Pharmaceutical Tablets: Dosage & Formulation

• Tablets are conventional dosage forms.

Learning Outcomes

• Students should be able to describe how tablets are made.
• Students should be able to explain the requirements of a versatile tablet formulation.
• Students should be able to discuss the importance and methods of granulation.
• Students should be able to discuss the selection of tablet excipients.
• Students should be able to describe the function of each ingredient in the formulation.
• Students should be able to discuss the evaluation of tablets.

Definition of Tablets

• Tablets are solid dosage forms that contain the desired amount of drug(s) within a single unit, with or without the use of excipients.
• Tablets come in all shapes and sizes.
• Most medications are dispensed as tablets, unless formulation is impossible.

Essential Properties of Tablets

• Tablets should have accurate medicament dosage and uniformity in weight, appearance, and diameter.
• Tablets should be strong enough to withstand mechanical shocks during production, packaging, shipping, and dispensing.
• Tablets should release medicinal agents in the body in a predictable and reproducible manner.
• Tablets should be elegant with an acceptable size and shape.
• Tablets should have chemical and physical stabilities.

Advantages of Tablets

• Production aspect advantages:
  • Tablets allow large scale production at the lowest cost.
  • Tablets are the easiest and cheapest to package and ship.
  • Tablets have high stability.
  • Tablets allow multi-drug therapy.
• User aspect advantages:
  • Tablets are easy to handle.
  • Tablets are the lightest and most compact dosage form.
  • Tablets offer the greatest dose precision and least content variability.
  • Tablet coating can mask unpleasant tastes and improve patient acceptability.
  • Tablets offer a wide range of doses and routes of administration.
  • Tablets allow multiple drug therapy.

Disadvantages of Tablets

• The tablet manufacturing process involves a series of unit operations, which can lead to product loss.
• Difficult to administer tablets to patients in an unconscious state, as well as pediatric and geriatric groups.
• Some drugs resist compression into dense compacts.
• Drugs with poor wetting, slow dissolution, and intermediate to large dosages may not formulate into tablets that provide adequate drug bioavailability.
  • Example: amorphous compounds
• Drugs with bitter tastes or objectionable odors, or that are sensitive to oxygen or moisture, may need encapsulation or entrapment prior to compression; the tablets may require coating.

Types of Tablets Based on Manufacture

• Compressed Tablets
  • An example is paracetamol tablets.
  • Nearly all tablets are compressed.
  • Designed to provide rapid disintegration and drug release.
  • Manufacture compresses granules or powders, containing drug, into required geometry.
• Multiply Compressed Tablets
  • These tablets can be layered or coated.
  • They are most useful for separating incompatible drugs into separate layers.
  • Designed to deliver therapeutic agents at different rates or to different sites within the gastrointestinal tract.
• Molded Tablets
  • Tablets triturate are small cylindrical tablets containing potent drugs mixed with filler (lactose) and binder (acacia).
  • The mixture is a soft mass that can be easily moulded using wooden or plastic moulds.
  • Designed for rapid dissolution.
    • Example: nitroglycerine tablets.

Tablet Types Based on Coating

• Sugar Coated Compressed tablets are coated with a water soluble coating that protects from the environment and masks objectionable tastes.
• Advantages: elegance.
• Disadvantages: require expertise, increase in size and uncoated tablet weight.
• Compressed Coated
  • Coating material is compressed onto a core tablet.
  • Anhydrous and safe for moisture labile drugs.
  • Uniform, less coating material.
  • Easy to handle.
• Film Coated
• Thin layer of coating on compressed tablets.
• Tablets are colored.
• Durable, less bulky, and less time consuming to apply.
• Design ruptures and exposes the core to have the desired location.
• Enteric Coated
  • Offer delayed release features.
  • The drug releases in the intestines and bypasses the gastric environment. Ecotrin tablets (GSK) are an example.

