Tablets PDF

# Tablets - Solid dosage forms of medicinal substances - Usually prepared with the aid of suitable pharmaceutical excipients - Generally by compression - And mostly intended for oral administration ## Advantages of Tablets 1. They are a unit dose form, and they offer the great capabilities of all...

# Tablets - Solid dosage forms of medicinal substances - Usually prepared with the aid of suitable pharmaceutical excipients - Generally by compression - And mostly intended for oral administration ## Advantages of Tablets 1. They are a unit dose form, and they offer the great capabilities of all oral dosage forms for the high dose precision and the very low content variability. 2. Their cost is one of the lowest among oral dosage forms. 3. They are the one of the lightest and most compact of all oral dosage forms. 4. They are in general the easiest and cheapest to package and ship of all oral dosage forms. 5. Product identification is potentially simplest and cheapest, requiring no additional processing steps when employing an embossed or monogrammed punch face. ## Disadvantages of Tablets 1. Some drugs resist compression into dense compacts, owing to their amorphous nature or flocculent, low-density character. Hygroscopic drugs are also not suitable candidate for compression into tablets. 2. Drugs with poor wetting properties, slow dissolution profile, intermediate to large dosages, low absorption in the gastrointestinal tract, or any combination of these features may be difficult or impossible to formulate and manufacture as a tablet. Naturally liquid drugs are also difficult to formulate as tablets. 3. Bitter-testing drugs, drugs with an objectionable odor, or drugs that are sensitive to oxygen or atmospheric moisture require encapsulation or entrapment prior to compression, or the tablets may require coating. In such cases, the capsule may offer the best and lowest cost approach. 4. Some drugs which preferably get absorbed from the upper part of GIT may cause bioavailability problem in tablet dosage form. 5. Swallowing of tablets especially by children and critically ill patients is very difficult.. ## Types of Tablets ### A) Tablets ingested orally 1. Compressed tablets or standard compressed tablets (CT) 2. Multiple compressed tablets (MCT) 3. Layered tablets 4. Compression-coated/ press-coated tablets 5. Delayed-action and enteric coated tablets 6. Repeat action tablets 7. Sugar- and chocolate-coated tablets 8. Film-coated tablets 9. Chewable tablets ### B) Tablets used in the oral cavity 1. Buccal tablets 2. Sublingual tablets 3. Troches and lozenges 4. Dental cones ### C) Tablets administered by other routes 1. Implantation tablets 2. Vaginal tablets ### D) Tablets used to prepare solutions 1. Effervescent tablets 2. Dispensing tablets 3. Hypodermic tablets 4. Tablet triturates ## Compressed Tablets (CT) - Uncoated - Compression made - Intended to provide rapid disintegration and drug release - Most tablets of this type contain drugs those exert local effect in GIT - Compressed tablets can also contain systemic effect producing drugs ## Multiple Compressed Tablets (MCT) - **Prepared for either of the two reasons:** - To separate physically and chemically incompatible ingredients - To produce repeat-action or prolonged-action - The performance of repeat-action products is highly dependent on gastric emptying time because the immediate release part disintegrates at stomach and the sustained release part (insoluble in gastric media) at intestine. - If the product quickly leaves the stomach, different blood level profile results from the early release of the sustained release part than anticipated. - So, for producing repeat-action, this type of tablets is less used. - **Two types:** - **Layered tablets:** These tablets are sandwich type; edges of each layer are exposed and are prepared by layer of granulation compressed together. - **Compression coated/ Press coated/ Dry coated tablets:** All qualities of compressed tablet with benefits of taste masking of core tablet and protection of core tablet from stomach fluid. Tablet surrounded by granules compressed together to form this type of tablet. - **Both types may be either two component or three component systems:** - 2 layer or 3 layer tablets - a tablet within a tablet or a tablet within a tablet within a tablet. ## Multiple Compressed Tablets (MCT) - Produced by light compression at each stage and then final main compression. Therefore, production speed of these tablets are slower than compressed tablets especially compression coated