Chapter 8: TABLETS

38 Patacsil, Jarrah 41 Ramirez, Diana 39 Perez, Aijean 40 Pua, Mark

Define 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.

TABLETS

For oral administration of drugs, others sublingually, bucally 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

ADVANTAGES

1. Tablets are elegant in appearance and convenient to use. 2. The tablets dosage form are simple,economical in manufacturing,most stable and most convenient in packaging,shiping and transportation. 3. These can be manufactured to show product identification, e.g. exhibiting the required markings on the surface. 4. A wide range of tablet types is available, offering a range of drug release rates and durations of clinical effect. Tablets may be formulated to offer rapid drug release or controlled drug release, the latter reducing the number of daily doses required (and in so doing increasing patient

ADVANTAGES

5. Tablets may be formulated to contain more than one therapeutic ingredients showing a combination thus reducing multiple tablets use. 6. It is very easy to mask the taste of bitter active ingredients thus make convenience for patient. 7. Tablets can be formed for local effects e.g. In ulcerative colitis special tablets can be used for rectal insertion. 8. Tablets provides accurate dosage to the patient 9. Tablets are generally an inexpensive dosage form.

DISADVANTAGES

1. Its manufacturing involve several unit operation thus at each step there is loss of ingredients of tablets 2. Finding of good compatibility between active and inactive ingredients for tablets formulation require huge hit and substantial experimentation. 3. The absorption of therapeutic agents from tablets is dependent on physiological factors, e.g. gastric emptying rate and shows inter-patient variation. 4. May be problematic for children and elders due to difficulties in swallowing.

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.

Types of Tablets

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)

Types of Tablets

Sugarcoated tablets (SCT) Compressed tablets with colored or uncolored sugar layer: Protects the enclosed drug from the environment Provides a barrier to objectionable taste of odor Enhances the appearance Permits imprinting of identifying manufacturers information

Types of Tablets

Disadvantages: Time and expertise needed in the coating process Increased shipping cost: 50% larger and heavier than uncoated

Types of Tablets

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-coated

Types of Tablets

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 ease in swallowing and more tamper evident

Types of Tablets

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)

Types of Tablets

Needed when drug substance: Destroyed by gastric acid Irritating to the gastric mucosa By-pass the stomach and enhances the drug absorption in the intestines

Types of Tablets

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

Types of Tablets

Lozenges or troches Disc-shaped solid forms in a hard candy or sugar base Dissolved slowly for localized effect or systemic effect

Types of Tablets

Chewable tablets Pleasant-tasting, have smooth, rapid disintegration(chewed or allowed to dissolve in the mouth) Have a creamy base, specially flavored and colored mannitol Prepared buy compression or wet granulation Xylitol: may be used in the preparation of sugarfree chewable tablets

Types of Tablets

Effervescent tablets Prepared by compressing granular effervescent salts that release gas when in contact with water Molded tablet triturate(MT) May be prepared by molding rather than by compression Resultant tablets are very soft and soluble and are designed for rapid dissolution

Types of Tablets

The mold is made of hard rubber, hard plastic or metal Has 2 parts: the upper part(die) and the lower part(flat punches) Base is a mixture of finely powdered lactose with or without portion of powdered sucrose

Types of Tablets

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 in use

Types of Tablets

Hypodermic tablets(HT) Used by physicians for extemporaneous preparation of parenteral solutions rendered sterile. Dissolved in suitable vehicle sterility attained, and the injection performed

Types of Tablets

Easily carried in the physicians medicine bag and injections prepared to meet the needs of the individual patients Advent of prefabricated injectable products and disposable syringes, declined in use.