Tablet Types Based on Route of Administration

• Oral
  • Buccal
  • Designed for drug release in the mouth.
  • Avoids first-pass liver metabolism.
  • The drug diffuses into the blood directly through tissues through the oral mucosa.
  • Provides slow drug release
  • Lozenges are tablets used for local effect.
  • Sublingual
  • Similar to buccal.
  • Placed below the tongue.
  • Deliver fast action.
  • Example: nitroglycerine SL exerts in 2 minutes.

Other Tablet Types

• Chewable Tablets:
  • These tablets are mechanically disintegrated in the mouth by chewing.
  • Do not include a disintegrant.
  • Flavoring, sweetening, and coloring are important.
  • Mannitol produces a cooling effect and sweetening action due to negative heat of solution.
  • Provides quick and complete disintegration.
  • Allows rapid drug effect.
  • Easy to administer, especially for infants and elderly people.
  • Can be administered when water is not available.
  • Chewable aspirin and antacid tablets are examples.
• Effervescent Tablets:
  • Rapidly disintegrate and produce a drug suspension or aqueous solution when added to aqueous solutions
  • Disintegration caused by the components' chemical interaction:
  • Organic acid e.g., citric acid
  • Sodium bicarbonate in the presence of water.
  • The therapeutic agent is more absorbed more rapidly.
  • The evolution of carbon dioxide from this reaction leads to disintegration.
  • Main disadvantages:
  • Possible unavailability of water
  • Require moisture-impermeable packaging to inhibit the interaction of the acid and sodium bicarbonate with environmental moisture.
  • Usually aluminum foil.
• Implantation Tablets:
  • Placed subcutaneously by experts for administration.
  • Designed for prolonged and constant drug release
  • Small in shape
  • Osmotic pumps of insulin and contraceptives.
• Vaginal Tablets:
  • Also called pessaries.
  • Unique shape with one flat end and one ovoid end for easy insertion.
  • Following insertion, the tablet dissolves slowly to provide a local pharmacological effect

Tablet Types Based on Time of Drug Release

• Immediate Release:
  • Conventional tablets are intended to be swallowed for drug release in a relatively short time through disintegration and dissolution.
  • Tablet disintegration may be affected by the choice of excipients and the production conditions during manufacture.
  • No special rate controlling feature.
• Instant Release:
  • Intended for instant (less than 1 minute) dissolution in the mouth.
  • For pediatric and geriatric age groups.
  • Liquifies on the tongue.
  • Prepared by lyophyllisation and ij compression.
  • These use water soluble ingredients like gelatin and sugars, mannitol, sodium starch glycollate. Superdisintegrants are used for faster release of the drug.
  • Drugs can be pre- or post-loaded.
  • Disadvantage is that they are too soft and taste masking is poor.
• Extended Release:
  • Designed to release the drug slowly over a period of time.
  • May also have repeat action for timed release.

Manufacturing of Tablets

• Active ingredient
  • The most important ingredient that is fully characterised
• Excipients
  • Choice depends on the method of manufacture.
  • Typically:
  • Diluents/fillers
  • Binders
  • Disintegrants
  • Lubricants
  • Glidants, or
  • Miscellaneous flavorings, or colorants

Tablet Excipients

• Diluents/Fillers:
• Used to provide a tablet with the required bulk.
• Improve cohesion and promote powder flow for direct compression manufacturing.
• Desirable qualities:
• Non-toxic
• Physiologically inert
• Stable
• Uncontaminated
• Available in acceptable grade and color
• Low cost that do not alter bioavailability.

Examples of Diluents for Tablets

• Anhydrous lactose
• Lactose monohydrate
• Spray-dried lactose
  • Useful in direct compression
• Starch
  • Can also be used as a binder
• Directly compressible starch
• Dibasic calcium phosphate
  • Can't be used with acidic ingredients
• Microcrystalline cellulose (MCC)
  • Also called Avicel which can be used as a binder and disintegrating agent in wet granulation.
  • Avicel pH-101 (powder) and pH-102 (granules) are commonly used.
• Mannitol
  • Used as a diluent in chewable tablets.
  • Provides sweetness and negative heat of solution
• Sorbitol
• Calcium sulphate dihydrate.

