Tablets

By: Katryn Punsalang

Definition:
Solid dosage form Contains medicinal substances
With or without suitable diluents

Compressed/ molded powders or granules Single doses intended for oral administration Has lines or break marks (scorings) Has symbols or other markings

 Usually taken for Systemic effect

results after absorption from the various surfaces along the gastrointestinal tract.

Slower onset of action BUT greater duration of action Most natural Uncomplicated Convenient Safe means of administration

Classification of tablets
Tablet can be classified according to their:
A. Method of Manufacture
1. Compression 2. Molding

B. Intended use
. uncoated tablets; . coated tablets (including film-coated and sugar-coated tablets); . soluble tablets; . dispersible tablets; . effervescent tablets; . chewable tablets; . tablets for use in the mouth (including sublingual and buccal tablets); . modified-release tablets (including delayed-release tablets (gastro- resistant/entericcoated tablets) and sustained-release tablets (extended-/prolonged-release tablets)

Excipients used in Tablet Preparation

Diluents or fillers
add the necessary bulk to a formulation to prepare tablets of the desired size.

Binders or adhesives
promote adhesion of the particles of the formulation, allowing a granulation to be prepared and maintaining the integrity of the final tablet.

Disintegrants or disintegrating agents

promote breakup of the tablets after adminis- tration to smaller particles for ready drug availability.

 Antiadherents, glidants, lubricants, or lubricating agents

enhance the flow of the material into the tablet dies, minimize wear of the punches and dies, prevent fill material from sticking to the punches and dies, and produce tablets with a sheen.

Miscellaneous adjuncts:
Colorants- add to the pharmaceutical elegance of the product Flavorants- mask any unpleasant tastes Coatings- protect the active ingredient of the drug from any unwanted biological interaction before it reaches the intended site of action.

Manufacturing Methods
1. Compression
1. Wet granulation 2. Dry granulation (roll compaction or slugging) 3. Direct compression

2. Molding

Compressed Tablets
Contains medicinal agent(s) and suitable pharmaceutical excipients Tablets for oral, buccal, sublingual, or vaginal administration may be prepared by compression. Most widely used dosage form (USP)

Compressed Tablets
PHYSICAL FEATURES:
round, oblong, or unique in shape thick or thin large or small in diameter; flat or convex
determined by the die and punches used in compression. The less concave the punches, the flatter the tab- lets; conversely the more concave the punches, the more convex the resulting tablets.

unscored or scored in halves, thirds, or quadrants engraved or imprinted with an identifying symbol and/or code number coated or uncoated colored or uncolored one, two, or three layered.

Quality Standards and Compendial Requirements

Tablet weight Determined by the quantity of fill in the die of a tablet. Weight variation Weight variation test(USP), average weight of 10 tablets, weighed individually. Content uniformity 10 dosage units are individually assayed for their content Act. Ing. In each dosage unit should be 85%-115%, deviation less than 6% Thickness Determined by the diameter of the die, compaction characteristics of the fill material, and the force/pressure applied during compression Hardness Can affect disintegration and dissolution. Tablets are in general be sufficient enough to resist breaking during normal handling and soft enough to disintegrate after swallowing Pressure is a determinant: pressure= harder tablets: CONTROL PRESSURED is used Measured by hand gauze or automated equipment( Friabilator: tendency to crumble) Lozenges and buccal tabs= hard Immediate drug release tabs: soft

Disintegration Tablet must first disintegrate before absorption Important for tablets that should be absorbed in the GI tract. Provides drug particles with an increased surface area Must pass disintegration test via an in vitro

Dissolution It guides formulation and product development toward product optimization Manufacturing may be monitored as a component of the over all qlty assurance program Consistent in vitro dissolution testing ensures bioequivalence from batch to batch It is a requirement for regulatory approval of marketing products registered with the FDA GOAL is provide a reasonable prediction of the drugs in vitro bioavailability. Drugs solubility (high or low) and its intestinal permeability (high or low)

4 categories of Drug Dissolution

4 categories: I. high solubility and permeability: dissolution rate is slower than gastric emptying rate(rate limiting) II. low solubility and high permeability: dissolution may be the rate limiting step for absorption III. high solubility and low permeability: permeability is the rate controlling step IV. low solubility and low permeability: significant problems are likely for oral drug delivery.