tablet. - Layered tablets are preferred to compression coated tablet because - Surface contact between layers are less - Production is simple and more rapid ## Repeat-Action Tablets - Action depends on uncontrolled and unpredictable gastric emptying - Can be formulated as - Multiple compressed tablet - Sugar coated tablet: The core tablet is coated with shellac or enteric polymer and the second dose of drug is added in sugar coating, either as solution/suspension in sugar syrup or as dusting powder for rapid coat build up. ## Delayed-Action and Enteric Coated Tablets - **Reasons:** - To delay drug release time for controlled-release action e.g., intestinal antibacterial, antiseptic or for preventing nausea / vomiting - To let tablet pass some part through GIT., e.g., Enteric coated (intact in stomach but release drug in upper intestine). - Drugs inactivated or destroyed at stomach, e.g: Erythromycin - Drugs that irritate gastric mucosa, e.g,: aspirin on regular use and strong electrolyte e.g: NHCl, just delay the release ( compressed release dosage form or release drug diluted and highest concentrated)- intestinal, antibacterial, antiseptic, produce nausea / vomiting. ## Sugar-Coated and Chocolate-Coated Tablets ### Chocolate coated tablets - Now used rarely because children can mistake it as candy. ### Sugar-coated tablets - **Reasons:** - Elegant, glossy appearance and easy to swallow tablet - Using incompatible ingredient together (multivitamin and multivitamin-multimineral) - Masking objectionable odor or taste - Protecting from oxidation - **Limitations:** - Time consuming - Skilled personnel required - Increased tablet weight - High cost - Can be mistaken for candy ## Film-Coated Tablets - Generally, drug is not given in coating - Coating solution is prepared from one or more polymer (plasticizer+surfactant) dissolved in - organic solvent (costly, harmful, limitation of disposed to atmosphere; less used now) - or water - **Advantages:** - Better mechanical strength of coating (elasticity and flexibility) - Little increase in tablet weight - Ability to retain debossed marks through thin coat - Avoidance of sugar (contraindicated for some population) - Continuous and automated process used - Not mistaken for candy - Less time required for coating ## Chewable Tablets - Chewed in mouth and then swallowed. Not swallowed as intact. E. g., chewable aspirin for child and antacids - **Purpose:** - The purpose of chewable tablet is easy administration to child, infant and elderly who have difficulty in swallowing intact tablet. - Antacid formulations in which the size of the tablet is normally large and the neutralization efficacy of the tablet is related to particle size within the stomach. - **Limitations:** - Bitter or foul-tasting drugs can't be used. ## Buccal / Sublingual Tablets - Intended to be held in the mouth - Buccal: Tablet is held between cheek and teeth or in the cheek pouch - Sublingual: Tablet is held under tongue - Usually small and flat tablets - Release drug content for direct absorption through oral mucosa - Used for systemic effect, so good absorption though mucosa is required - Tasteless excipients, which don't stimulate salivation, should be used - Tablet should dissolve slowly (15-30 minutes) rather than disintegrate ## Buccal / Sublingual Tablets - **Advantages:** - Avoids first pass metabolism - Prevents nausea production upon swallowing certain drugs, e.g., methyl testosterone - Prevents drugs from extensive decomposition in gastric environment, e.g., certain steroids and hormones. - Rapid onset than swallowed tablet - **Limitations:** - Bitter or foul-tasting drugs can't be used. ## Troches and Lozenges - Used for local effect in mouth and throat like treating sore throat, controlling cough in common cold, e.g.., local anesthetic, demulcents, antiseptic and antibacterial, astringent, antitussive. - Tablet should dissolve slowly (30 minutes or less) rather than disintegrate ### Lozenges: - Drug is incorporated in flavored hard candy sugar base - Formed by compression / fusion/ candy molding ### Troches: - Formed by compression ## Dental Cones - Minor tablet, placed in empty socket remaining after tooth extraction - **Prevent bacterial multiplication by:** - slow releasing antibacterial agent or - reducing bleeding by astringent or coagulant.. - **Commonly used vehicle of these tablets are NaHCO3 NaCl, Amino acid** - Dissolve or erode slowly (20-40 minutes) in presence of small volume of serum or fluid of the extraction site. ## Implantation Tablets / Depot Tablets - Subcutaneous