Chapter 8: Tablets Tablets
Solid dosage forms prepared by compression with the aid of suitable pharmaceutical excipients Vary in: size, shape, weight, hardness, thickness, disintegration and dissolution characteristics and in other aspects, depending on their intended use and method of manufacture For oral administration of drugs, others sublingually, buccally or vaginally, with features mist applicable to the routes of administration Some are scored allow to be easily broken into two or more parts
Characteristics of Ideal Tablets
Free of defects: chips, cracks, discoloration and contamination Strength to withstand mechanical stresses of production Stable Release medicinal agents in a predictable and reproducible manner
Types of Tablets
Compressed tablets (CT) No special coating manufactured with tablet machine with great pressure or compacting the powdered or granulated tableting material Contain pharmaceutical adjuncts: diluents or filters, binders or adhesives, disintegrants, antidiarrheals, etc Multiple compressed tablets (MCT) Prepared by: subjecting the fill material to more than a single compression Result: multiple layer or a tablet within a tablet, inner tablet (core) and outer portion (shell) Sugarcoated tablets (SCT) Compressed tablets with colored or uncoloured sugar layer: Protects the enclosed drug from the o environment Provides a barrier to objectionable o taste of odor Enhances the appearance o Permits imprinting of identifying o manufacturer’s information Disadvantages: o Time and expertise needed in the coating process o Increased shipping cost: 50% larger and heavier than uncoated Film-coated tablets (FCT) Are compressed tablets coated with a thin layer of polymer (cellulose acetate phthalate) capable of forming a skin like film Advantage: more durable, less bulky and less time consuming to apply than sugar-coating Gelatin-coated tablets (GCT) Innovation product: gelcap, a capsule shaped compressed tablet
Allows the coated product to be about 1/3 smaller than a capsule filled with an equivalent amount of powder More case in swallowing and more tamper evident Enteric-coated tablets (ECT) Have delayed release features Pass unchanged through the stomach to the intestines (tablet disintegrate and allow drug dissolution and absorption and/ or effect) Needed when drug substance: Destroyed by gastric acid Irritating to the gastric mucosa By-pass the stomach enhances the drug absorption in the intestines Tablets used in the oral cavity: Buccal and sublingual tablets Flat oval tablets to be dissolved in the buccal pouch (buccal tablet) or beneath the tongue (sublingual tablet) For oral absorption of drugs destroyed by gastric acid or poorly absorbed in the GIT Lozenges or troches Disc-shaped solid forms in a hard candy or sugar base Dissolved slowly for localized effect or systemic effect Chewable tablets Pleasant tasting have smooth, rapid disintegration (chewed or allowed to dissolve in the mouth) Have a creamy base, specially flavoured and colored mannitol Prepared by compression or wet granulation Xylitol: may be used in the preparation of sugar0free chewable tablets Effervescent tablets Prepared by compressing granular effervescent salts that release gas when in contact with water Molded tablet triturate (MIT) May be prepared by molding rather than by compression Resultant tablets are very soft and soluble and are designed for rapid dissolution The mold is made of hard rubber, hard plastic or metal Has 2 parts: the upper part (die) and the mower part (flat punches) Base is a mixture of finely powdered lactose with or without portion of powdered sucrose Compressed tablet triturate (CTT) Small, usually cylindrical, molded or compressed tablets (limited pressure) containing small amounts of usually potent drugs Sucrose and lactose are used for diluents Declined its use Hypodermic tablets (H.T.) Used by physicians for extemporaneous preparation of parenteral solutions rendered sterile
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Dissolved in suitable vehicle sterility attained, and the injection performed Easily carried in the physician’s medicine bag and injections prepared to meet the needs of the individual patients Advent of prefabricated injectable products and disposable syringes, declined its use Dispensing tablets (D.T.) Compounding tablets Used by the pharmacist to compound prescription and not dispensed to patients Contains large amount of potent substances enabling the pharmacist to obtain pre-measured amounts For compounding multiple dosage units Immediate-release tablets (I.R.) Disintegrate and release their medication with No special rate-controlling features, such as special coating and other techniques Instant disintegrating or dissolving tablets Disintegrate or dissolve in the mouth within 10 seconds to 1 minute Method of instant-release or disintegrating tablets Lyophilized foam (lyophilization techniques) Prepared by foaming a mixture of o gelatin, sugar, drug and other components and pouring the foam into a mold st o Zydis: 1 entry into the RTD field Disadvantage: taste masking can be a o problem since the drug is incorporated during the formation of the tablet Soft direct compression o Using standard tableting technology will enhance fluid uptake and tablet disintegration and dissolution Example product: Dimetapp: ND orally o disintegrating tablet Use of water-soluble excipients Designed to “wick” water into the o tablet for rapid disintegration Large scale lyophilizers o Water is removed from temperature sensitive or unstable product solutions and transformed to stable dry products with its original properties Extended-release tablets (E.R.) or controlled release (C.R.) tablets Are designed to release their medication in a predetermined manner over an extended period Vaginal tablets or inserts Uncoated bullet-shaped or ovoid tablets inserted into the vagina for local effect Contain antibacterials (against Hemophilia vaginitis) and antifungals (against Candida albicans)