3 methods in Compressed Tablet Manufacturing

1.Wet granulation 2.Dry granulation 3.Direct compression

Wet granulation
Steps: 1. Weighing and blending the ingredients
Act. ing. + diluent/filler+ disintegrating agent= POWDER mixture Fillers: lactose, microcrystalline cellulose, starch, powdered sucrose, and calcium phosphate. Disintegrating Agents: croscarmellose, corn/ potato starches, sodium starch glycolate, sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), crospovidone, cation exchange resins, alginic acid, and other materials that swell or expand on exposure to moisture and effect the rupture or breakup of the tablet in the gastrointestinal tract.

2. Preparing the dampened powder or damp mass

Powder mixture + liquid binder= damp powder/ mass Liquid binder: facilitate adhesion to powder particles povi- done, an aqueous preparation of cornstarch (10% to 20%), glucose solution (25% to 50%), molasses, methylcellulose (3%), carboxymethyl- cellulose, and microcrystalline cellulose

3. Screening the dampened powder or damp mass into pellets or granules

Dampened powder granules: screened Wet mass: passed through a screen Resultant granules: spread evenly on large lined trays, dried to consistent weight or constant moisture content

4. Drying the granules

Thermostatically controlled ovens Constant recording of: time, temp., humidity

5. Sizing the granulation by Dry screening

Necessary so that die cavities for tablet compression may be completely and rapidly be filled by the free- flowing granulation. Dried Granules: passed through screen of a smaller mesh Smaller the tablet to be produced: smaller granules 12-20 mesh size are used Air spaces of too large granules: production of uneven tablets

6. Adding lubricant and blending

Dry lubricant is dusted over the spread out granulation through a fine mesh screen. Lubricants: magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate improve the flow of the granulation in the hopper die cavity. Prevent adhesion of the tablet formulation to the punches and dies during compression. Reduce friction bet. Tablet and die wall during the ejection of the tablet from the machine. Give a sheen to the finished tablet

7. Forming tablets by compression

All in one Granulation Methods

A. Allow the entire process of granulation to be completed in a continuous fluid bed process using the fluid bed granulator. STEPS: 1. Pre-blending the formulation powder (Act. Ing., fillers, disintegrants) in a bed with fluidized air 2. Granulating the mixture by spraying onto the fluidized powder bed, a liquid binder (aq. Soln. of acacia, hydroxypropyl cellulose, or povidone) 3. Drying the granulated product to the desired moisture content. B. Microwave vacuum processing: wet mass is mixed, vacuumed, and microwaved(to reduce the drying time). Overall process only takes usually 90 mins.

DRY GRANULATION
Powder mixture is compacted in large pieces Broken down or sized into granules Active Ing. Or the diluent must have cohesive properties Applicable to materials that cannot be prepared via wet granulation bec. They degrade in moisture or the elevated temps. Required for drying the granules. A. SLUGGING B. ROLLER COMPACTION

Dry Granulation
A.Slugging
1. Weigh and mixed the ingredients= Powder mixture 2. Powder mixture is slugged, or compressed into a large flat tablets or pellets (1 inch in diameter)= slugs 3. Slugs are broken up by hand or by a mill 4. Passed through a screen of desired mesh

. Lubricant is added in the usual manner and tablets are prepared by compression. . Ex. Aspirin (hydrolyzed on exposure to moisture)

Dry Granulation
B. Roller Compaction Powder compactors increase density of powder by pressing it bet. Rollers at 1-6 tons of pressure. Compacted material: broken up, sized, lubricated and prepared by compression. Preferred over slugging Binding agents used: methylcellulose or hydroxymethylcellulose (6% to 12%)(produce good tablet hardness and friability)

Tableting of Granulation
Various types of tablet presses/ tableting machines Similar in basic function and operation All compress a tablet formulation within a steel die cavity by the pressure exerted by the movement of two steel punches: LOWER and UPPER punch
Single- punch tablet press Rotary tablet machines
Single rotary press (16 sets of punches and dies) Double rotary press (27,33,37,41,49 sets of punches and dies, two tablets for each die) Induced die feeders (for high speed production, 10,000 or more tablets per min. of operation)
Problems: Lamination (horizontal striations)

: tablet capping (top of the tablet separates due to insufficient time to bond after compression)

DIRECT COMPRESSION
Free- flowing and cohesive properties allow the direct compression of some granular chemicals (eg. KCl) Pharmaceutical excipients maybe used for chemicals without these properties:
Fillers: pray-dried lactose, microcrystals of alpha-monohydrate lactose, sucroseinvert sugarcorn starch mixtures, microcrystalline cellulose, crystalline maltose, and dicalcium phosphate Disintegrating agents: direct compression starch, sodium carboxymethyl starch, cross-linked carboxymethylcellulose fibers, and cross-linked polyvinylpyrrolidone Lubricants: magnesium stearate and talc Glidants: fumed silicon dioxide

Problems encountered: capping, splitting, laminating of tablets due to air entrapment during direct compression. Solution: use forced or induced feeders Tablet Dedusting- removal of traces of loose powder adheering to tablets after compression.

