Tablet Dosage Form Design PDF

TABLET DOSAGE FORM DESIGN Dr AHMAD EID TABLETS Tablets are Solid Dosage Forms containing a single dose of one or more active ingredients and obtaining by compressing uniform volume of particles. They may be classed according to the method of manufacture, such as MOLDED or COMPRESS...

TABLET DOSAGE FORM DESIGN Dr AHMAD EID TABLETS Tablets are Solid Dosage Forms containing a single dose of one or more active ingredients and obtaining by compressing uniform volume of particles. They may be classed according to the method of manufacture, such as MOLDED or COMPRESSED TABLETS. At present tablets are the most used and produced (70%), Compares to other Dosage Forms such as Injection, Powder, Liquid, Cream, Ointment. 1  TABLETS…… cont. Some of the tablets are swallowed whole, some after being chewed, some are dissolved or disperse in water before administration and some are retained in the mouth, where the active ingredient is liberated. A tablet consist of one or more active ingredients plus adjuvant (additives) e.g. Diluents, Binder, Lubricant, Sweetener and Colorant. Advantages of Tablets Light, ease to carry and delivered. The preparation procedure enables accurate dose of the drug (Dosage can vary from 0.1 - 1,000 mg/tablet) and least content variability. Tablets are convenient to handle and can be prepared in a versatile way with respect to their use and to delivery of drug (Many Mode of Actions). Variation of Colours, Shapes, Sizes. Tablet dosage forms are more stable physically and chemically compare to liquid dosage forms. Tablets can be produced in large scale and cheaper than other dosage form. Convenient and easy on administration. The release rate of drugs from tablets can be tailored to meet pharmacological requirement 2  Disadvantages of Tablets Some drugs may cause local irritant effects to GIT. Can not be used in unconscious patients. Very low bioavailability compared to e.g Parenteral dosage form. Small Children can not take Tablets. Some drugs resist compression into dense compacts. Types of Tablets 1. Single Compressed Tablets: 2. Multiple compressed tablets (Layered Tablets): Compressed Coated Tablet Core Tablet Inert Material 3  Types of Tablets….. cont 3. Sugar-coated tablets Sugar Coating Layers Core Tablet 4. Film-coated tablets: Core Tablet 5. Enteric coated tablets: Film Coating Layer Types of Tablets….. cont 6. Buccal or sublingual tablets: 7. Chewable tablets: 8. Effervescent tablets: 9. Lozenges: 4  Types of Tablets….. cont 10. Implants: 11. Sustained Release Tablets: What you must know to design a dosage form Physicochemical properties of the drug – Reactivity, stability – Solubility, acid/base, solid state behaviour Biopharmaceutical considerations – What is the intended site of action? Systemic? Topical? – Where/how well is the drug absorbed? – What is the intended onset of action? Immediate-release, sustained-release, pulse releases 5  Some questions about Dosage Form Design About the drug – Aqueous solubility, pKa, partition coefficient – Chemical stability in solution About the dosage form – Dissolution characteristics – Transdermal characteristics – Stability in storage About the biopharmaceutics – Extent of absorption – First-pass metabolism – Intended use: topical vs. systemic? General Considerations in Dosage Form Design Physiological factors Factors Affecting Drug Age Presentation to the Body  Route of drug entry into the body Diurnal variation (fluctuations  Physical form of the drug product that occur during the day)  Design and formulation of the product Pregnancy  Method of manufacture of the product Sex  Physicochemical properties of the drug and Menopause excipients Body weight Physicochemical properties of the drug Time of administration product Tolerance Control and maintenance of location of drug at Temperature the absorption site Control of the release rate of the drug from the Physiological reserve drug product 6  General Considerations in Dosage Form Design…cont. 2.1 Preformulation Studies Chemical characterization Physical characterization 2.2 Drug and Drug Product Stability General considerations in dosage form design…cont Before formulating a drug substance into a dosage form, the desired product type must be determined, Then various initial formulations of the product are developed and examined for desired features (e.g., drug release profile, bioavailability, clinical effectiveness) and for pilot plant studies and production scale-up. The formulation that best meet the goals for the product is selected to be its master formula. Each batch of product subsequently prepared must meet the specifications established in the master formula. 7  There are many different forms into which a medicinal agent may be placed for the convenient and efficacious treatment of disease. Most commonly, a manufacturer prepares a drug substance in several dosage forms and strengths for the efficacious and convenient treatment of disease. Before medicinal agent is formulated into one or more dosage forms, among the factors considered are such therapeutic matters as: 1. The nature of the illness, 2. The manner in which it is treated (locally or through systemic action) 3. The age and anticipated condition of the patient. Tablet Excepients 1) Essential Excepients 2) Non Essential Excepients 1.1 Diluents or Filler. 2.1 Surfactant. 1.2 Binder. 