Compressed Tablets
Physical features of compresses tablets are well known: oblong, round or unique in shape, thick or thin; large or small in diameter; flat or convex; unscored or scored in halves, thirds or quadrant The less concave the punch the more flat the resulting tablets Punches with raised impressions will have recessed impressions on the tablets Tablet diameters and shapes are determined by the die and punches used in compression
Tablet Weight and USP Weight Variation Test
Quantity of ill in die of a tablet press determines the weight of the tablet
Content Uniformity
Amount of active ingredient in each dosage unit lies within: 85% to 115% of the label claim is less than 6% standard deviation
Tablet Thickness
Determined by the diameter of the die, amount of fill permitted to enter the die, the compaction characteristics of the fill material, and the force or pressure applied during compression
Quality Standards and Compendial Requirements
Tablet thickness The greater the pressure, the harder the tablet Hard enough to resist breaking (normal handling) and yet soft enough to disintegrate (after swallowing) Minimum requirement for a satisfactory tablet: force of 4 kg (hardness tester) Tablet hardness and friability A tablet’s durability or tendency to crumble: the use of a friabilator Acceptable: maximum weight loss of not more than 1% of the weight of the tablets Tablet disintegration The basket rack assembly is raised and lowered in the immersion fluid at 29-32 cycle per minute, the wire screen always below the level of the fluid Tablet dissolution In vitro dissolution testing of solid dosage forms is important: Guides formulation and product development toward product optimization Manufacturing monitored: a component of the overall quality assurance program Ensures bioequivalence from batch to batch A requirement for regulatory approval of marketing for products registered with the FDA and regulatory agencies of other countries
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Factors Affecting Tablet Disintegration and Dissolution
Particle size of the drug substance Solubility and hygroscopicity of the formulation Type and concentration of the disintegrant, binder and lubricant Manufacturing, particularly the compactness of the granulation and compression force used in tableti ng
Apparatus Assembly Used for Drug Release and Dissolution Testing
USP apparatus 1 and 2 consists of the following:
Variable: speed stirrer motor Cylindrical stainless steel basket on a stirrer shaft (USP Apparatus 1) or a paddle as a stirring element (USP Apparatus 2) 1L vessel of glass or other inert transparent material fitted with a cover having a center port for the shaft of the stirrer and 3 additional ports, two for removal of samples and one for the thermometer Water bath
Pooled dissolution testing
The tablet must meet the stated monograph requirement for rate of dissolution Steps:
A volume of the dissolution medium is placed in o o the vessel and allowed to come to 37 C + 0.5 C Stirrer rotated at the speed specified at stated interval samples of the medium are withdrawn for chemical analysis of the proportion of drug dissolved
Successful in Vivo in Vitro Correlation (IVIVC)
Relates combination of drug’s solubility (high or low) and its intestinal permeability (high or low)
Categories:
High solubility and high permeability: dissolution rate is slower than the rate of gastric emptying Low solubility and high permeability: dissolution may be rate-limiting step for absorption High solubility and low permeability: permeability is the rate-controlling step, and only a limited IVIVC may be possible Low solubility and low permeability: significant problems are likely for oral drug delivery
Method of Compressed Tablet Manufacture
Wet Granulation Widely employed method for production of compressed tablets
Advantages: Traditional method for many drugs since it imparts compressibility Useful for fluffy powder (don’t flow or mix well) Thermolabile compounds Powders generating static change Wide range of available excipients Disadvantages: Some drugs are moisture sensate (esterhydrolysis) or heat sensitive Binder needed in the excipient mix Multiple steps, lots of equipmenttime, space, money, personnel, material loss Expertise required Steps: Weighing and blending Diluents or filler, and o disintegrating agent are mixed by mechanical powder blender or mixer until uniform Preparing the damp mass A liquid blender is added to o the powder mixture to facilitate adhesion of the powder particles Screening the damp mass into pellets or granules o The wet mass is pressed through a screen to prepare the granules Drying the granulation Granules may be dried in the o thermostatically controlled ovens that constantly record the time, temperature, and humidity Sizing the granulation by drying screening After drying, the granules are o passed through a screen of a smaller mesh than that used to prepare the original granulation Adding lubrication and blending o After dry screening, a dry lubricant is dusted over the spread-out granulation through a mesh screen Wet granulation pelletization Two all-in-one granulation methods Fluid bed granulator performs the following steps: (continuous operation) Preblending the formulation o powder Granulating the mixture by o spraying onto the fluidized powder bed Drying the granulated o product to the desired moisture content