Types of Compressed Tablets

MULTIPLY COMPRESSED TABLETS
a tablet within a tablet Multiple layer
Inner layer- core Outer layer- shell Each layer has different colors Each layer may contain different active ingredients
chemical or physical incompatibility, staged drug release, or unique appearance of the layered tablet.

Prepared by:
initial compaction of a portion of fill material in a die followed by additional fill material and compression to form multiple layers.

Sedative hypnotic 2 layers: layer 1 released immediately which puts one to sleep other layer prolongs action keeping you asleep

SUGAR COATED TABLETS

Coated with a colored or uncolored sugar layer Coating: ADVANTAGES:
Water soluble Quickly dissolves after swallowing Protects the enclosed drug from the environment Provides barrier against objectionable taste or odor Enhances the appearance of the product Permits imprinting of identifying manufacturers info.

DISADVANTAGES:
Time and expertise are required in process Increase in size, weight, and shipping costs May add up to 50% to the weight and bulkiness of the product

Examples:
-

Tofranil-has sugar coating applied to it isosorbide HCL Antidepressant

FILM COATED TABLETS

Coated with a thin layer of polymer capable of of forming a skin-like film. Film:
Colored Advantage over sugarcoatings: more durable, less bulky, less time consuming to apply Designed to rupture and expose the core tablet at the desired site of action in the GI tract. Examples:

Clarithromycin

GELATIN COATED TABLETS

Recent innovation (Gelcap) Capsule shaped compressed tablet Allows coated product to be about one- third smaller than a capsule filled with an equal amount of powder. Gelatin coating:
Facilitates swallowing More tamper evident Example: Extra Strength Tylenol PM Gelcaps

ENTERIC COATED TABLETS

Have delayed release features Designed to pass unchanged through the stomach to the intestines(where the tablet disintegrates and allow absorption to occur) Enteric coating is used:
when the product is destroyed by gastric acid The product is irritating to the gastric mucosa When bypass of the stomach enhances drug absorption Example: Ecotrin Tablets and Caplets (Smith Kline Beecham)

Dulcolax OTC-AI is bisacodyl [tablet] irritant laxative

BUCCAL AND SUBLINGUAL TABLETS

Flat, oval tablets Buccal- dissolved in the buccal pouch
Erode slowly

Sublingual- dissolved beneath the tongue

Dissolve promptly Provide rapid drug effects Example: Nitroglycerin

Enable oral absorption of drugs that are destroyed by the gastric juice and/or are poorly absorbed in the GI tract

Testosterone Buccal tablet Hormone for men 30mg buccal tablet, MFG: ACTIENT

Sublingual Tablet Isosorbide 30, 60 mg Mfg: Parke Davis treat:angina pectoris

LOZENGES or TROCHES
Disc shaped Act. Ing. + flavoring subs. (hard candy/ sugar base) Intended to be slowly dissolved in the oral cavity For local effects/ systemic absorption Example: Mycelex Troches (Bayer)

Cepastat Lozenge Antiseptic PHENOL/Menthol for sore throat 14.5 mg phenol MFG: GSK

CLOTRIMAZOLE MFG: paddock labs I: antifungal, thrush, ORALPHARYNGEAL CANDIDIAS 10mg oral lozenge

CHEWABLE TABLETS
Smooth, rapid disintegration Chewed or allowed to dissolve in the mouth Creamy base( flavored and colored mannitol: 70% as sweet as sugar, 50% of the weight of the tablet.) Sorbitol, lactose, dextrose, glucose, crystalline maltose can be alternatives to mannitol. Xylitol is used for sugar free chewable tablets Useful for administration to patients with difficulty in swallowing large tablets (children and adults) Antacids (CaCo3) Antibiotics (erythromycin) analgesics (acetaminophen) vitamins Prepared by wet granulation and compression using only minimal degrees of pressure to produce a soft tablet Doesnt contain disintegrant Examples: Pepcid Chewable Tablets (J&J Merck)

Mylanta chewable tablets (swallowed whole)

