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Download Tablets - Faculty of Pharmaceutical Sciences, KKU
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Tablets Assoc. Prof. Dr. Jomjai Peerapattana Faculty of Pharmaceutical Sciences Khon Kaen University Scope Introduction Advantages and disadvantages of compressed tablets Types of tablets Tablet compression machine Tableting methods – Direct compression Introduction 1843 a patent was granted to Thomas Brockedon (Englishman) for manufacturing pills and lozenges 1874 both rotary and eccentric presses 1885 glyceryl trinitrate tablets was in the BP No other tablet monograph appeared until 1945 1980 nearly 300 monographs for tablets Advantages Production aspect – Large scale production at lowest cost – Easiest and cheapest to package and ship – High stability User aspect (doctor, pharmacist, patient) – Easy to handling – Lightest and most compact – Greatest dose precision & least content variability – Coating can mark unpleasant tastes & improve pt. acceptability Disadvantages Some drugs resist compression into dense compacts Drugs with poor wetting, slow dissolution, intermediate to large dosages may be difficult or impossible to formulate and manufacture as a tablet that provide adequate or full drug bioavailability Bitter taste drugs, drugs with an objectionable odor, or sensitive to oxygen or moisture may require encapsulation or entrapment prior to compression or the tablets may require coating Absorption of drug form tablets Ingredients used in tablet formulations Drugs Fillers, diluent, bulking agent – To make a reasonably sized tablet Binders – To bind powders together in the wet granulation process – To bind granule together during compression Disintegrants – To promote breakup of the tablets – To promote rapid release of the drug Lubricants – To reduce the friction during tablet ejection between the walls of the tablet and the walls of the die cavity Glidants – Reducing friction between the particles – To improve the flow properties of the granulations Antiadherants – To prevent adherence of the granules to the punch faces and dies Dissolution (enhancers and retardants) Wetting agents Antioxidants Preservatives Coloring agents Flavoring agents Essential properties of tablets Accurate dosage of medicament, uniform in weight, appearance and diameter Have the strength to withstand the rigors of mechanical shocks encountered in its production, packaging, shipping and dispensing Release the medicinal agents in the body in a predictable and reproducible manner Elegant product, acceptable size and shape Chemical and physical stabilities Types of tablets Route of administration – Oral tablets – Sublingual or buccal tablets – Vaginal tablets Production process – Compressed tablets – Multiple compressed tablets Tablet within a tablets: core and shell Multilayer tablet – Sugar coated tablets Protect tablets from moisture Mask odor and flavor Elegance – Film coated tablets Thin film coat Soluble or insoluble polymer film – Chewable tablets Rapid disintegrate Antacid, flatulance: rapid action Children drug – Effervescent tablets Dissolve in the water before drink Tablet production Powders intended for compression into tablets must possess two essential properties – Powder fluidity The material can be transported through the hopper into the die To produce tablets of a consistent weight Powder flow can be improved mechanically by the use of vibrators, incorporate the glidant – Powder compressibility The property of forming a stable, intact compact mass when pressure is applied Tableting procedure Filling Compression Ejection Tablet compression machines Hopper for holding and feeding granulation to be compressed Dies that define the size and shape of the tablet Punches for compressing the granulation within the dies Cam tracks for guiding the movement of the punches Feeding mechanisms for moving granulation from the hopper into the dies Single punch machine The compression is applied by the upper punch Stamping press Single Punch Machine (Tablets) Upper and Lower Collar Collar locker Multi-station rotary presses The head of the tablet machine that holds the upper punches, dies and lower punches in place rotates As the head rotates, the punches are guided up and down by fixed cam tracks, which control the sequence of filling, compression and ejection. The portions of the head that hold the upper and lower punches are called the upper an lower turrets The portion holding the dies is called the die table The pull down cam (C) guides the lower punches to the bottom, allowing the dies to overfill The punches then pass over a weight-control cam (E), which reduces the fill in the dies to the desired amount A swipe off blade (D) at the end of the feed frame removes the excess granulation and directs it around the turret and back into the front of the feed frame The lower punches travel over the lower compression roll (F) while simultaneously the upper punches ride