Name:

Pharmaceutical Dosage

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:

o Protects the enclosed drug from the environment

o Provides a barrier to objectionable taste of odor

o Enhances the appearanceo Permits imprinting of identifying

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 sugar-0free

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 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)

o Prepared by foaming a mixture of gelatin, sugar, drug and other components and pouring the foam into a mold

o Zydis: 1st entry into the RTD field

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o Disadvantage: taste masking can be a problem since the drug is incorporated during the formation of the tablet

Soft direct compressiono Using standard tableting technology will

enhance fluid uptake and tablet disintegration and dissolution

o Example product: Dimetapp: ND orally disintegrating tablet

Use of water-soluble excipientso Designed to “wick” water into the

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

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 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 rate of dissolution

Steps:

A volume of the dissolution medium is placed in the vessel and allowed to come to 37oC + 0.5oC

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

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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: Weighing and blending

o Diluents or filler, and disintegrating agent are mixed by mechanical powder blender or mixer until uniform

Preparing the damp masso A liquid blender is added to 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 granulationo Granules may be dried in the

thermostatically controlled ovens that constantly record the time, temperature, and humidity

Sizing the granulation by drying screening o 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 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)

o Preblending the formulation powder

o Granulating the mixture by spraying onto the fluidized powder bed

o Drying the granulated product to the desired moisture content

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

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

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

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

Fluid Bed Processor

For granulation, coating and pelletization, and solution layering

The GPS of Fluid Bed Process

Control real time process determination

Microwave Vacuum Process

Using microwave Powder mix is mixed, wetted, agglomerated and dried

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

Results from excessive moisture or substances with low melting point temperatures in the formulation

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

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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 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

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

Enteric Coating

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.

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 sustained-release 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

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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

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

Lollipop 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, SynthroidFilm coated: Erythrocin filmtab, Tagamet, ElavilEnteric 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-LaxChewable: Flintstone’s Multivitamins, Tums, Vitamin C Chewable Tablets, Dilantin, Infatebs and Amoxil, Chewable Tablets Pepcid, Complete Chewable TabletEffervescent: 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

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