2.2 Colorant. 1.3 Lubricant. 2.3 Flavour. 1.4 Disintegrant. 2.4 Sweetener. 1.5 Glidant. 2.5 Adsorbent. 1.6 Anti-adherent 8 Excipients function Excipient category Function in formulation Working principle Examples Diluents Fillers Make up the bulk of solid unit Lactose,Starches, dosage forms when drug itself Dextrose, Sorbitol is inadequate to produce the bulk. Binders and Impart cohesive qualities to Improves free flow qualities by Acacia, Gelatin, Starch Adhesives powdered material. formulation of granules to paste, Glucose, povidone. desired hardness and size. Lubricants Reduce inter-particular Interpose a film of low shear Talc, Stearic acid, friction, prevent adhesion. strength that interface between Polyethylene glycol the tabletting mass and die wall Glidants Improve flow characteristics Added in dry state prior Colloidal Silicone dioxide of powder mixture compression, it reduces friction (Carbosil), Asbestos free between particles starch, Corn starch. Disintegrants Facilitate breakup or Function by drawing water into Starches, Clays, disintegration after the tablet, swelling it and Cellulose, Cross administration causing the tablet to burst apart. Povidone, Sodium starch glycolate. Coloring agents ( Impart aesthetic FD and C, D and C dyes these must be appearance to dosage and lakes. approved and form, disguising off color certified by F.D.A) drugs, product identification Excipients function Excipient Function in formulation Working principle Examples category Sweeteners. Impart sweet taste to the Mannitol, Saccharin.etc formulation; use is limited to chewable tablets Sorbents. Moisture proofing Limits the fluid sorbing, taking up of Silica gel, activated liquid or gas either by adsorption or carbon, clay ect. absorption in dry state Coating Protect tablet ingredients Hydroxypropylmethyl materials from detoriation by moisture, cellulose (HPMC), help swallowing unpleasant Synthetic polymers, tasting tablets Shellac, Corn protein Zein, Polysaccharides, Plasticizers. For soft gelatin capsule Produce elasticity and flexibility to the Castor oil, Diacetylated preparation, gelatin based coating materials in case of tablets, Monoglycerides, suppositories, film coated determine hardness of capsule shell Polyethylene glycol, tablets etc in case of soft gelatin capsule and impart softness and resilience to suppositories. Flavors. Limited to chewable tablets/ Mask unpleasant taste Spray dried and other tablets intended to dissolve in flavors, syrups etc mouth. 9  Excipients selection Excipients can be considered as indispensible component of medicinal products. They are present in greater proportion with regards to active pharmaceutical ingredient, as it forms the bulk of the formulation. It is always necessary to select an excipient which satisfies the ideal properties for a particular excipient Excipients selection Selection based characteristics: Functionality. Material consistency. Regulatory acceptance. Cost. Availability. Sources Interaction with AI, other excipient an packaging. 10  Excipients selection Rout of administration. physicochemical properties. Stability. Compatibility issue. Pharmacokinetic attributes. Permeation characteristics. Absorption behavior. Drug delivery platform. Excipient interaction Excipient compatibility tests allows us to determine drug excipient interactions which can be either avoided or can be modified to utilize in an efficient manner which helps in minimizing the risk associated with the excipients. Drug-excipient interaction Excipient-excipient interaction Package-excipient interaction 11 SELECTION OF TEChNOLOgY FOr SOLId dOSagE FOrmS dC & graNULaTION 12  Tablet Formulation Indeed powder intended for tablet formulation must possess two essential properties. Fluidity (good powder flowability) - The materials can be transported through the hopper into the die. - To produce tablet in constant weight. Powder flow can be improved mechanically by the use of vibrator and/or incorporate glidant. Compressibility. The property of forming a stable, intact compact mass when compression is applied. If we cannot get good compressibility even after adding binder. Thus, there is need for granulation prior tablet formulation. STAGES IN TABLET FORMATION The process of tabletting can be divided into three stages: 1) Die filling: The flow of the powder from a hopper into the die. 2) Tablet formation: The upper punch descends and enters the die and the powder is compressed until a tablet is formed. 3) Tablet ejection: The lower punch rises until its tip reaches the level of the top of the die. 13  STAGES IN TABLET FORMATION Needs Needs Free Flowing Good Binding Granules Filling Compression Needs Needs Lubrication Lubrication Tablet Ejection Tablet Removal Stages in tablet formation 14 Compression and Compaction Compression: Reduction in bulk of volume of material due to displacement of gaseous phase. Consolidation: Increase in mechanical strength of material due to particle- particle interaction. Compaction: It is the compression and consolidation of two phases (solid & gas) system due to applied force. 