implantation - Provide prolonged drug effect (1 month to 1 year) through as constant drug release rate as possible - Usually small, cylindric/ rosette shaped (length ≤ 8mm) - **Limitations (safety problems):** - Surgical technology needed to discontinue the therapy. - Tissue toxicity in implantation area can occur. ## Vaginal Tablets - Slow distribution and drug release in vaginal cavity - Ovoid or pear shaped tablets - **Uses:** - to treat infection with antibacterials, antiseptics, astringents - to release steroids for systemic absorption ## Effervescent Tablets - Rapidly soluble with simultaneous release of CO₂ (1 min or less) - Active ingredient is mixed with organic acid (e.g., citric or tartaric acid) and NaHCO3 - Produce clear solution and also a pleasantly flavored carbonated drink - Water soluble excipients required - **Advantages:** - Extemporaneously prepare solution with accurate dose - Helps in taste masking - **Limitations:** - Limited use as difficult to produce chemically stable product because moisture in air is adequate to initiate effervescent activity - Special packing required to protect from moisture after opening the container and also due to soft nature ## Dispensing Tablets (DT) - Intended to be added to a given volume of water - Commonly incorporated materials are bichloride of mercury, germicidal solution - Totally soluble components are used in formulation - May contain buffering or isotonicity creating excipients - **Limitations:** - Less commonly used now as water quality is unknown to produce sterility - Some components are extremely hazardous, even lethal if swallowed accidentally. ## Hypodermic Tablets (HT) - Readily water soluble - Added to sterile water or water for injection - Not used now, used previously in rural areas by physicians (They usually carried hypodermic tablets, lots of vial and one bottle of water for injection to visit patients at their home. Non sterility can occur). ## Tablet Triturates (TT) - Small, cylindrical, molded or compressed (through boar wood or plastic and pegboard to eject) tablet - Potent drugs are used. - **Limitations:** - Soft and fragile tablets - Drug loss ## Formulation of Tablets Compressed tablets usually consists of active ingredients mixed with a number of inert substances known as excipients or additives like - 1. Diluents 2. Binders 3. Disintegrating agent 4. Lubricants 5. Coloring agents 6. Flavoring agents 7. Sweetening agents ### 1. Diluents/ Fillers: - Employed in the formulation of tablets (by all methods) to increase the mass of the tablets that contain a low concentration of therapeutic agent - Render the manufacturing process more reliable and reproducible - Must exhibit good compression properties - Should be inexpensive - **Examples:** - (1) anhydrous lactose; (2) lactose monohydrate; (3) spray-dried lactose; - (4) starch - (5) dibasic calcium phosphate - (6) microcrystalline cellulose (MCC) - (7) mannitol. ### 2. Binders: - Predominantly (but not exclusively) polymeric components - Employed in the production of tablets by the wet granulation method - Can be added as a solution or as a solid into the powder mix (following which the granulating fluid, typically water, is added). - **Examples:** - Binder | Concentration | General comments - :----- | :------------ | :--------------------- - Hydroxypropylmethylcellulose | 2-5% w/w | The required concentration is dependent on molecular weight (grade) used - Polyvinylpyrrollidone | 0.5-5% w/w | The required concentration is dependent on molecular weight (grade) used - Hydroxypropylcellulose | 2-6% w/w | The required concentration is dependent on molecular weight (grade) used - Sucrose | 50-67% w/w | Added as a syrup - Microcrystalline cellulose | 20-90% w/w | Produces hard tablets whose properties are affected by moisture. Often used as a binder and diluent. - Acacia | 1-5% w/w | Produces hard tablets ### 3. Disintegrating agents: - Employed in tablet formulations to facilitate the breakdown of the tablet into granules upon entry into the stomach. - There are several mechanisms by which disintegrants elicit their effect: - 1. By increasing the porosity and wettability of the compressed tablet matrix - 2. By swelling in the presence of aqueous fluids, thereby expediting tablet disintegration due to the increase in the internal pressure within the tablet matrix - 3. By the production of gas whenever the tablet contacts aqueous fluids. - **Examples:** Starch, MCC, sodium starch glycolate, croscarmellose sodium, crospovidone, pregelatinised starch ### 4. Lubricants: - Act at