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TABLETS TABLETS - DEFINITION http://www.uspbpep.com/bp2008/data/5765.asp • Tablets are solid preparations each containing a single dose of one or more active substances. • They are obtained by compressing uniform volumes of particles or by another suitable manufacturing technique, such as extrusion, moulding or freeze-drying (lyophilisation). • Tablets are intended for oral administration. Some are swallowed whole, some after being chewed, some are dissolved or dispersed in water before being administered and some are retained in the mouth where the active substance is liberated. • The particles consist of one or more active substances with or without excipients such as diluents, binders, disintegrating agents, glidants, lubricants, substances capable of modifying the behaviour of the preparation in the digestive tract, colouring matter authorised by the competent authority and flavouring substances. • Tablets are usually straight, circular solid cylinders, the end surfaces of which are flat or convex and the edges of which may be bevelled. They may have break-marks and may bear a symbol or other markings. Tablets may be coated. CATEGORIES OF TABLETS • Uncoated tablets • Coated tablets (including film-coated and sugar- coated tablets) • Soluble tablets • Dispersible tablets • Effervescent tablets • Chewable tablets • Tablets for use in the mouth (including sublingual and buccal tablets) -modified-release tablets (including delayed-release tablets (gastro- resistant/enteric-coated tablets) and sustainedrelease tablets (extended- /prolonged- release tablets) Controls • Uniformity of mass • Uniformity of content • Dissolution/disintegration • Uncoated tablets are made in such a way that the release of active ingredients is unmodified. A broken section, when examined under a lens, shows either a relatively uniform texture (single-layer tablets) or a stratified texture (multilayer tablets), but no signs of coating. • Coated tablets are tablets covered with one or more layers of mixtures of substances such as natural or synthetic resins, polymers, gums, fillers, sugars, plasticizers, polyols, waxes, colouring matters, flavouring substances, and sometimes also API. A broken section, when examined under a lens, shows a core which is surrounded by a continuous layer of a different texture. Three main categories of coated tablet may be distinguished: sugarcoated, film-coated, and certain modified-release tablets. • Modified-release tablets are coated or uncoated tablets, or matrix tablets that contain special excipients or are prepared by special procedures, or both, designed to modify the rate, the place or the time at which the active substance(s) are released. Modified-release tablets include sustained-release tablets and delayed-release tablets • Sustained-release tablets (extended-/prolonged-release tablets): designed to slow the rate of release of the APIs in the gut. • Delayed-release tablets (gastro-resistant/enteric-coated tablets): intended to resist gastric fluid but disintegrate in intestinal fluid. • Soluble tablets are uncoated or film-coated tablets. They are intended to be dissolved in water before administration. The solution produced may be slightly opalescent due to the added excipients used in the manufacture of the tablets. • Effervescent tablets are uncoated tablets generally containing acid substances and carbonates or hydrogen carbonates, which react rapidly in the presence of water to release carbon dioxide. They are intended to be dissolved or dispersed in water before administration. TABLETS - ADVANTAGES 1. They are unit dosage form and offer the greatest capabilities of all oral dosage form for the greatest dose precision and the least content variability. 2. Cost is lowest of all oral dosage form. 3. Lighter and compact. 4. Easiest and cheapest to package and strip. 5. Easy to swallowing with least tendency for hang-up. 6. Sustained release product is possible by enteric coating. 7. Objectionable odour and bitter taste can be masked by coating technique. 8. Suitable for large scale production. 