beneath the upper compression roll (G) 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 (H) The lower punches ride up the cam (I) which brings the tablets flush with or slightly above the surface of The tablets strike a sweep off blade affixed to the front of the feed frame (A) and slide down a chute into a receptacle At the same time, the lower punches re-enter the pull down cam (C) and the cycle is repeated Although tablet compressing machinery has undergone numerous mechanical modifications over the years, the compaction of materials between a pair of moving punches within a stationary die has remained unchanged The principle modification from earlier equipment has been an increase in production rate which is regulated by – Number of tooling sets – Number of compression stations – Rotational speed of the press Special adaptations of tablet machines allow for the compression of layered tablets and coated tablets A device that chills the compression components to allow for the compression of low-melting point substances such as waxes i.e. suppositories Tableting methods Dry methods – Direct compression – Dry granulation Wet methods – Wet granulation Direct compression Tablets are compressed directly from powder blends of the active ingredient and suitable excipients No pretreatment of the powder blends by wet or dry granulation procedures is necessary Advantages – Economy Machine: fewer manufacturing steps and pieces of equipment Labor: reduce labor costs Less process vallidation Lower consumption of power – Elimination of granulation process Heat (wet granulation) Moisture (wet granulation) High pressure (dry granulation) Processing without the need for moisture and heat which is inherent in most wet granulation procedures Avoidance of high compaction pressures involves in producing tablets by slugging or roll compaction – Elimination of variabilities in wet granulation processing Binders (temp, viscous, age) Viscosity of the granulating solution (depend on its temp), How long it has been prepared, Rate of binder addition and kneading can affect the properties of the granules formed The granulating solution, the type and length of mixing and the method and rate of wet and dry screening can change the density and particle size of the granules, which can have a major effect on fill weight and compaction qualities Type and rate of drying can lead not only to critical changes in equilibrium MC but also to unblending as soluble active ingredients migrate to the surfaces of the drying granules More unit processes are incorporated in production, the chances of batch-to-batch variation are compounded – Prime particle dissociation Each primary drug particle is liberated from the tablet mass and is available for dissolution Disintegrate rapidly to the primary particle state – Uniformity of particle size – Greater stability of tablet on aging Color Dissolution rate Fewer chemical stability problems would be encountered as compared to those made by the wet granulation process Concerns – Excipient available from only one supplier and often cost more than filler used in granulation – Procedure conservation – Machine investments – Lack of material knowledge – Physical limitation of drug No compressibility No flowability – Physical characteristics of materials (both drug and excipient) Size and size distribution Moisture Shape and surface Flowability Density – Lot to lot variability – Dusting problem – Coloring Direct compression fillers Common materials that have been modified in the chemical manufacturing process to improve fluidity and compressibility Lactose Soluble fillers – Spray dried lactose Lactose is placed in aqueous solution, removed impurities and spray dried Mixture of large alpha monohydrate crystals and spherical aggregates of smaller crystals Good flowability but less compressibility Poor dilution potential Loss compressibility upon initial compaction Problem of browning due to contamination of 5-hydroxyfurfural which was accelerated in the presence of basic amine drugs and catalyzed by tartrate, citrate and acetate ions – Fast-Flo lactose (early 1970s) Spherical aggregates of microcrystals lactose monohydrate Held together by a higher concentration of glass (amorphous lactose) Much more compressible Highly fluid Non hygroscopic Tablets are three to four times harder than regular spray dried – Tabletose: aggromerate form of lactose More compressible than spray dried but less compressible than Fast Flo lactose – Anhydrous lactose: free flowing crystalline lactose Produced by crystallization above 93C which produces the beta form Pass through steam heated rollers Good flow property, contained high amount of fines, its fluidity is less than optimal Can be reworked At high RH anhydrous lactose will pick up moisture forming the hydrated compound increase in the size of tablets if the excipient makes up a large portion of the total tablet weight Excellent dissolution property Sucrose – Di-Pac: cocrystallization of 97% sucrose and 3% modified dextrin Small sucrose crystals glued together by dextrin Good flow properties and needs a glidant only when atmospheric moisture levels are high (>50%RH) Excellent color stability on aging Concentration of moisture is extremely critical in terms of product compressibility compressibility increases rapidly in a moisture range of 0.3-0.4%, plateaus at a level of 0.4-0.5% and rises again rapidly up to 0.8% when the product begins to cake and lose fluidity Dilution potential 20-35% Tablets tend to harden slightly during the first hours after compression or when aged at high humidities and then dried (this is typical of most direct compression sucroses or dextroses) – Nutab: 95.8% sucrose, 4% convert sugar (equimolecular mixture of levulose and dextrose) and 0.1 to 0.2% each of cornstarch and magnesium strarate Large particle size distribution and good fluidity Poor color stability Dextrose – Emdex: spray crystallized 90-92% dextrose, 3-5% maltose and the remainder higher glucose polysaccharides Available both anhydrous and a hydrate product Excellent compressibility Largest particle size, blending problem may occur Sorbitol – Exists in a number of polymorphic crystalline forms and amorphous form – Widely used in sugar-free mints and as a vehicle in chewable tablets – Cool taste and good mouth feel – Forms a hard compact – Hygroscopic and will clump in the feed frame and stick to the surfaces of the die table when tableted at humidities > 50% – Lubricant requirements increase when the MC of the sorbitol drops below 0.5% or exceeds 2% Mannitol – Exists in a number of polymorphic forms – Not make as hard a tablet as sorbitol – Less sensitive to humidity – Widely used where rapid and complete solubility is required – Use as a filler in chewable tablets – Cool mouth feel but expensive Maltodextrin – Maltrin Highly compressible Completely soluble Very low hygroscopic Starch Insoluble fillers – Starch 1500: intact starch grains and ruptured starch grains that have been partially hydrolyzed and subsequently aggromerated Extremely high MC (12-13%) Does not form hard compacts Dilution potential is minimal Not generally used as filler-binder but as filler disintegrant – Retains the disintegrant properties of starch without increasing the fluidity and compressibility of the total formulation – Deforms elastically when a compression force is applied, it imparts little strength to compacts – Lubricants tend to dramatically soften tablets containing high concentrations of Starch 1500 – Spray dried starch Era-Tab: spray-dried rice starch Good fluidity MC 10-13% Compressibility depend on moisture Reworkability Low bulk density Celulose – Microcrystalline cellulose (Avicel) The most important tablet excipient developed in modern times Derived from a special grade of purified alpha wood cellulose by severe acid hydrolysis to remove the amorphous cellulose portions, yielding particles consisting of bundles of needlelike microcrystals PH101 powder PH102 more agglomerated, larger particle size, slightly better fluidity but not significant decrease in compressibility Most compressible Highest dilution potential A strong compact is formed due to the extremely large number of clean surfaces brought in contact during the plastic deformation and the strength of the hydrogen bonds formed Extremely low coefficient of friction, no lubricant requirement When >20% of drugs or other excipients are added, lubrication is necessary Not used as the only filler because of its cost and density Usually used in the conc of 10-25% as a fillerbinder-disintegrant, rapid passage of water into the compact and the instantaneous rupture of hydrogen bonds Fluidity is poor because of its relatively small particle size, small amount of glidant are recommended in the formulations containing high conc of MCC Tablets are soften on exposure to high humidities This softening is reversible when tablets are removed from the humid environment >80% MCC may slow the dissolution rates of AI having low water solubility Small particles get physically trapped between the deformed MCC particles, which delays wetting and dissolution This phenomenon can be overcome by adding portions of water soluble excipient Inorganic calcium salts – Dicalcium phosphate (Emcompress or DiTab) Free flowing aggregates of small microcrystals that shatter upon compaction Inexpensive and possesses a high degree of physical and chemical stability Nonhygroscopic at a RH of up to 80% Good fluidity Slightly alkaline with a pH of 7.0 to 7.3 Precludes its use with AI that are sensitive to even minimal amounts of alkalinity – Tricalcium phosphate (TriTab) is less compressible and less soluble, higher ratio of calcium ions References ยาเม็ด (ม.มหิ ดล) Pharmaceutics. The science of dosage forms design. (M.E. Aulton) The theory and practice of industrial pharmacy. Pharmaceutical dosage forms : Tablets. Volume 2. Pharmaceutical dosage forms and drug delivery systems.