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Dry granulation
Powder mixture is compacted in large pieces or slugging and broken down or sized into granules Either the active ingredient or the diluents must have cohesive properties Advantages: for materials degraded by moisture or elevated temperature during drying
The GPS of Fluid Bed Process
Microwave Vacuum Process
Types of dry granulation
Slugging: after weighing or mixing the ingredients, the powder mixture is slugged, or compressed into large flat tablets, or pellets about 1 inch in diameter Roller compaction: powder compactors (instead of slugging) used to increase the density of the powder by pressing it between roller at 1 ton to 6 tons of pressure Property of granulation important in making tablets Provides the powders free flowing Increases material density (use of roller compaction) improving powder compressibility
Mixing and granulation Combines the active powder with a binder solution using a high speed mixing blade and chopper Capacity: from 36 to 1800L Precision Granulation
Capping: partial or complete separation of the top or bottom crowns of a tablet from the main body of the tablet and unclean punches and imperfectly smooth or by granulation with too much fine Splitting/laminations/horizontal striations: separation of the tablet into 2 or more distinct layers, aging tablets or improper storage
Results from excessive moisture or substances with low melting point temperatures in the formulation
High Shear Granulation
Results from air entrapment and high speed p roduction
Using microwave Powder mix is mixed, wetted, agglomerated and dried
Tablet Production Processing Problems Encountered
Conditions at which materials are applicable for dry granulation
Possesses free flowing and cohesive properties Thus, be compressed directly in a tablet machine without the need of granulation Direct compression tableting Compressed directly into a tablet machine without need of granulation Granular chemicals possess free flowing and cohesive properties (example: potassium chloride) Free flowing property of a drug mixture is a requirement for the manufacture of tablets of these methods: wet granulation, dry granulation and direct compression
Control real time process determination
Picking: removal of tablet’s surface area Sticking: adhesion of tablet material to a die wall
Results from use of a drug with a color from that of the tablet excipients or from a drug with a colored degradation products Mottling: unequal distribution on a tab with light or dark areas, standing out on an otherwise uniform surface Tablet dedusting: removes traces of loose powder adhering to tablets following compression, the tablets are conveyed directly from the tableting machine to a deduster
Manesty Tablet Deduster Reasons for Tablet Coating
Protect medicinal agent against destructive exposure to air and/or humidity Mask the taste of the drug Provide special characteristics of drug release Provide aesthetics or distinction to the product
Granulate soluble and hygroscopic materials Granulate fine particles
Fluid Bed Processor
For granulation, coating and pelletization, and solution layering
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Tablet Coatings
Sugarcoating tablets Divided into following steps: Waterproofing and sealing: containing components that may be adversely affected by moisture Subcoating: 3 to 5 subcoat of a sugar-based syrup are applied Smoothing and final rounding: 5 to 10 additional coating of a thick syrup and applied to complete the rounding and smooth the coating Finishing and coloring: performed in a clean pan free from previous coating materials Polishing Coated tablets may be polished in several ways Special drum-shaped pans or ordinary coating pans lined with canvass as or other cloth impregnated with carnauba wax or beeswax
Enteric Coating
Three ways of Imprinting Logos or ID on Tablets
Debossed: imprinted with a mark below the surface Embossed: imprinted with a mark raised above the surface Engraved: imprinted with a code that is cut into the surface during production
Film-Coating Tablets
Places: a thin, skintight coating of a plastic-like material over the compressed tablet Developed to produce coated tablets having essentially the same weight, shape, and size as the originally compressed tablet More resistant to destruction by abrasion than are sugarcoated tablets
Types of Materials Found in Nonaqueous Film-Coating Solutions
Film former Capable of producing smooth, thin films reproducible under convention coating conditions and applicable to a variety of tablet shape Example: cellulose acetate phthalate Alloying substance Water solubility or permeability to the film to ensure penetration by body fluids and therapeutic availability of the drug Example: PEG (polyethylene glycol) Plasticizer To produce flexibility and elasticity of the coating and thus provide durability Example: castor oil Surfactant To enhance spreadability of the film during application
