Nahla Barakat, PhD King Saud University Dept. of Pharmaceutics 1431/1432

Tablets Tablets are oral solid unit dosage form of medicaments with or without suitable diluents and prepared either by molding or compression. They are solid, flat or biconvex disc in shape. They vary greatly in shape, size and weight which depend upon amount of medicament used and mode of administration. They also vary in hardness, thickness, disintegration and dissolution characteristics and in other aspects depending upon their intended use and method of manufacture They are used for local & systemic effect. Usually used for oral administration 10/12/20154 Introduction

Tablets are popular due to: 1.A convenient and safe way of drug administration. 2.Compared to liquid dosage form they are more physically & chemically stable. 3.Enables more accurate dosing, easy to use, handle by the patient 4.Can be prepared in different ways according to their use. 5. Tablets are provides a sealed covering which protects the tablets from atmospheric conditions like air, moisture and light etc. 6. The manufacturing cost of tablets is low as compared to other dosage form. 7. The unpleasant taste and odor of medicament(s) can be easily masked by sugar. 8.Tablets provide administration of even minute dose of drug in an accurate amount. 9. Tablets are formulated as a special release of products such as enteric or delayed release products. 10/12/20155

Disadvantages of tablet: 1.It’s not suitable for poorly water-soluble or poorly absorbable drugs, less bioavailability. 2.Enhances local irritant effect of some drugs or cause harm to the gastrointestinal mucosa. 3.Some drugs resist compression into dense compacts. 4. Hygroscopic drugs are not suitable candidate for compressed tablets. 5. Drugs having bitter taste and unpleasant odor requires special treatment like coating or encapsulation which may increase their production cost. 6. Drugs that are sensitive to oxygen or may also require special coating. 10/12/20156

7 General properties of Tablet dosage forms: 1.A tablet should have elegant product identity while free of defects like chips, cracks, discoloration, and contamination. 2.Should have sufficient strength to withstand mechanical shock during its production packaging, shipping and dispensing. 3.Should have the chemical and physical stability to maintain its physical attributes over time 4.The tablet must be able to release the medicinal agents in a predictable and reproducible manner. 5.Must have a chemical stability over time so as not to follow alteration of the medicinal agents. 6.The appearance of the tablet should be elegant and its weight, size and appearance should be consistent

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9 1- Disintegrating tablets Most common type is intended to be swallowed and releases the drug in a relatively short time after disintegration and dissolution thus fast & complete drug release in vivo (conventional or plain tablets). A disintegrating tablets include the following types of excipients: filler (if the dose of drug is low), disintegrant, binder, glidant, lubricant and antiadherent. Steps of drug release from disintegrating tablets

10/12/ Conventional tablet may be single layer or multilayer. Multilayer tablets are prepared by repeated compression of powders and are made primarily to separate incompatible drugs from each other. Tablet, multilayer: This is a solid dosage form that contains medicinal substances that have been compressed to form a multiple-layered tablet or a tablet-within-a-tablet (the inner tablet being the core and the outer portion being the shell).

10/12/ Chewable tablets They are chewed so mechanically disintegrated in the mouth. The drug is not dissolved in the mouth but swallowed and dissolves in the stomach or intestine., and it does not leave a bitter or unpleasant after-taste. Advantages of chewable tablets: 1. Quick and complete disintegration of the tablet - and hence obtain a rapid drug effect e.g. antacid tablets. 2. Facilitate the intake of the tablet for elderly and children who have difficulty in swallowing; e.g. vitamin tablets. 3. Can be taken when water is not available. Mannitol is normally used as a base due to low hygroscopy and more importantly, it gives pleasant, cooling sensation. They are similar in composition to conventional tablets except that a disintegrant is normally not included.

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10/12/ Effervescent tablets Effervescent tablets are dropped into a glass of water before administration, during which carbon dioxide is liberated. CO 2 facilitates tablet disintegration and drug dissolution; the dissolution of the tablet should be Complete within a few minutes.