the interface between the face of the die and the surface of the tablet (during compression) and act to reduce the friction at this interface during ejection of the tablet from the tablet press - Inadequate lubrication : tablets with a pitted surface - There are two main categories of lubricant: - (1) Insoluble: Added to the final mixing stage prior to tablet compression. E.g.: magnesium stearate, stearic acid, Glyceryl palmitostearate - (2) Soluble: principally employed to overcome the possible deleterious effects of their insoluble counterparts, but less efficient compared to insoluble lubricants. E.g. Polyethylene glycol (PEG 4000/6000/8000), polyoxyethylene stearates ### Considerations for lubricant addition: - The concentration of lubricant used is an important consideration in the subsequent disintegration and dissolution of the drug from the tablet: - high lubricant concentrations reduced rates of disintegration and dissolution possible failure of the quality control tests - The time of mixing of the lubricant with the granules/powders and the particle size of the lubricant will affect the performance of the lubricant: - overmixing may adversely affect tablet disintegration and drug dissolution - Mixing of the disintegrant and the insoluble lubricant together should be avoided. ### 5. Glidants: - Enhance the flow properties of the powders within the hopper and into the tablet die in the tablet press. - Ability of the particles of the glidants to locate within the spaces between the particles/granules reduced friction - Typically hydrophobic care should be taken about the conc. Used - **Example:** - Talc, colloidal silicon dioxide ## Methods used for the manufacturing of tablets - Materials intended for compression into a tablet must possess two characteristics - fluidity and compressibility. Unfortunately most materials do not easily form spheres, the ideal physical form to flow smoothly and uniformly. - Therefore, attempts are taken to improve the flow of powdered materials by forming sphere-like or regularly shaped aggregates called granules. This process of forming granules is known as granulation. - Tablets are commonly manufactured by one of the following manufacturing processes: : - Direct compression - Dry granulation (slugging or roller compaction) - Wet granulation ## Methods used for the manufacturing of tablets ### Fluid bed granulation: - In addition to these three basic methods, recent technology has permitted the procedure of tablet granulation by the liquid bed process, known as 'fluid bed granulation'. It is called the all in one granulation method. ## Methods used for the manufacturing of tablets - The process performs the following with a single piece of equipment - the fluid bed granulator. - Preblending the formulation powder (including active ingredients, diluents & disintegrants etc.) - Granulation by means of a suitable liquid binder (e.g., aqueous solution of acacia, hydroxyl propyl cellulose, povidone etc.) - Drying the granulated product to the desired moisture content. ## Manufacture of tablets by direct compression - A potentially more attractive option for the manufacture of tablets- powder mixing compression of the powder mix {thereby obviating the need for granulation (and related unit operations)}. - This process is termed direct compression. ## Manufacture of tablets by direct compression - Some crystalline or granular substances e.g. NaCl, NaBr, KCI, NHCl etc. possess free flowing as well as cohesive properties that enable them to be compressed directly in a tablet machine without the need of either wet or dry granulation. - **Stages in the manufacture of tablets by direct compression:** - 1. Premilling of formulation components - Frequently the particle size properties of the drug may require to be modified by milling (Fitzmill or Quadro Comil) - 2. Mixing of the therapeutic agent with the powdered excipients (including the lubricant) - 3. Compression of the mixed powders into tablets ## Manufacture of tablets by direct compression - **The feed throat**: introduces material on a tangential path to the comminuting chamber - **Blade profile**: Helps determine degree of reduction based on material being processed - **Screen type**: Helps regulate particle output within a specified size range - **Rotor speed**: Helps regulate particle output within the specified size range ## Manufacture of tablets by direct compression - Excipients used in direct compression should have the following characteristics: - Possess good flow and compressibility - Inert - Tasteless - Re-workable - Able to disintegrate - Inexpensive - **Commonly used excipients are-** - Diluent- Spray dried lactose, microcrystalline cellulose, dicalcium phosphate etc. - Disintegrants- Direct compressible starch (sta-Rx-1500), sodium carboxy methyl starch, povidone etc. - Lubricants- Mg- stearate, talc, polyethylene glycol etc. ## Manufacture of tablets by direct compression - **Advantages:** - 1. Low labor input. - 2. Few processing steps. - 3. Capping or splitting is reduced. - **Disadvantages:** - 1. Diluents and other additives may interfere with the compressibility of the active ingredient. - 2. Difference in particle size and bulk density between the drug and diluents may lead to stratification within the powder. The powder stratification may then result in poor content uniformity of the drug in the compressed tablets especially with low dose drugs. - 3. Most materials cause relatively weak intermolecular action or are covered with films of adsorbed gas hinder compaction. Thus most large dose drugs do not lend themselves of this process. To facilitate compression large amount of diluents are required. The resultant tablets are costly and difficult to swallow. - 4. Diluents may interact with the drugs e.g. reaction between amine drug and spray-dried lactose causes a yellow discoloration. - 5. Because of the dry nature of the direct compression, static charge build up can occur on the drug during routine screening and mixing, which may prevent a uniform distribution of the drug on the mass. ## Manufacture of tablets by DRY GRANULATION - Dry granulation is formed not by moistening or adding a binding agent to the drug mixture but by compacting large masses of the mixture and subsequently crashing and sizing these into smaller granules. By this method either the active ingredients or the diluents must have cohesive properties in order for the large manufactured form. - Aspirin, enzyme and vitamin tablets etc. are prepared by this method. ## Manufacture of tablets by DRY GRANULATION - There are two methods by which dry granules are formed: - (1) slugging: powders are mixed and then compressed into a oversized tablet using a tableting press that is capable of applying a high stress (to ensure that aggregation of the particles and then aggregation of granules occur during compaction). Following this the tablet is milled to produce granules of the required size. - (2) roller compaction: the powders are fed from a hopper on to a moving belt and then transported to, and compressed by, the passage between the narrow gap between two (oppositely) rotating rollers to produce a sheet/film of compressed material. The compressed sheet is then milled to produce granules of the required size. ## Manufacture of tablets by DRY GRANULATION - **Excipients used in dry granulation** - Similar to those described for wet granulation. Typically, the following excipients are required:- - Diluent/filler, e.g.: anhydrous lactose or lactose monohydrate - starch - dibasic calcium phosphate - МСС. - Disintegrants, e.g.: starch - MCC - sodium starch glycolate - croscarmellose sodium - crospovidone. - Lubricants, e.g.: stearates (magnesium stearate, stearic acid) - glyceryl fatty acid esters (glyceryl behenate, glyceryl palmitostearate) - PEG - polyoxyethylene stearates - sodium lauryl sulphate. - Glidants, e.g.: - talc - colloidal silicon dioxide - Miscellaneous excipients (colours, sweetening agents, etc.). ## Manufacture of tablets by DRY GRANULATION - **Advantages** - 1. Both roller compaction and slugging require conventional (i.e. non-specialist) grades of excipients. - 2. These methods are not generally associated with alterations in drug morphology during processing. - 3. No heat or solvents are required. - **Disadvantages** - 1. Specialist equipment is required for granulation by roller compaction. - 2. Segregation of components may occur post-mixing. - 3. There may be issues regarding powder flow. - 4. The final tablets produced by dry granulation tend to be ---------- those produced by wet granulation, rendering them more using post-tableting techniques, e.g. film coating. - 5. Slugging and roller compaction lead to the generation of considerable dust. Therefore, containment measures are required. - 6. Furthermore, there may be a reduction in the yield of tablets. ## Manufacture of tablets by WET GRANULATION - Wet granulation is the most widely employed method used in the manufacturing of tablet. - This method is popular as the granules meet all the qualities required for a good tablet. ## Manufacture of tablets by WET