Tablet Binders

• These are used to hold the powder together and promotes adhesion allowing granulation.
• Binders maintain a tablet's integrity
• They are used in wet as dry powders or pre-mixed in water or hydroalcoholic solutions.

General Categories of Binders

• Sugars or polymeric materials.
  • Natural polymers: starches or gums that include;
    • acacia, tragacanth, and gelatin.
  • Synthetic polymers: includes;
    • polyvinylpyrrolidone, and methyl- and ethylcellulose, and hydroxypropylcellulose.

Disintegrants

• These facilitate the breakdown of the tablet into granules upon entry into the stomach.
• Disintegration for conventional tablets should typically occur within 15 minutes. Add disintegrant before and after granulation for improved action.

Mechanisms of Disintegration

• Increases the porosity and wettability of the compressed tablet matrix to allow gastrointestinal fluids to readily penetrate the tablet matrix.
• Examples of disintegrants:
  • Starch
  • MCC
  • Sodium starch glycolate
• Swelling from aqueous fluids increases internal pressure within the matrix, causing it to burst. Examples:
  • Sodium starch glycolate.
  • Croscarmellose sodium (a cross-linked sodium carboxymethylcellulose) with a 0.5-5.0% w/w of working range.
  • Crosspovidone (a cross-linked polyvinylpyrollidone) with a 2-5% w/w of working range.
  • Pregelatinised starch with a 5%w/w of working concentration
• Effervescence mechanisms
• Enzymatic action to destroy binders
• Optimized sodium starch glycollate

Lubricants and Glidants

• Lubricants are intended to prevent adhesion of the tablet materials to the surface of dies and punches, reduce inter particle friction, and improve the flow rate of tablet granulation.
  • Examples of lubricants:
  • Stearic acid
  • Magnesium stearate
  • Talc
  • Polyethylene glycols (PEG)
  • Surfactants
• Glidants promote the flow of granules or powder by reducing the friction between the particles in the tableting machine.
• Examples of glidants:
• Corn starch at 5%-10% concentration
• Talc at 5% concentration
• Silica derivative - Colloidal silicas includes Cab-O-Sil and Aerosil in 0.25 - 3% concentration.

Other Tablet Excipients

• Sweetening Agents and Flavors:
  • These control the taste and increase tablet acceptability.
  • Example: sugar, mannitol saccharin (artificial) aspartame (artificial).
• Colorants in colored tablets:
• Improve appearance
• To hide color variation in the compressed or finished tablet uniquely
• Approved colorants are FD & C yellow 6 -sunset yellow; FD & C yellow 5 – Tartrazine; FD & C green 3-Fast green.

Ingredients with Multiple Uses

• Ethylcellulose at 1-3% used as a wet/dry binder or at 1-3% used as a controlled-release coating.
• Glyceryl palmitostearate at 0-5% used as a lubricant or at 10-50% used as a controlled-release excipient.
• Hydroxypropylmethyl cellulose (HPMC), low viscosity used at 2-5% as wet or dry binder, at 2-10% as a film former, or at 5-25% as a controlled-release excipient
• Magnesium aluminum silicate used at 2-10% as a binder or at2-10% as a disintegrant.
• Microcrystalline cellulose (MCC) is used at 0-8% to improve adhesion of film coats to the core of the table, at 0.2-0.5% as a glidant, at 5-20% as an antiadherent, at 5-20% as a disintegrant, or at 5-95% as a binder/filler.
• Polyethylene glycol is used at 0-10% as a lubricant, at 0-15% as a thermoplastic filler/binder, or at 5-40% as a controlled release excipient.
• Poly(methacrylates) are used at 2-10% as a flim former, at 5-20% at a controlled release excipient, at 10-50% as a filler, or at 5-10% as a coating excipient
• Poly(vinyl pyrrolidone) (Povidone, PVP) are used at 5-15% as a wet binder, at 5-10% as a coating excipient, at 5-30% as a disinitegrant, or at 10-35% as a controlled release excipient
• Starch is used at 3-15% as an intragranular binder/disintegrant, at 5-25% as a wet binder, or at 5-20% as a disintegrant.