15  Production Process May be divided into 2 Methods 1. Wet Method (Indirect Method) 1.1 Wet Granulation by Aqueous Solution 1.2 Wet Granulation by Organic Solvent 2. Dry method 2.1 Granulation by Compression (Slugging, Roller Compaction) 2.2 Direct Compression 16  Wet Granulation Widely employed method for the production of compressed tablets. In this process granules are formed from wetted mixtures of the pre-blended tablet ingredients , which are then dried , screened and compressed into tablets. This method is often employed in tablets that have either a low dose or very potent active ingredients but are not moisture and heat sensitive. Steps: weighing and blending the ingredients. preparing the wet granulation (wet mass). screening the damp mass into pellets or granules. drying dry screening lubrication and blending. tabletting by compression. Wet Granulation (1) Active Ingredient Dry Mixing Additive Machines used Wet Mixing Binder Solution Solvent is either in Dry Mixing Organic Solvent Wet Mixing or Water Wet Granulation Wet Granulation Next 17  Mixer & Wet Granulator Raw Material in fine Powder Wet Granules Wet Granulation (2) Wet Granulation Q.C. -Moisture Machines used Content in Drying Drying Next 18  Dryer Dried Granules Wet Granules Wet Granulation (3) Drying Q.C. Machines used in - Content Dry Granulation - Moisture Dry Blender Dry Granulation Disintegrant Dry Lubricant Blending Tabletting 19  Dry Granulator & Dry Blender Granules for Tabletting Dried Granules Mixers Ribbon Mixer Zigma Blade Mixer 20 High Speed Mixer & Wet Granulator 21 High Speed Mixer Wet Granulator 22 Dryers Tray Drying Oven Fluid Bed Dryer 23  Fluid Bed Dryer Granulators Dry Granulator 24 25 Tablet Production Process Weighing Dry Mixing Wet Mixing Dry Granulation Drying Wet Granulation Dry Blending Tabletting Film Coating Packaging 26  Fluid Bed Spray Granulation Can replace granulation & drying process Weighing Dry Mixing Wet Mixing Dry Granulation Drying Wet Granulation Dry Blending Tabletting Film Coating Packaging Dry granulation method It is often used with ingredients which are moisture or heat sensitive. Dry granulation utilizes dry, pre-blended mixtures of ingredients which are then compacted into large granules (“slugs”). The granules are then crushed, screened and compressed into tablets. This method is useful in the granulation of aspirin and effervescent tablets. 27 Dry Granulation Dry Mixing Active Ingredient Slugging or Additive Compaction Dry Granulation Q.C. Lubricant Content Dry Mixing Disintegrant Tabletting 28  Direct Compression In the direct compression process, tablets are compressed directly from blends of the active ingredients and suitable excipients. These blends include all appropriate fillers, disintegrants, and lubricants and require no further pre- treatment prior to tabletting. Direct compression has become widely accepted and continues to grow in popularity because it offers several major advantages, such as Economical ( reduced labour costs , manufacturing time , less equipment , energy and space ). Suitable for heat and moisture sensitive drug. Optimized tablet disintegration. Stable. Direct Compression Mill Active Ingredient & Sieve Diluent for Direct Compression Disintegrant (if necessary) Mix Glidant (if necessary) 15 min Other excipient (Color, etc.) Mix Lubricant 5 min Q.C. Content Compress Tablet 29 How The Tablets can be prepared by wet granulation method 1. Weighing and blending: The active ingredient and any filler and disintegration agent ( or part thereof ) are weighed and mixed thoroughly. 2. Preparing the wet granulation: The powder is converted to granules in order to improve flow characteristics. The wet mass will be prepared by adding a liquid binder. Colours and flavours can also be added. If the drug substance is affected by water, then a non aqueous binder can be used. 3. Screening the damp mass into pellets or granules: Pass the wet mass through a sieve or screen, wet granules are obtained. How The Tablets can be prepared by wet granulation method…… cont 4. Drying the granulation: Spread in a single layer over a sheet of paper or a shallow tray and put in oven or dry in a fluidized bed drier. 5. Dry screening: After the granules are dried, pass through a screen of smaller size than the one used for the wet mass. This process is necessary to select granules of uniform size to allow even fill in the die cavity. 6. Lubrication: A dry lubricant, antiadherent and glidant are added to the granules either by dusting over the spread-out granules or by blending with the granules. 7. Tabletting: The granule/lubricant mixture is fed through a hopper in the die cavity and then compressed between a lower and an upper punch. 30  Tabletting machine Tablets are prepared by compressing solid powders using tabletting machines. There are 2 types of tablet press; the single punch or eccentric machine and the rotary tablet machine. Irrespective of the type of tablet machine, in general the most important parts of the machinery include: a) Hopper for storing the materials into the dies ; b) Feed frame (hopper shoe) for distributing the materials into the dies ; c) Dies for controlling the size and shape of the tablet ; d) Punches for compacting the materials within the dies ( they also shape the tablet ; and e) Cams for guiding the punches. Types of Tablet machine Single punch press Rotary punch press 31  Single Punch Tablet Press  Single punch tablet press is also called as a eccentric press or single station press.  It is most simplest machine for tablet manufacturing.  Single station tablet press employs a single tooling station that is a die and a pair of upper and lower punches.  