EFFERVESCENT TABLETS
Prepared by compressing granular effervescent salts that release gas when in contact with water. Contains Act. Ing. That dissolves rapidly when added to water Bubble action: assist in breaking up the tablet and enhancing the dissolution of the active drug Examples: Alka-seltzer Original, Zantac EFFERdose (GlaxoSmithKline)

Effer-K Potassium Chloride Supplement Effervescent Tablets

MOLDING
Other way of preparing tablets Commercial preparation of tablets by molding has been replaced by tablet compression. Intended for tablets to dissolve rapidly in the mouth Do not contain disintegrants, lubricants, coatings. Prepared on a small laboratory scale
Mold: hard rubber, hard plastic, metal Two parts: upper part (flat plate: DIE) and lower part (squat, flat: PUNCHES) BASE: Fine powders+ powdered lactose(w/ or w/o powdered sucrose for lessen brittleness of tablet) A. Mix the dry ingredients via geometric dilution B. powder mixture is wetted with 50% mixture of water(binds the powder mixture upon drying) and alcohol( hastens drying) C. Fill the die with the material completely D. Fit the die in the punch and press the die down E. punches gently lift the fill material from the holes to rest upon the punches for drying

MOLDED TABLETS
Prepared by molding rather than by compression Resultant tablets are very soft and soluble Designed for rapid dissolution

TABLET TRITURATES
Small Usually cylindrical Contains small amounts of usually potent drugs Must be readily and completely soluble in water Only a few tablet triturate products are available commercially(ex. Nitroglycerin)
Most of these are already prepared by compression

minimum amount of pressure is applied in manufacturing Combination of Sucrose and lactose are used as diluents Used by pharmacists in compounding
Triturates are inserted into capsules or dissolved in liquid to provide accurate amts. Of potent drug subs.

HYPODERMIC TABLETS
No longer available Originally used by physicians in extemporaneous prep. Of parenteral solns.
Convenience to the physicians since they could easily carry them in their bags and meet the needs of indv. Patients.

Required number of tablets are dissolved in a suitable vehicle, sterility attained, and the injection performed.
Issues on Sterility and availability of prefabricated injectable products have eliminated their use.

DISPENSING TABLETS
No longer used Compounding tablets
Rxists used them to compound Rx.

they were not dispensed much to patients Tablets contained large amts. Of highly potent drug subs.
Rxists could rapidly obtain premeasured amts. Of compounding multiple dosage units.

Had a dangerous potential of being inadvertently dispensed

IMMEDIATE RELEASE TABLETS

Designed to disintegrate and release their medication with no special rate controlling features (ex. coatings).

CATAFLAM (DICLOFENAC POTASSIUM)(NSAID)

INSTANTLY DISINTEGRATING/ DISSOLVING TABLETS

Instant release tablets/ rapid dissolving tablets (RTDs) Disintegrating/ dissolving in the mouth within 15-30 seconds Designed for patients with difficulty in swallowing (children and adults) Liquefy on tongue. Patients swallow the liquid Prepared using very water soluble excipients designed to wick water into the tablet for rapid disintegration/dissolution Techniques used in preparation:
Lyophilization (ex. Zydis, R.P. Scherer) Soft direct compression (ex. Wow-Tab, Yamanouchi- Shaklee Pharma) Other methods (ex. Quicksolv, Janssen)

Original fast dissolving tablets were molded for SUBLINGUAL use. (act. Ing. + alcohol-water mixt.= paste) Have been used for drugs that are destroyed in the GI tract (ex. Testosterone; sublingually)

INSTANTLY DISINTEGRATING/ DISSOLVING TABLETS

More convenient to carry and administer (comp. to oral liquids) Packaged in cards or bubble type packaging
Each individual tablets on its own cavity

Disadvantages:
Drug loading Taste masking Friability Manufacturing costs Stability of the product

INSTANTLY DISINTEGRATING/ DISSOLVING TABLETS

Lyophilized Foam
First entry in the RDT field was the Zydis delivery system Fastest disintegrating system on the market
Dissolves in tongue in few seconds

Prepared by:
Mixture of gelatin, act. Ing., other components, pouring foam into the mold(serves as a unit dose dispensing pck.) The foam is lyophilized and the tablets in the mold are packaged

Disadvantages:
Masking of taste can be a problem Difficulty in removing from the package

Claritin (loratidine) rapidly disintegrating tablets (Reditabs, Schering Corporation): disintegrates within seconds after being placed on tongue, w/ or w/o water.

