet. As per IP apparatus I (paddle) and apparatus II(basket) are used.

         But as per USP dissolution apparatus used areUSP 30 classification

                                                             

i.      Rotating Basket (Ph.Eur./BP/JP)                                                            ii.      Paddle (Ph.Eur./BP/JP)                                                          iii.      Reciprocating Cylinder (Ph.Eur.)                                                          iv.      Flow Through Cell (Ph.Eur./BP/JP)                                                            v.      Paddle Over Disk (Ph.Eur.)                                                          vi.      Rotating Cylinder (Ph.Eur.)                                                        vii.      Reciprocating Holder

         The dissolution time and rate is compared to the values mentioned in the monograph.

The in-process variables TABLET DISSOLUTION TEST USP dissolution apparatus 2 PADDLE METHOD USP dissolution apparatus 1 BASKET METHOD

Apparatus 1 and 2 in IP/USP

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are used principally for immediate release solid dosage forms consist of a variable speed stirrer motor, a cylindrical stainless steel basket on a stirrer shaft (apparatus 1) or a paddle as the stirring element (apparatus 2), a 1000-ml vessel of glass fitted with a cover having a center port for the shaft of the stirrer, and three additional ports, two for the removal of samples, one for the placement of a thermometer, and a suitable water bath to maintain the temperature of the dissolution medium in the vessel.

Test method (24 TABLETS)

a) A volume of the dissolution medium is placed in the vessel and allowed to come to 37oC±0.5oC. b) The stirrer is rotate at the specified speed. c) At stated intervals, samples of the medium are withdrawn for chemical analysis time limitation is 60 minutes

Requirement for rate of dissolution

Stage 1 T1; six tablets are tested & accepted if each of them is not less than the monograph specified limit +5% (p+5%).

Stage 2 T2; If the dosage form fails T1 then additional six tablets are tested. The results is acceptable if the average of the 12 tablets is greater than or equal to P , and none of them is less than( P-15%).

Stage 3 T3; If the tablets fails the test, then additional twelve (12) tablets are tested & are accepted if the average of all the twenty four is greater than or equal to P, If not more than two are two are less than P-15% and none of them is less than P-25%.

Interpretation of data

The results are expressed in terms of concentration of the drug versus time

The value for t50%,t90% and % dissolved in 30 minutes are used guide lines.

A value of t90% at 30 minutes considered at be satisfactory

As per USP t 75% for tablets should be 45 minutes.

Inconsistencies in dissolution occur not between dosage units from the same production batch, but rather between batches or between products from different manufacturers.

References1.Lachman L., Liberman H. and Kanig J.; The Theory and Practice ofIndustrial Pharmacy; Third Edition: 293-345, 346-373.

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2.Aulton M.; Pharmaceutics: The Science of Dosage Form Design;International Student Edition: 304-321, 347-668.

3.Lachman L., Liberman L. and Schwartz J.; Pharmaceutical Dosage Forms:Tablets; Second Edition : Volume I.

4.Remington J., Remington: The Science and Practice of Pharmacy; NineteenthEdition: Volume II : 1615-1641.

5. Banker G. and Rhodes C.;Drug and Pharmaceutical Sciences: Modern Pharmaceutics; Third Edition; Volume72: 333-394.

6. Martin E.; Dispensing ofMedication; Edition Seventh: 740-741.

7. Lachman L., Liberman L. and Schwartz J.;Pharmaceutical Dosage Forms: Tablets; Second Edition : Volume II.

8. Indian Pharmacopoeia; 1996.

9.British Pharmacopoeia;2001.

10. The United State Pharmacopoeia 24; The National Formulary 19; 2000.

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