Methods of Manufacture

• Three basic methods:
  • Wet Granulation
  • Uses liquid binder to form granules.
  • Dry Granulation
  • Compresses the drug, binder, filler and disintegrant mixture into slugs which are then passed through a sieve to form granules.
  • Direct compression
  • No initial granulation; material is mixed and compressed using specially made excipients.

Wet Granulation Steps

• Milling of drugs and excipients.
• Mixing of milled powders.
• Preparation of binder solution.
• Mixing binder solution with powder mixture to form wet mass.
• Coarse screening of wet mass using 6- to 12-mesh screens.
• Drying moist granules.
• Screening dry granules with lubricant and disintegrant.
• Mixing screened granules with lubricant and disintegrant.
• Tablet compression.

Dry Granulation Steps

• Milling of drugs and excipients.
• Mixing of milled powders.
• Compression into large, hard tablets called slugs.
• Screening of slugs
• Mixing with lubricant and disintegrating agent.
• Tablet compression.

Direct Compression Steps

• Milling of drugs and excipients.
• Mixing the ingredients.
• Tablet compression

Phenylpropanolamine Hydrochloride Tablets Example of Wet Granulation

• Final blend is made of phenylpropanolamine hydrochloride, calcium sulfate, starch paste, starch, and magnesium stearate is compressed using standard cup punches.
• Initial mix of with calcium sulfate is processed for 15 mins.
• The Starch paste is made from 10% starch being heated and boiled into white paste. Granules should remain moist so they can be successfully dry up.

Aspirin Tablets Example of Direct Compression

• The blended mix made from aspirin, avicel PH 102, and cornstarch.
• Has a 20 min process of blending mix The final mix is then compressed with standard concave tooling

Advantages of Wet Granulation

• Reduces the segregation of formulation components, leading to reduced intra-batch and interbatch variability.
• Useful for tablets needing lower concentrations of a therapeutic agent.
• Employs conventional excipients e.g., cornstarch.
• Most manufacturing plants use the wet granulation process.
• Tablets produced by wet granulation are amenable to postprocessing unit operations, e.g. tablet-coating techniques.

Disadvantages of Wet Granulation

• Requires several processing steps.
• Use of solvents:
  • Drug degradation may occur in the presence of the solvent, so hydroalcoholic (water/alcohol), ethanol or isopropanol is the granulation medium of choice.
  • Drug may be soluble in the granulation fluid.
  • Upon drying the powder, the drug may change chemically/physically.
• Heat is required to remove the solvent.
  • May degrade thermally labile therapeutic agents.
  • Need to ensure that the therapeutic agent is chemically stable during the granulation process.

Advantages of Dry Granulation

• Does not need heat or solvents.
• Safe alterations to drug morphology during processing.
• Both roller compaction and slugging use conventional grades of excipients.

Disadvantages of Dry Granulation

• Compaction needs specialized granulation equipment.
• Segregation of components may occur from the mixing process.
• Could be powder issues regarding flow.
• The dry granulation production is softer in texture which is hard to post coat since it wont maintain for more processing. Lead could be made in considerable dust, therefore need for consideration for containment measures, and may reduce the production of tablets.

Advantages of Direct Compression

• Does not require water, or solvents, or drying step.
• Lubrication performed by vessel for reduced loss of contaminants.
• Has fewer processing steps that are cheap
• High cost-effectiveness

Disadvantages of Direct Compression

• Specialist excipients are required and are difficult to compression using this technique.
• Formulation has a high drug amount of physical properties that may not be suitable for process of compression with this technique.
• Direct compression not used if formula isn't met with the appearance for resulting formula.
• Requires easy power flow to be mixed.
• Not meant with a colourant

The Tablet Machine

• Two designs of tablet presses:
  • Single-punch presses
  • Rotary presses
• The machine's efficiency depends upon:
  • Using as many punches as possible is important,
  • High points of compression
  • High number of stations

Essential Tablet Machine Parts

• Hopper for feeding and holding granulation to compress
• Dies for defining shape and size of the tabet
• Punches for compressing
• Cam tracks for guiding movement of tablets.
• Mechanisms move process

The Single Punch Press

• The tablet press that uses a set of punches.
• Makes 200 tablest per minute.
• Used for a light scale or pilot test of slugs

The Rotary Press

• Meant for the production of largest scale.
• Able to produce up to 10 000 tablets per minute. Has series of punches, and they are each housed within a table with rotary.
• Each are lowered and elevated by upper/lower rollers.