9. Greatest chemical and microbial stability over all oral dosage form. 10. Product identification is easy and rapid requiring no additional steps when employing an embossed and/or monogrammed punch face. - Delayed release (DR) - Extended release (ER) - Immediate release (IR) TABLETS - DISADVANTAGES 1. Mistaken as candy 2. Cannot be administered to patients if vomiting or unconscious 3. Some patients have difficulty swallowing tablets especially children 4. Formulation sometimes limited: large dose drugs usually lack the properties to be formed into tablets 5. Problems in attaining acceptable content uniformity (accuracy and precision of unit dose content) for low dose drugs 6. Compromised bioavailability (poor drug solubility; malformulation); Drugs with poor wetting, slow dissolution properties, optimum absorption high in gastrointestinal (GIT) may be difficult to formulate or manufacture as a tablet that will still provide adequate or full drug bioavailability. 7. Some drugs resist compression into dense compacts, owing to amorphous nature, low density character. 8. Bitter testing drugs, drugs with an objectionable odor or drugs that are sensitive to oxygen may require encapsulation or coating. In such cases, capsule may offer the best and lowest cost TABLET PROPERTIES 1. Mechanical and physical strength 3. • Should have sufficient strength to withstand mechanical shock during its production packaging, shipping and dispensing. • A tablet should have elegant product identity while free of defects like chips, cracks, discoloration, and contamination. • Should have sufficient strength to withstand mechanical shock during its production packaging, shipping and dispensing. 2. 4. Chemical nature of tablet ingredients • Should have the chemical and physical stability to maintain its physical attributes over time • Must have a chemical stability over time so as not to follow alteration of the medicinal agents. Smooth surface • The tablet must be able to release the medicinal agents in a predictable and reproducible manner. Physical shape 5. Hygroscopicity TABLETS INGREDIENTS – EXCIPIENTS • Tablet ingredients in addition to active ingredients, tablet contains a number of inert materials known as additives or excipients. • Two types of excipients • General/classical excipients • Excipients for direct compression TABLETS INGREDIENTS – GENERAL EXCIPIENTS Tablet ingredients in addition to active ingredients, tablet contains a number of inert materials known as additives or excipients. Different excipients are: 1. Diluent 2. Binder and adhesive 3. Disintegrants 4. Lubricants and glidants 5. Colouring agents 6. Flavoring agents 7. Sweetening agents DILUENT • Diluents are fillers used to make required bulk of the tablet when the drug dosage itself is inadequate to produce the bulk. • Functions : increase the bulk volume: final product has the proper volume for patient handling • Drugs used at low doses: < 50 mg and diameter of tablet higher than 5 mm • To minimise incompatibilities: the contact can be reduced by dilution • Selection criteria: compressibility, compactibility, flow • Secondary reason is to provide better tablet properties such as improve cohesion, to permit use of direct compression manufacturing or to promote flow. • Filler requirements: inert, non-hygroscopic, soluble, cheap, compactable, tasteful DILUENT A diluent should have following properties: 1. They must be non toxic 2. They must be commercially available in acceptable grade 3. There cost must be low 4. They must be physiologically inert 5. They must be physically & chemically stable by themselves & in combination with the drugs. 6. They must be free from all microbial contamination. 7. They do not alter the bioavailability of drug. 8. They must be color compatible. COMMONLY USED TABLET DILUENTS 1) Lactose-anhydrous and spray dried lactose • Lactose: most widely used diluent in tablet formulation. • Lactose has no reaction with most drugs, whether it is used in hydrous or anhydrous form. • Lactose is incompatible with amino acids, aminophylline and amphetamine • Anhydrous lactose has advantage over lactose that it does not undergo maillard reaction which is browning and discolouration of tablets due to the interaction of amine drug with lactose. • Spray dried lactose in concentration 20-25% of active ingredient is used for direct compression COMMONLY USED TABLET DILUENTS 2) Starch i. Directly compressed starch - Sta Rx 1500 ii. Hydrolyzed Starch - Emdex and Celutab iii. Microcrystalline cellulose-avicel (PH 