10/12/ Advantages of effervescent tablets: 1. Rapiddrugaction,e.g. analgesic drugs. 2. Facilitate the intake of the drug, e.g. vitamins. 3. Fast drug bioavailability

10/12/ Effervescent tablets are usually contained: Carbonate or bicarbonate and a weak acid such as citric or tartaric. Flavor and a colourant A water-soluble lubricant is preferable in order to avoid a film of a hydrophobic lubricant on the surface of the water after tablet dissolution

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10/12/ Effervescent tablets should be:  protected from moisture, so that a special package is needed;  each tablet is completely covered with aluminum foil and kept in a water-proof container, often including a desiccant.  Effervescent tablets may be packed in blister packs.

10/12/ Lozenges They are tablets that dissolve slowly in the mouth and so release the drug dissolved in the saliva. They can thus be described as slow-release tablets for local drug treatment. Use of lozenges: Local medication in the mouth or throat in common cold, to treat cough by: antiseptics, antibiotics, demulcents, antitussive agents or astringents.

10/12/ Lozenges are usually contain: 1. They are similar in composition to conventional tablets. 2. Disintegrants are not used. 3. Colour and flavour. 4. High concentration of Fillers which are mainly sugars, such as glucose, sorbitol or mannitol. 5. High concentration of binder; e.g. gelatin Lozenges are usually contain: 1. They are similar in composition to conventional tablets. 2. Disintegrants are not used. 3. Colour and flavour. 4. High concentration of Fillers which are mainly sugars, such as glucose, sorbitol or mannitol. 5. High concentration of binder; e.g. gelatin Lozenges are usually contain: They are similar in composition to conventional tablets. 2. Disintegrants are not used. 3. Colour, sweetener and flavour. 4.High concentration of Fillers which are mainly sugars, such as glucose, sorbitol or mannitol. 5.The tablet generally contains sucrose or lactose and gelatin solution to impart smooth taste Lozenges are prepared by Compaction at high applied pressures in order to obtain a tablet of high mechanical strength and low porosity which can dissolve slowly in the mouth.

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10/12/ Sublingual and buccal tablets Used for drug release in the mouth followed by systemic uptake of the drug. Rapid systemic drug effect can thus be obtained without first-pass liver metabolism. Sublingual tablets are placed under the tongue and buccal tablets are placed in the side of the cheek. They are often small and porous, to facilitate fast disintegration and drug release.

10/12/ 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. It’s preferred for pediatric patients who cannot swallow a solid dosage form and the AP I 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 common examples of API formulated in this dosage form are analgesics e.g., aspirin, ibuprofen, etc.

10/12/ Sublingual tablets are placed under the tongue, Ex. Nitroglycerin sublingual tablet; it exerts its action within two minutes for rapid relief of "Angina pectoris" attack, because the sublingual area is rich in blood supply. Also other cardiovascular drugs, barbiturates, and vitamins are prepared as sublingual tablet dosage form

10/12/ Buccal tablets are placed in the side of the check for absorption through oral mucosa. N.B. Buccal tablets may be also prepared for their local application.

10/12/ Tablets used to prepare solution 8. Soluble tablet Soluble tablets are uncoated or film- coated tablets. Tablets are solids of uniform shape and dimensions, usually circular, with either flat or convex faces. 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. All the excipients used to formulate these tablets are required to be completely soluble in water

10/12/ Hypodermic tablet  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.

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Tablet Manufacturing Tablet Compression Machine Design: 1.Hopper for holding and feeding granules or powder to be compressed. 2.Dies that define the size and shape of the tablet. 3.Punches for compressing the granules within the dies. 4.Cam tracks for guiding the movement of the punches. 5.A feeding mechanism for moving granules from the hopper into the dies. 10/12/201529

Tablet tooling; punches and dies 10/12/201530

10/12/ Caplet Shape Dies We offer caplet shaped dies that are able to efficiently handle different types of punch pressing applications. These offers effortless performance and a single punch are capable of creating multiple dies. These are catering to different engineering and metal casting industries Oval Shapes Dies We offer a vast range of oval shape dies. Used in diverse industrial application for die casting and injection moulding processes, these rods are offered in various diameters and lengths to suit different requirements.