Compression Stages

• The powders and granulates are transferred to an surface of the table.
• It is transported into feed frame.
• Space is occupied by the portion of the tablet that determines the weight and dose drug and tablet.
• Lower punch can adjust for weight.
• Shoe is retracted.
• The force is applied as well
  • Changes the hardness.
• Eject upper compression from original position.
• And hopper then push the compress tablest of force.

Problems During Compression

• Arise during the processing with capping and laminations.
• Relates to a issues for double impression. The exipients chip tablets pick, bind, stic crack, and for motting or also during process for issues with capping.
• Remove surface due to punch, table material.
• Cracking happens at the tablets the top that are due expansion from the tablets

Picking Problems Solution

• Engravins will occur through the surface.
• To remove roughing of the face needs to coated.
• Add silica of colloidal to prevent stick.
• Too much volume.
• And too much material for the result for coheasivness.

S no 2-4 Solution

• Cause it may not fully process to compression and the surface has a sticky situation, lower divines must have more dephts
• The binder need to use right material to results pickiness.

Sticking Problems Solution

• Causes could have low or fast pressure
• Has higher convavity.

Capping Problem Solution

• Has high volume to fines.
• Try the right proper technique
• Dry more.
• Use right binders to avoid cap. Also try apply with higher compress, or set it as correct setting.

Lammation Problem Solution

• May contain oil try correct the compression
• Fast to decompress split.

Mottling Problem Solution

• Dyes migrate due migration issues during table setting
• Bad solutions or not even to distritbure

Cracking & Chiiping Problem Solution

• Way its coated dried or sprayed to the tablest it needs moisture.
• And to polish has needs surface if they uneven to the finsh.

Quality Control Tests

• Beginning, during and end of compression Important tests for:
  • Weight uniformity
  • Content uniformity
  • Hardness and friability
  • Disintegration
  • Dissolution

Weight Uniformity

• 20 take out has that way will be that are indvilually measure will have as weight. USP test, tablets more in % will have limit to error 10%

Content Uniformity

• Is is that by 30 tablets that are cleareads the tablets is more then to test percentage that are label drugged test

Hardness

• A strength that needs crush the tablet on the end that determines and needs ajdustemnts.

Problems to tablet for time

There are problems that can occur that it effect for hardness to it doesn't need or that are more tablet to handling

Factors Of the Hardness.

• Force or compressing, More binders to hardness, More methods of granulation. Tablets are hard to maintain quality and has the limits that is quite unofficial to at the numbers of max and min levels.

Friability

Tendcy that is tested to packaage handling, test. Is used to called the fiabiloty 10 tablets total or 4 mins loss for tablets. Has tablet types but are high with limit for types

Disintergration

• When time requires to break from the tablets.
• important has to have a promoted drugs to has in GIT.
• has be the right hardnerss also.

What water would be simulated fluid: can make some sort impact of how much more harder tablet should come for some form of stress

Procedure Of Test

6 tubes 3 inch, and 10 mesh screen at the end Table placed in each tube, and tablets remain and meshs. Uncoated takes abou 5 mins coated takes 8 hours. And is is what the test test in tablets if they dont not fully within same

Dissolution

Is important to know that it in vitro. A idea what that has be drugs and body types. Dissolution that is test dose

Apparatus tests

Basket: from about to 120 for tablet forms also.

And used for recpricoating for extednt test.

Apparatus Procedure

• Made with same batch

• Basking on dry tablets

• With about dry some so

• Fluid to keep the tempeartures And 2 mls to prevent some conditoins.

• Other apparatus make to dissolve and the same.

Test

A passes will results ± 5%

A tested drugs will have a lot the specified that not had to be 2 tablet more than limits had been specifiers.