101and PH 102) • Starch (rice, wheat, corn, potato) starch has no listed incompatibilities filler, binder, disintegrant, glidant • Sta-Rx 1500 is free flowing, direct compressible starch used as diluent, bider and/or disintegranting agent. • two hydrolysed starch Emdex and Celutab, which are combination of 90-92% of dextrose and 3-5% of maltose are free flowing and direct compressible COMMONLY USED TABLET DILUENTS 3) Microcrystalline cellulose • having trade name Avicel: used for direct compression. • These are two type : PH101 (Powder) and PH102 (Granules), 4) Sucrose • Some sugar-based diluents are used for direct compression. They are: a) Sugartab: 90-93% sucrose and 7-10% invert sugar b) DiPac: 97% sucrose and 3% modified dextrin c) Nu Tab: 95% sucose and 4% invert sugar with small amount of corn starch and magnesium stearate COMMONLY USED TABLET DILUENTS 5) Dibasic calcium phosphate and calcium sulphate • used as diluents but incompatible with tetracycline antibiotics, indomethacin, aspirin, aspartame, ampicillin, cephalexin and erythromycin 6) Others • Mannitol • Sorbitol • Dextrose BINDERS AND ADHESIVES • Binders / aggregates or agglutinants (2-10%) • These materials are added either dry or in wet-form to form granules or to form cohesive compacts for directly compressed tablet. • Type of binders • Dry powder added to the mixture prior to the wet granulation process • Solution that is used in the wet granulation process • Add right before the tabletting process (direct compression) BINDERS AND ADHESIVES • Binder functions: • To ensure mechanical strength of tablets and granules • To “glue” (promote adhesion) the particles together into granules helping to hold the overall tablet together: improves compactibility • To provide the ¨cohesiveness¨ to a formulation enhancing its compressibility and flow properties (maintain the integrity of the tablet) • To improve the mechanical strength of a tablet • To improve the flowability of the powder or granules or both drawback: significant effect on bioavailability and therapeutic efficacy, because it affects hardness and friability of tablet. • Commonly used binders • Hydrophillic cellulose derivatives (1-4%, water, alcohol…) hydroxypropylcellulose, carboxymethylcellulose, ethylcellulose, methylcellulose • Starch (starch 1500) (1-4%) • Polyvinylpyrrolidone (PVP): plasdone (2-5%, alcohol, water) • Saccharose / sucrose / glucose (2-20%, water) • Gelatine (1-4%, water) • Acacia gum (2-5%, water, alcohol), tragacanth gum (1-3%, water) • PEG 4000 y 6000, palmitate stearate glycerol / PEG • Sodium alginatr • Others: glucose, sorbitol, excipients for direct compression • TO BE CONTINUE DISINTEGRANTS • Added to a tablet formulation to facilitate its breaking or disintegration when it contact in water in the GIT. • Disintegrant functions: to ensure that when tablets are in contact with water, they are rapidly breaking into smaller fragments, facilitating their dissolution. • Important for immediate release products where rapid release is required • more effective if added 50% intragranularly, and 50% extra-granularly • some tablet fillers (e.G., Starch and MCC) aid in disintegration • selection criteria: active / drug disolution, bioavailability DISINTEGRANTS • Example: Starch- 5-20% of tablet weight Starch derivative- Primogel and Explotab (1-8%) Starch and starch derivatives (5-15%) Cellulose derivatives: avicel RC591®: mixture of MCC and sodium CMC Polysaccharides: alginic acid, sodium alginate, tragacanth gum, guar gum Methylated caseine: Esma Spreng® Colloidal silicon dioxide: aerosil®, cab-o-sil® [lubricant group] Magnesium Aluminum Silicate: veegum F® Clays- Veegum HV, bentonite 10% level in colored tablet only PVP (Polyvinylpyrrolidone) cross-linked • Superdisintegrants: Swells up to ten fold within 30 seconds when contact water • Superdisintegrants (0.5-2.0%, for hard gelatin capsules 4-8%) • Sodium starch glycolate: Primojel®, Explotab® (1-6%) high concentrations may cause gelling and loss of disintegration. • Croscarmellose sodium / carboxymethylcellulose: Vivasol®, Ac-Di-Sol (0.5-5%) • Soy polysaccharides: Emcosoy® • Crospovidone / cross-linked PVP: Polyplasdone® XL (2-4%) • L-HPC low-substituted hydroxypropyl cellulose (1-5%) Example: Crosscarmellose- crosslinked cellulose, Crosspovidone-crosslinked povidone (polymer), Sodium starch glycolate-cross linked starch. These cross-linked products swell up to 10 fold within 30 seconds when in contact with water. A portion of disintegrant is added before granulation and a portion before compression which serve as glidants or lubricants. Evaluation of carbon dioxide in effervescent tablets is also one way of disintegration. LUBRICANTS AND GLIDANTS • Definition To prevent the compacted powder from sticking to the equipment during the tabletting. Its aids ejecting of the tablet from the dies, and may improve powder for LUBRICANTS AND GLIDANTS Lubricants roles • True lubricants role • Reducing friction between sliding surface, at the tablet-die wall interface during tablet formation and ejection. Also applies to capsule plugs. • Antiadhesion role • Preventing sticking to surface. To reduce adhesion between te powder and the punch faces and thus prevent tablet sticking to the punches • Glidant roles • Improving flow by modifying the interaction between particles • Example • Lubricantss : Stearic Acid, Stearic Acid Salt- Stearic Acid, Magnesium Stearate, Talc, Peg (Poluethylene Glycols), Surfactants • Glidants: Corn Starch (5-10%), Silica Derivatives-colloidal Silicas Such As Cab-o-sil.Syloid, Aerosol In 0.25-3% Conc. • Concept of a "lubricant system“ Frequently two substances are used in a formulation to maximize lubricant effect in all three areas: combining magnesium stearate with a colloidal silica • Lubricant issues The most effective true lubricants are hydrophobic and if too much is used, they can interfere with disintegration and dissolution Lubricant generally interfere with bonding and can soften tablets Alkaline metal stearates are incompatible with some drugs, e.g. Aspirin and AA Laminar lubricants (mg stearate, Ca stearate) are "mixing sensitive” under the rigors of mixing they delaminate: effect equivalent to adding too much lubricant Lubricants are always added last after all other components have been thoroughly mixed (mixing time of 2-5 min) Water soluble lubricants are not as effective: for water soluble tablets COLOURING AGENT • The use of colours and dyes in a tablet has three purposes: 1) Masking of off colour drugs 2) Product identification 3) Production of more elegant product • All colouring agents must be approved and certified by FDA. • Two forms of colors are used in tablet preparation – FD & C and D & C dyes. • 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 and C red 22 – Eosin Y OTHERS Flavouring agents: for chewable tablet – flavour oil are used Sweetening agents: for chewable tablets : sugar, mannitol, Example: Saccharine (artificial): 500 times sweeter than sucrose Disadvantage: bitter aftertaste and carcinogenic Aspartame (artificial) Disadvantage: lack of stability in presence of moisture EXCIPIENTS FOR DIRECT COMPRESSION Characteristics - Generally, direct compression Filler-binders are common fillers that have been physically modified. - Fillers posseses both diluent and binders properties; sometimes, also glidants - In general, these excipients are used in a large amount (50-80%) - Main aspect: Improving flowability (add glidants) Today, tableting equipment compressing 8,000 to 10,000 tablets per minute. It is critical to have an excellent flowing granulation/powder blend. Many sugar-based excipients, such as maltose, mannitol, and sorbitol are not compressible in their natural state and need to be modified for use in direct compression tableting • Classification: 4 groups • Cellulose derivatives • Starch derivatives • Sugars • Mineral products 1. Celullose And Derivatives A) Microcrystaline Cellulose, MCC • Binder properties: tablet compactibility: low friability • Inherent lubricant properties: tablets self disintegrate and require little lubricant • Most compactible material available for pharmaceutical use • Example • Avicel PH-101, PH-102, PH-103, PH-105, PH-112, PH-200 • Emcocel®: Contains a little amount of calcium phosphate • Prosolv SMCC™: Combination of MCC and Colloidal Silicon Dioxide. • Others: Vivacel®, Vivapur® B) Powdered Celluloses • Elcema ® : -Cellulose • Solka-floc® and Justfiber® 2. Starch And Starch Derivatives • Binder, self-lubricant: permits to reduce the amount of traditional lubricants • Super disintegrant: 2-10% of starch 1500 provides disintegrant action • Flow aid: excellent flow properties. • In formulations containing starch, it is necessary to include excipients able to increase the compactability (the hardness of the resulting tablet): 5-10% Silartex® Or Compressil® • Starch 1500 • Sta-Rx® 1500 • Paygel® 90 3. Sugars a)Lactose b) Compressible Sugar • Lactochem® • Compressible Sugar (95-98% Sucrose) • Lactopress®: Lactopress® Spray-dried And Lactopress® Anhydrous • Di-pac®: It Contains 97% Sucrose And 3% Maltodextrines. • Microcelac 100 Is A Spray-dried Compound Containing 75% -Lactose Monohydrate And 25% MCC. • SugarTAB® • Ludipress®: Lactose (93.4%), Kollidon® 30 (3.2% PVP, Binder) And Kollidon® CL (3.4% Cross-linked PVP, Flow Aid). • Starlac: Lactose / Starch (85:15) • Others: Zeparox®, DCL-30®, Pharmatose®, Tablettose®, Lactose Fast Flow®, Flowlac 100, Cellactose 80 • Compressuc®: Saccharose + Maltodextrines. • Others: NU-TAB® 4001, Sucre CD1®: Tabfine S100 I c) Glucose / Dextrose • Emdex®: Glucose (90-92%), Maltose (35%) And Little Amount Polysaccharides. • Tabfine D97 Hs®: Glucose (97%) And Starch (3%) As Binder. d) Fructose / Levulose • Tabfine F94 M®: Fructose (96%) And Maltose (4%) f) Mannitol • Pearlitol®: It Allows Sugar-free Formulations (Including Chewing Gums) g) Maltose Advantose™ 100: It Can Be Also Used As Sugar Substitute For Great-tasting Sugar-free And Lowcalorie Products. e)Sorbitol Neosorb®: h) Maltitol • Neosorb60 (10%max>315 M), Neosorb60w (105-420 M) • Maltisorb® Is Well Suited To The Formulation Of Powder Forms (Sachets, Dry Syrups, Capsules) And Tablet Forms, Whether Chewable, Suckable, Coated Or Effervescent. ® 4. Mineral Products A. Dibasic CaHPo4·2H2O • Emcompress® Dihydrate) Calcium (Dibasic Phosphate Dihydrate: Calcium Phosphate • Emcompress Anhidrous®: Especially Designed For Drugs Sensible To Moisture • A-TAB® (Anhidrous), Calstar®, Di-tab® B. Tribasic Calcium Phosphate: Ca3(PO4)2 ; Ca5(OH)(PO4)3 Tri-cal® WG, Tri-tab® C. Calcium CaSo4·2H2O Sulphate: Compactrol, CAL-TAB® D. Hydrated Magnesium Silicate Silartex®, Compressil® Ca(So4); OVERVIEW OF MANUFACTURING METHODS OVERVIEW OF MANUFACTURING METHODS • Methods of Tablet Preparation • Wet Granulation • Dry Granulation • Direct Compression WET GRANULATION • Improve compressibility, flowability, and content uniformity of powder blend • Step: • Size drug, weigh and blend with excipients • Add liquid binder to prepare damp mass • Adhesion of powdered particles to form granules for tableting (granulation) aids in holding tablet together after compression • Binding agents: aqueous or organic Cautions: overwetting/underwetting • Screen damp mass • Dry and size: spread evenly on shallow trays temperature and humidity controlled ovens drying in fluid- bed apparatus • Second screening: smaller mesh screen • Lubricate formulation • Compress into tablets WET GRANULATION PROCESS DRY GRANULATION • Dry Granulation Method (Slugging) • Steps • Size drug, weigh and blend with excipients • Filler, binder, lubricant (disintegrant, glidant) • Compact large masses of powders : no moisture/binding agent added • Crush and size pieces into smaller granules • Lubricate • Disintegrant, lubricant • Compress into tablets • Active or diluent/filler must have cohesive properties • Drugs that degrade in moisture or heat DIRECT COMPRESSION • Direct Compression: Must be a free-flowing and compressible mixture • Steps: • Size drug • Weigh appropriate amounts of active and excipients • Blend with excipients • Compress into tablets • Direct Compression Problems • Problems with high-dose drugs: compressibility • Problems with low-dose drugs: content uniformity • May require glidant to improve flowability • Segregation in hopper possible • Blending of lubricant critical: weaker tablets, slower drug release DIRECT COMPRESSION • Strategies • Decrease the size of drug particles: micronisators • Firstly, mix the fine drug with filler-binder product. • Then, add the rest of ingredients and • Magnesium stearate at the end (mix 3 minutes and compress). Never mix all the ingredients of the formula (drug and excipients) in only one step TABLETING / COMPRESSION Tablet presses: single ended compression TABLET PRESSES: SINGLE-ENDED COMPRESSION TABLET PRESSES MULTISTATION / ROTARY PUNCH https://upload.wikimedia.org/wikipedia/commons/5/5a/Tablet_press_animation.gif QUALITY CONTROL OF FINISHED TABLETS