10/12/ Pharmaceutical Tablet Dies Tablet punch & die machines that are designed for pressing round tablets from various granular materials, applicable to lab used for research and development and to small-scale production. It is a continuous press driven by motor or manpower. Only one set of punch and die is mounted, the depth of the filling material and the thickness of the tablets can be adjusted. We provide dies in following shapes. Star Shape Tablet Punches Heart & Triangular Shape Tablet Punches Snap Tap Tablet Punches Under Cut With Threading Tablet Punches Animal Shape Tablet Punches Multi tip Tablet Punches We offer solutions with pharmaceutical industry demands in mind. Our high quality punches and dies support tablet manufacturing on a daily basis. Our high quality and expedited deliveries are well known making us a leader in the industry. Pharmaceutical Tablet Dies Star Shape Tablet Punches Heart & Triangular Shape Tablet Punches Snap Tap Tablet Punches Under Cut With Threading Tablet Punches Animal Shape Tablet Punches Multi tip Tablet Punches

10/12/ Round Shape Dies We offer a vast range of P.U rods. These sturdy and durable dies are offered in round shape. Used in diverse industrial application for die casting and injection moulding processes, these rods are offered in various diameters and lengths to suit different requirements

Stages of Tablet Formation (Compaction Cycle) Die filling Gravitational flow of the powder from hopper via the die table into the die. (The die is closed at its lower end by the lower punch). Tablet formation The upper punch descends, enters the die,the powder is compressed until a tablet is formed. - after maximum applied force is reached, the upper punch leaves the powder 10/12/201534

Tablet ejection 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. 10/12/201535

Tabletting Process Basics –powders fed into a die Powder compressed between punches 10/12/201536

Stages of Tablet Formation (Compaction Cycle) 1.forcing particles into close proximity to each other by powder compression. 2.compression takes place in a die by the action of two punches (lower & upper). Powder compression The reduction in volume of a powder owing to the application of a force. compaction The formation of a porous specimen of defined geometry by powder compression 10/12/201537

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Single Punch press (Eccentric Press): bench-top models that make one tablet at a time (single-station presses) Disadvantages: Production of small batches of tablets (200 tablets per minute). Tablet press 10/12/201539

2- Rotary Press( Multi station Press): It was developed to increase the output of tablets ( tablets per minute), used for Large scale production. It consists of a number of dies and sets of punches ( from 3 up to 60). The dies are mounted in a circle in the die table and both the die table & the punches rotate together during operation of the machine. 10/12/201540

Rotary Press Machine 10/12/201541

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The powder is held in a hopper whose lower opening is located just above the die table. The powder flows on to the die table & fed into the die by a feed frame. During powder compression both punches operate by vertical movement. After tablet ejection, the tablet is knocked away as the die passes the feed frame. 10/12/201543

Tablet Ingredients (excipients) 10/12/201544

Tablets Excipients Their role:ensure that tablets of specified quality are prepared. The common types of tablet’s excipients are described in the figure. 10/12/201545

10/12/ use: to make required bulk of the tablet. to provide better tablet properties such as to improve cohesion, to permit use of direct compression manufacturing to improve flow Most common fillers in tablets: 1.Lactose; frequently used, water soluble, improves tablet disintegration. 2.Dicalcium phosphate dihydrate, insoluble in water, disintegrating agent is a must. 3. Mannitol, dextrose, sucrose, 4. Lactose-anhydrous and spray dried lactose 5. Directly compressed starch-Sta Rx Hydrolyzed starch-Emdex and Celutab 7. Microcrystalline cellulose-Avicel (PH 101, 102). 1- Filler or diluent

10/12/ Requirements for a good filler: 1.Chemically inert, biocompatible, cheap. 2.Non-hygroscopic. 3.Good biopharmaceutical properties. (water soluble or hydrophilic). 4. Good technical properties (compactability ) 5.Have an acceptable taste. 6. They must be free from all microbial contamination. 7. They do not alter the bioavailability of drug. 8. They must be color compatible. 9. They must be non toxic 10.They must be commercially available in acceptable grade 11. They must be physically, chemically stable in combination with the drug

10/12/ Role: to ensure that the tablet, when in contact with a liquid, breaks up into small fragments, which promotes rapid drug dissolution. Mode of action: 1. Facilitate water uptake into the pores of tablet, e.g. surface active agents 2.facilitate rupture of tablet by swelling during water sorption, e.g. Sodium –starch glycolate, Crosscarmelose- cross linked cellulose; modified cellulose, Ac-Di-Sol 3. Release of gases to disrupt the tablet structure, normally carbon dioxide, in contact with water. e.g. effervescent tablets. 2- Disintegrant

10/12/ The Method of Disintegrant Addition: 1.Mixed with other ingredients prior to granulation & thus incorporated within the granules (intragranular addition). 2.Mixed with the dry granules before the complete powder mix is compacted (extragranular addition). 3.incorporated as both an intragranular and an extragranular portion.