Example: polyoxyethylene sorbitan derivatives Opaque and colorant To make the appearance of the coated tablets handsome and distinctive Example: Opaquant: titanium dioxide Colorant: FD&C and D&C dyes Sweeteners, flavors, and aromas To enhance the acceptability of the tablet to the patient Examples Sweeteners: saccharin Flavors and aromas: vanillin Glossant To provide luster to the tablet without a separate polishing operation Example: beeswax Volatile solvent To spread of the other components over the tablets while allowing rapid evaporation to permit an effective yet speedy operation Example: alcohol mixed with acetone
Pass through the stomach intact to disintegrate and release their drug content for a absorption along the intestine Applied to either whole compressed tablets or to drug particles or granules used in the fabrication of tablets or capsules Coating applied in multiply portions to build a thick coating or as a thin film coat Designed to dissolve at pH 4.8 and greater Materials used: pharmaceutical shellac hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, diethyl phthalate, and cellulose acetate phthalate Important factor to consider for enteric coated tablets: transmit time required for passage to the intestines and pH
Fluid Bed or Air Suspension Coating
Spray coating of powders, granules, beads, pellets or tablets held in suspension by a column of air Fluid bed equipment is multifunctional and may also be used in preparing tablet granulation
Flo-Coater
Systems to provide the fastest possible spray rates and the most efficient drying results Providing benefits for both top spray granulation and fluid bed drying processes
Wurster Process
Named after its developer The items to be coated are fed into a vertical cylinder and are supported by a column of air that enters from the bottom of the cylinder.
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Lozenges
Types of Fluid Bed System
Top sprays Provides greater capacity up to 1500kg than the other air suspension coating method For taste masking, enteric release, and barrier films on particles or tablets Most effective when coatings are applied from aqueous solutions, latexes, or hot melts Tangential spray technique Used in rotary fluid bed coater Used for layering coating and for sustainedrelease and enteric coated Bottom Spray For sustained-release and enteric-release products Employed using a modified apparatus used for bed coaters
Pharmaceutical Spray Dryers (PSD)
Dries solutions, suspensions, and emulsions into powders
Compression Coating
Anhydrous operation safely employed in the coating of tablets containing a drug that is labile to moisture Preparation of multiple compressed tablets having inner core and outer shell of drug material, core tablets may be sugarcoated by compression
Impact of Manufacturing Changes on solid Dosage Forms
Changes in formulation arising from use of: Starting raw materials including both the active ingredient and pharmaceutical excipients that have different chemical or physical characteristics than the standard set of the original components Different pharmaceutical excipients Different quantities of the same excipients in a formulation Addition of a new excipient to a for mulation Changes in the method of manufacture Use of processing or manufacturing equipment of a different design Change in the steps or order in the process or method of manufacture Different in process controls, quality test, assay methods Production of different batch size Employment of different product reprocessing procedures Employment of a different manufacturing site
Lollipop
Can be made by compression or molding Compressed lozenges are made using a tablet machine and large, flat punches Have a special place in the delivery of medication Fentanyl actiq: a raspberry lollipop that differs from the fentanyl oralet Sugar-based lozenge on a tstick and contain fentanyl citrate Provide almost immediate relief as the drug starts being absorbed in the mouth and starts to work within minutes Effect lasts for only about 15 minutes
Pills
Small, round solid dosage forms containing a medicinal agent and intended to be administered orally
Examples of Types of Tablets Compressed: Actifed, Thyroid, Synthroid Film coated: Erythrocin filmtab, Tagamet, Elavil Enteric coated: various brands of ASA, Slow-Fe, Entabs, Entrophen, AltiErythromycin, Sugar Coated Advil, M&Ms, Smarties, Chlortripolon, Repetabs, Dimetapp, Extentabs, Dixarit; small, blue, sugar coated tablets containing 0.025mg Clonidine, Cytoxan (cyclophosphamide), Ex-Lax Chewable: Flintstone’s Multivitamins, Tums, Vitamin C Chewable Tablets, Dilantin, Infatebs and Amoxil, Chewable Tablets Pepcid, Complete Chewable Tablet Effervescent: Alka-Seltzer, Gramcal, Redoxon, K-lyte, Novartis Phosphate
Precautions in Packaging and Storing Volatile Drugs
Containing nitroglycerin: drug migrate between tablets in the container, resulting in a lack of uniformity among tablets Packaging materials (cotton and rayon) and glycerine tablets: absorb varying amounts of nitroglycerin, thus reducing potency of tablets Nitroglycerine tablets (according to USP): preserved in tight containers (glass) at controlled room temperature and dispensed in original unopened container with the warning label “to avoid loss of potency and closed tightly after use
Other Solid Dosage Forms for Oral Administration
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