GRANULATION - **Steps involved-** - 1. Weighing and blending: The active ingredient, any diluent and disintegrating agent (or portion of it) are weighed and mixed thoroughly with a motor-driven blender or mixer. Example of blenders or mixers- planetary bowl mixers, drum mixers, high-speed mixers, ribon/trough mixers. - 2. Wet massing of the powders: This step employs a solution, suspension or slurry containing a binder, which is usually added to the powder mixture to make it moist (rather than wet or pasty). However the binder may be incorporated dry into the powder mix and the liquid may be added then. The method of binder introduction depends on its solubility and on the components of the mixture. Commonly used wet granulators- high-speed mixers/granulators, fluidized-bed granulators. - 3. Wet Milling or screening or sizing: The wet screening process involves converting the moist mass into coarse granular aggregates by passage through a hammer mill or oscillating granulator, equipped with screen having large perforations. Generally the wet granulation is pressed through a No-6 or No-8 mesh screen. The purpose is to further consolidate granules, increase particle contact point and increase surface area to facilitate drying. - 4. Drying: A drying process is required in all wet granulation procedures to remove the solvent that was used in forming the aggregates and to reduce the moisture content to an optimum level of concentration within the granules. Commonly used dryers: fluidized-bed dryer, tray dryer, spray dryer. - 5. Dry screening/sifting: After drying the granules are passed through a screen of a smaller mesh than that used to prepare the original granules. The size of the screen depends upon the grinding equipment used and the size of the tablet to be made. - 6. Lubrication and blending: After dry screening, a dry lubricant is generally added to the granules. So that each granule is covered with lubricant, it may be dusted over the spread-out granulation through a fine mesh screen or blended in a powder mixer. - 7. Tableting by compression: Tableting means the production of tablets by compression of the tablet granulation within a steel die cavity by the pressure excreted by movement of two steel punches, a lower punch and an upper punch. ## Manufacture of tablets by WET GRANULATION - **Flow diagram of wet granulation** - Drug+Diluent - Weighing and blending - Adhesive/binder - Wet massing of the powder - Wet sizing/milling - [Screening of large mass of granules (mesh no. 6-7)] - Drying (≤60°C) - Dry screening (mesh no. 12-20) - Lubricant - Lubrication and blending - Tabletting ## Manufacture of tablets by WET GRANULATION - **Advantages** - 1. Reduced segregation of formulation components less intra- and inter-batch variability. - 2. Useful technique for the manufacture of tablets containing low concentrations of therapeutic agent. - 3. Employs conventional excipients. - 4. Most manufacturing plants are built around wet granulation tablet manufacture. - 5. Tablets produced by wet granulation are amenable to post-processing unit operations, e.g. tablet-coating techniques. ## Manufacture of tablets by WET GRANULATION - **Disadvantages** - 1. Often several processing steps are required. - 2. Drug degradation may occur in the presence of the solvent. - 3. The drug may be soluble in the granulation fluid. During the drying process the drug will then precipitate/crystallize, resulting in possible changes in the polymorphic form. If the drug and some excipients are soluble in the granulation medium, subsequent drying will result in deposition of these components on the surface of the insoluble particles and, in so doing, this may enhance the hardness of the granule. - 4. Heat is required to remove the solvent. This may result in the degradation of thermally labile therapeutic agents. - 5. Drying is a costly operation. - 6. If alcohols are used as the granulation medium, there are issues regarding solvent recovery and flammability. ## TABLETING: - Tableting means the final stage of tablet formation in which the tablet is produced by compressing a formulation containing a drug or with excipients on stamping machine called press. - **Basic component of tablet compression machine or tablet press:** - 1. Hopper(s) for holding and feeding granulation to be compressed. - 2. Dies that define the size and shape of the tablet. - 3. Punches for compressing the granulation within the dies. - 4. Cam tracks for guiding the movements of the punches. - 5. A feeding mechanism for moving granulation from hopper into the dies.