10/12/ Commonly Used Disintegrants: 1. Starch: - conc. Up to 5-20% of tablet weight - Swell in contact with water 2. Super disintegrants (e.g. crrosecarmelose, sodium starch glycolate, Crosspovidone-cross linked povidone) Swells up to ten fold within 30 seconds when contact water. 3. Clays: bentonite, Veegum 10 % level in coloured tablet only

10/12/ Role: Ensure that granules and tablets can be formed with the required mechanical strength ( glue that holds powders together to form granules ). -In dry powder form -In solution -Examples: starch mucilage 10-20%, gelatin solution 10-20%, gum acacia, Solution glucose 50%, Cellulose derivative Polyvinylpyrrolidone 2% (PVP) 3- Binder and adhesive

10/12/ Role:Lubricants prevent adherence of granule/powder to die wall and to promote smooth ejection from the die after compaction, reduce inter particle friction and may improve the rate of flow of the tablet granulation Mechanisms of Action : 1.Fluid lubrication. 2.Boundary lubrication. 4- Lubricant

10/12/ Disadvantages of lubricants 1. Lubricants tend to be hydrophobic, so their levels (typically 0.3 – 2%) need to be optimised: – Under-lubricated blends tend to flow poorly and show compression sticking problems – Over-lubricated blends can adversely affect tablet hardness and dissolution rate, as well as tablet strength. – To overcome these problems; - optimum conc. < 2% - Addition of SAA

10/12/ Commonly used Lubricants A. Water- insoluble ( Fatty acids-based) lubricant Magnesium Stearate Calcium Stearate Stearic Acid, stearic acid salt Talc Silica derivative- c olloidal silica such as Cab-O-Sil, Syloid, Aerosil in % conc. liquid Paraffin, propylene glycol (PG) B. water-soluble lubricant -PEG 6000; less effective -Magnesium lauryl sulfate; good lubrication and surface wetting effect

10/12/ Role:Improve flowability of the powder & added during direct compaction and to granulation before tabletting ( they reducing interparticulate friction).. Common Glidants: 1.Talc (at concentration 1-2 %). 2.silica (0.2 %). 5- Glidants

10/12/ Role: Reduce adhesion between the powder and the punch faces & thus prevent particles sticking to the punches; Many lubricants, such as magnesium stearate, have also antiadherent properties. Also talc and starch can act as antiadherents. 6- Antiadherant

10/12/ Definition: are substances that are capable of sorbing some quantities of fluids in an apparently dry state. Thus, oils or oil-drug solutions can be incorporated into a powder mixture which is granulated & compacted into tablets. e.g. Microcrystalline cellulose & silica. 7- Sorbent

10/12/ Flavour Use: give the tablet a more pleasant taste or to mask an unpleasant one. (Chewable tablet) Flavouring agents are often thermolabile and so cannot be added prior to an operation involving heat. They are often mixed with the granules as an alcohol solution. Ex: Flavour oil

10/12/ Colourant Uses: It is added to tablets to aid identification and patient compliance. Mask of off color drug Production of more elegant product. All coloring agents must be approved and certified by FDA. Two forms of colors are used in tablet preparation – FD &C and D & C dyes. These dyes are applied as solution in the granulating agent or Lake form of these dyes. Lakes are dyes absorbed on hydrous oxide and employed as dry powder coloring.

10/12/ Example: FD & C yellow 6 sunset yellow FD & C yellow 5- Tartrazine FD & C green 3- Fast Green FD & C blue 1- Brilliant Blue FD & C blue 2 - Indigo carmine D & C red 3- Erythrosine. D & C red 22 – Eosin Y It is added during coating. It can also be added prior to compaction. ( can be added as an insoluble powder or dissolved in the granulation liquid

10/12/ Sweetener They are used in chewable tablet to exclude or limit the use of sugar in the tablets. e.g. Mannitol, 72% as sweet as sucrose. Saccharin, 500 times sweeter than sucrose. Disadv.: has a bitter after taste and carcinogenic. Aspartame, largely replace saccharin. Disadv.: lack of stability in the presence of moisture.