This tablet press is available as both manually operated and power driven.  The compaction force on the fill material is exerted by only the upper punch while the lower punch is immovable such as action equivalent to hammering motion. 32 33 Rotary Tablet Press It is also called multi station tablet press. Multi station presses are termed rotary because the head of the machine that holds the upper punches, dies and lower punches in place rotates. 34  Auxiliary Equipments 1.Granulation Feeding Device: In many cases, speed of die table is such that the time of die under feed frame is too short to allow adequate or consistent gravity filling of die with granules, resulting in weight variation and content uniformity. These also seen with poorly flowing granules. To avoid these problems, mechanized feeder can employ to force granules into die cavity. 2..Tablet weight monitoring devices:- High rate of tablet output with modern press requires continuous tablet weight monitoring with electronic monitoring devices 35  Auxiliary Equipments…. Cont. 3. Tablet Deduster In almost all cases, tablets coming out of a tablet machine bear excess powder on its surface and are run through the tablet deduster to remove that excess powder. 4. Fette machine Fette machine is device that chills the compression components to allow the compression of low melting point substance such as waxes and thereby making it possible to compress product with low meting points. 36  Quality Control of Tablets 1. Uniformity of Weight. 2. Uniformity of Diameter. 3. Uniformity of Thickness. 4. Hardness Test. The hardness of tablets is related to their strength and ability to withstand the shocks and frictions during normal handlings, packing, shipping, storage, and dispensing. 5. Friability Test Friction, pressure and shock are the forces which may cause the tablets to chip, cap or break during production, handling, transportation and storage. The friability test is design to induce self-abrasion and pressure as the cylinder rotate and shock as the tablets falls 6 inches on each turn. 37 HARDNESS TESTER Friability tester 38  Quality Control of Tablets….. cont 6. Disintegration Test The disintegration test simply identifies the times required for a tablet to break up under the test condition and for all particles to pass through a 10 mesh screen. The test offers no assurance that the resultant particles will release the drug in solutions at appropriate rate. 7. Dissolution Test In order for a drug to be absorbed, it must first be dissolved in the fluid at the absorption site. For instance, a drug administered orally in tablet or capsule form cannot be absorbed until the fluids in the gastrointestinal tract solubilize the drug particles. Disintegration Tester 39  Dissolution Tester TABLET PROCESSING PROBLEMS AND ITS REMEDIES Capping The upper or lower segment of the tablet separates horizontally, either partially or completely from the main body and comes off as a cap, during ejection from the tablet press, or during subsequent handling. Reason: Due to the air–entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die. 40 The Causes and Remedies of Capping related to ‘Machine’ Lamination Separation of a tablet into two or more distinct horizontal layers. Reason: Air–entrapment during compression and subsequent release on ejection. The condition is exaggerated by higher speed of turret. 41 The Causes and Remedies of Lamination related to ‘Machine’ Chipping Breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations. Reason: Incorrect machine settings, specially mis-set ejection take-off. 42 The Causes and Remedies of Chipping related to ‘Machine’ Cracking Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as ‘Cracks’. Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used. 43 The Causes and Remedies of Cracking related to ‘Machine’ Sticking Tablet material adhering to the die wall. Filming is a slow form of sticking and is largely due to excess moisture in the granulation. Reason: Improperly dried or improperly lubricated granules. 44  The Causes and Remedies of Sticking related to ‘Machine’ Picking Small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face. The problem is more prevalent on the upper punch faces than on the lower ones. Reason:  Picking is of particular concern when punch tips have engraving or embossing letters.  Granular material is improperly dried. 45 The Causes and Remedies of Picking related to ‘Machine’ Double Impression  Involves only those punches, which have a monogram or other engraving on them.  If the upper punch is uncontrolled, it can rotate during the short travel to the final compression stage and create a double impression. Reason:  At the moment of compression, the tablet receives the imprint of the punch.  The lower punch freely drops and travels uncontrolled for a short distance before riding up the ejection cam to push the tablet out of the die  Now during this free travel, the punch rotates and at this point, the punch may make a new impression on the bottom of the tablet, resulting in ‘double impression’. 46 The Causes and Remedies of Double Impression Mottling: It is an unequal distribution of color on the surface of the tablet. Reason: Can be due to drug and excipients of different colours and/or formation of degradation products. 47 48