INSTANTLY DISINTEGRATING/ DISSOLVING TABLETS

Compression
standard tableting technology with a composition that will enhance fluid uptake and tablet disintegration and dissolution
Ex. Super-disintegrants incorporated with a small quantity of effervescent material will lead to intermediately fast disintegration.

compressed a little thinner than standard tablets to allow for a larger surface area exposed to the saliva in the mouth Steps:
placement in the mouth the disintegrant starts wicking water into the tablet. The effervescent materials start dissolving and aid in the breakup. This continues until the tablet has disintegrated.

Ex. Dimetapp ND Orally Disintegrating Tablet (Nondrowsy Allergy Tablets).

EXTENDED-RELEASE TABLETS
Controlled release tablets designed to release their medication in a predetermined manner over an extended period. Ex. Simvastatin Niacin Extended Release Tabs.

VAGINAL TABLETS
Vaginal inserts uncoated, bullet-shaped or ovoid tablets inserted into the vagina for local effects pre- pared by compression shaped to fit snugly on plastic inserter devices that accompany the product. They contain:
anti-bacterials for the treatment of nonspecific vaginitis caused by Haemophilus vaginalis antifungals for the treatment of vulvovaginitis candidiasis caused by Candida albicans and related species.

Ex.

Vagifem vaginal tablet 10mcg treats atropic vaginitis

TABLET COATING
protect the medicinal agent against destructive exposure to air and/or humidity to mask the taste of the drug to provide special characteristics of drug release (e.g., enteric coatings) to provide aesthetics or distinction to the product. to prevent inadvertent contact with the drug substance and the effects of drug absorption
Ex. Proscar tablets (finasteride, Merck)

 SUGARCOATING TABLETS (a)waterproofing and sealing if needed

one or more coats of a waterproofing substance (eg.) pharmaceutical shellac or a polymer

(b) Subcoating
three to five subcoats of a sugar-based syrup are applied.
This bonds the sugar coating to the tab- let and provides rounding

(c) smoothing and final rounding

5 to 10 additional coatings of a thick syrup are applied to complete the rounding and smooth the coatings

(d) finishing and coloring if desired

several coats of a thin syrup containing the desired colorant are applied
attain final smoothness and the appropriate color to the tablets

(e) Imprinting and Polishing

passed through a special imprinting machine to impart identification codes and other distinctive symbols.
Debossed, embossed, engraved

Special drum-shaped pans or ordinary coating pans lined with canvas or other cloth with carnauba wax and/or beeswax can be used for polishing while tumbling on a pan

TABLET COATING
Film coating
Non aqueous or aqueous solutions Contents of Non Aq.:
Film former Alloying substance Plasticizer Surfactant Opaquants and colorants Sweeteners, flavors, aromas Glossant Volatile oil

Contents of Aq.:
Film-forming polymer (7% to 18%) Plasticizer (0.5% to 2.0%) Colorant and opacifier (2.5% to 8%) Vehicle

TABLET COATING
Enteric coating
intended to pass through the stomach intact to disintegrate and release their drug content for absorption along the intestines

design is based on the transit time required for passage to the intestines
may be accomplished through coatings of sufficient thickness

Based on pH pharmaceutical shellac, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, diethyl phthalate, and cellulose acetate phthalate.

TABLET COATING
FLUID BED OR AIR SUSPENSION COATING
-spray coating held in suspension by a column of air Bottom- spray method (WURSTER process) Top- spray method Tangential- spray technique

COMPRESSION COATING
core tablets (multiple layered tablets) may be sugarcoated by compression coating material: form of a granulation or powder more uniform and uses less coating material
Tablets are lighter, smaller, and easier to swallow and less expensive to package and ship.

IMPACT OF MANUFACTURING CHANGES ON SOLID DOSAGE FORMS

Alteration in quality and performance due to changes in: FORMULATION

(a) the use of starting raw materials (b) the use of different pharmaceutical excipients (c) the use of different quantities of the same excipients in a formulation (d) the addition of a new excipient to a formulation

IMPACT OF MANUFACTURING CHANGES ON SOLID DOSAGE FORMS

METHOD OF MANUFACTURING
use of processing or manufacturing equipment of a different design a change in the steps or order in the process or method different in-process controls, quality tests, or assay methods production of different batch sizes employment of different product repro- cessing procedures employment of a different manufacturing site.

PACKAGING AND STORING TABLETS

Tablets are stored in tight containers in places of low humidity protected from extremes in temperature. desiccant packet- against decomposition caused by moisture. light-resistant containers- for drugs that are adversely affected by light properly stored tablets will remain stable for several years or more.