Types of Tablets

Dispensing tablets (DT) Compounding tablets Used by the pharmacist to compound prescription and not dispensed to patients Contains a large amount of potent substances enabling the pharmacist to obtain pre-measured amounts

Types of Tablets

Immediate-release tables(IR) 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

Types of Tablets

Method of instant-release or disintegrating tablets: Lyophilized Foam Prepared by foaming a mixture of gelatin, sugar, drug and other components and pouring the foam into a mold Zydis: 1st entry into the RTD field Disadvantage: taste masking can be a problem since the drug is incorporated during the formation of the tablet

Types of Tablets

Soft direct compression Using standard tableting technology will enhance fluid uptake and tablet disintegration and dissolution Example product: Dimetapp: ND orally disintegrating tablet

Types of Tablets

Use of water-soluble excipients Designed to wick water into the tablet for rapid disintegration Large-scale lyophilizers Water is removed from temperature sensitive or unstable product solutions and transformed to stable dry products with its original properties

Types of Tablets

Extended-release tablets(ER) or controlled release tablets(CR) 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)

Types of Tablets

Compressed Tablets Physical features of compressed 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 tablet

Types of 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

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 4kg (hardness tester)

Quality Standards and Compendial Requirements

Factors affecting Tablet thickness: Diameter of the die Amount of fill permitted to enter the die The compaction characteristics of the fill material The force or pressure applied during compression Apparatus used for measuring Tablet Thickness Hand Gauge during production or by automated equipment (See Fig. 8.10 to 8.12;

Quality Standards and Compendial Requirements

Tablet hardness and friability Friability - a tablets durability or tendency to crumble Acceptable: maximum weight loss of not more than 1%

Quality Standards and Compendial Requirements

Apparatus used in measuring Tablets Friability and Hardness: Special dedicated hardness testers or multifunctional systems used to measure the degree of force (in kilograms, pounds, or in arbitrary units) required to break a tablet (See Fig. 8.13 and 8.12; page 233 to 234) Friabilator determines tablets friability (See Fig. 8.14; page 234)

Quality Standards and Compendial Requirements

Tablet disintegration Important for tablets containing medicinal agents 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 (See Fig. 8.15; page 234)

Quality Standards and Compendial Requirements

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

Quality Standards and Compendial Requirements

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

Quality Standards and Compendial Requirements

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.

Factors Affecting Tablet Disintegration and dissolution

Particle size of the drug substance Solubility and hygroscopy of the formulation Type and concentration of the disintegrant, binder, and lubricant Manufacturing, particularly the compactness of the granulation and compression forced used in tableting.

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 the rate of dissolution Steps: A volume of the dissolution medium is placed in the vessel and allowed to come to 37C + 0.5C Stirrer rotated at the speed specified at stated interval samples of the medium withdrawn for chemical analysis of the proportion of drug dissolved

Successful in Vivo in Vitro Correlation (IVIVC)

Relates combination of drugs 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

Successful in Vivo in Vitro Correlation (IVIVC)

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:

A. WET GRANULATION
Widely employed method for production of compressed tablets Advantages: Traditional method for many drugs since it imparts compressibility Useful for fluffy powder (dont flow or mix well) Thermo labile 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 equipment - time, space, money, personnel, material loss Expertise required

Steps in Wet Granulation Method

Weighing and blending Diluents or filler, and disintegrating agent are mixed by mechanical powder blender or mixer until uniform Preparing the damp mass A liquid blender is added to the powder mixture to facilitate adhesion of the powder particles Screening the damp mass into pellets or granules The wet mass is pressed through a screen to prepare the granules

Steps in Wet Granulation Method

Drying the granulation Granules may be dried in the thermostatically controlled ovens that constantly record the time, temperature and humidity Sizing the granulation by dry screening After drying, the granules are passed through a screen of a smaller mesh than that used to prepare the original granulation Adding lubrication and blending After dry screening, a dry lubricant is dusted over the spread-out granulation through a mesh screen

All-in-one granulation methods

a.
b.

c.

Fluid Bed Process continuous process for granulation, coating and pelletization, and solution layering Fluid bed granulator performs the following steps: Pre-blending the formulation powder Granulating the mixture by spraying onto the fluidized powder bed Drying the granulated product to the desired moisture content (See Fig. 8.20 and 8.21; page 239 to 240) The GPS of fluid bed process

All-in-one granulation methods

Microwave Vacuum Process Allows the powders to be mixed, wetted, agglomerated, and dried within the confines of a single piece of equipment. (See Fig. 8.22; page 240) Wet mass is dried by gentle mixing, vacuum and microwave

Method of Compressed tablet manufacture:

B. 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

Types of dry granulation

I.

II.

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 (instead of slugging) used to increase the density of the powder by pressing it between rollers 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

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.

Tableting of Granulation

Single-punch tablet press Describes the basic mechanical process Multiple punches and dies Rotary tablet machines Operate via continuous rotating movement of the punches

Tablet Production Processing Problems Encountered

Results from air entrapment and high speed production 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

Tablet Production Processing Problems Encountered

Results from excessive moisture or substances with low melting point temperatures in the formulation Picking: removal of tablets 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

Tablet Production Processing Problems Encountered

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)

Method of Compressed tablet manufacture:

C. 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

Excipients used to impart the necessary qualities for the production of tablets: Fillers spray-dried lactose, microcrystals of alpha-monohydrate lactose, sucrose-invert sugar-corn starch mixtures, and d-calcium phosphate Disintegrating agents direct compression starch, sodium carboxymethyl starch, crosslinked carboxymetylcellulose fibers, and crosslinked polyvinylpyrrolidone Lubricants magnesium stearate and talc Glidants silicon dioxide

High Shear granulation 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 Granulate soluble and hygroscopic materials Granulate fine particles

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

Tablet Coatings
Sugarcoating tablets Divided into following steps:

Waterproofing

and scaling: containing components that may be adversely affected by moisture Subcoating: 3 to 5subcoat 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

and coloring: performed in a clean pan free 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

Finishing

3 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 the 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)

Types of materials found in Nonaqueous Film coating solutions

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

Types of materials found in Nonaqueous Film coating solutions

Opaque and colorant To make the appearance of the coated tablets handsome and distinctive Opaquant: Titanium dioxide Colorant: FD&C and D&C dyes Sweeteners, flavors, and aromas To enhance the acceptability of the tablet to the patient Sweeteners: Saccharin Flavors and aromas: Vanillin

Types of materials found in Nonaqueous Film coating solutions

Glossant To provide luster to the tablet without a separate polishing operation Example: beeswax Volatile solvent To spread the other components over the tablets while allowing rapid evaporation to permit an effective yet speedy operation Example: Alcohol mixed with acetone

Enteric Coating

Pass through the stomach intact to disintegrate and release their drug content for 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 multiple portions to build a thick coating or as a thin film coat

Enteric Coating

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

Types of Fluid bed system

Top spray 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 coating s are applied from aqueous solutions, latexes or hot melts

Types of Fluid bed system

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 formulation

Impact of Manufacturing changes on solid dosage forms

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

Other solid dosage forms for Oral administration

Lozenges 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 Pills Small round solid dosage forms containing a medicinal agent and intended to be administered orally

Other solid dosage forms for Oral administration

Lollipop Fentanyl actiq, a raspberry lollipop that differs from the fentanyl oralet Sugar-based lozenge on a stick 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

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 Glycerin tablets: absorb varying amounts of NTG, thus reducing potency of tablets Nitroglycerin 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, close tightly after use

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, Alti Erythromycin, Sugarcoated Advil, M&Ms, Smarties, Chlortripolon, Repetabs, Dimetapp, Extentabs, Dixarit; Small, blue, sugar coated tablets containing 0.025mg Clonidine, Cytoxn(cyclosphosphamide), Ex-Lax Chewable: Flintstones Multivitamins, Tums, Vit C Chewable tablets, Dilanting, Infatebs and Amoxil,. Chewable tablets Pepcid, Complete Chewable tablet Effervescent: Alka-Seltzer, Gramcal, Redoxon, Klyte, Novartis Phosphate