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Tablets

• Tablets are solid pharmaceutical dosage forms of many shapes and sizes.
• Tablets contain active principle(s) with or without suitable diluents.
• Tablets are prepared by compression or molding methods, as stated by RE King and JB Schwartz in 1985.
• Compressed tablets are manufactured on a large scale, while molded tablets are manufactured on a smaller scale.

Advantages of Tablets

• Tablets offer simplicity and economy of manufacture.
• Accommodate a large range of dose sizes.
• Provide stability
• Offer convenience in packaging, shipping, and dispensing.
• Offer convenient dosage accuracy, compactness, portability, a tastelessness that helps with ease of administration for the patient.

Tablet Types

• Compressed tablets can be uncoated or coated.
• Coated tablets include sugar, film, gelatin, and enteric coatings..
• Other tablet types include molded tablets, tablet triturates, hypodermic tablets, and dispensing tablets.
• Specialty tablets include chewable, effervescent, controlled release, extended release, sublingual, and buccal tablets.

Tablet Ingredients

• Active pharmaceutical ingredient (API, or 'active')
• Diluent
• Binder
• Lubricant These promote satisfactory processing and compression characteristics in the formulation.
• Glidant
• Disintegrant
• Color
• Flavor
• Sweetening agent These give additional desirable physical characteristics to the finished tablet.
• Binders such as starch paste, gelatin, or sugar solution help promote satisfactory processing and compression characteristics. Wet granulation methods help with this.

Tablet Ingredients: Diluent

• An inert substance added to increase bulk to make a tablet practical for compression, or adjust its size.
• 'Dilutes' the 'active' allowing handling of small quantities.
• Usually subjected to previous processes to give them flow-ability and compressibility.
• Examples include lactose, mannitol, di-calcium phosphate, calcium phosphate, and microcrystalline cellulose (Avicel®).
• Also called "excipients"
• It is important to test the compatibility of the active ingredient with the excipient.
• Water-soluble diluents can increase bioavailability of actives with low solubility. eg (Calcium salts can interfere with absorption of tetracycline in the GI tract.

Tablet Ingredients: Binder

• Imparts cohesive qualities to the powdered material and promotes adhesion of particles.
• Ensures tablet remains intact after compression
• Improves powder flow-ability
• The quality of the binder influences tablet characteristics.
• Too much/strong binder = strong/hard tablet that won't disintegrate, wearing down the tableting machine.
• For wet or dry granulation or direct compression.
• When wet, it is made into a paste or solution.
• When dry, it is blended with remaining ingredients before compression.
• Examples include starch paste (10-20% paste), gelatin (10-20% solution), sugar solution (sucrose, dextrose, lactose, molasses), natural/synthetic gums (acacia, sodium alginate), carboxy methyl cellulose (CMC), methyl cellulose (MC), polyvinyl pyrrolidone (PVP), alcohol/water (reacting with sugars), and microcrystalline cellulose (Avicel®).
• Different binders with tolbutamide can influence the hypoglycemic effects observed clinically.

Tablet Ingredients: Lubricant

• Generally hydrophobic materials.
• Prevents adhesion of the powder formulation to the surfaces of the dice and punches of the tableting machine.
• Reduce inter-particle friction.
• Facilitates ejection of tablets from dice cavity.
• Improves rate of flow of granulate
• Should be added to the granulated material, not during granulation.
• Examples include talc (~ 1-5%), magnesium stearate, calcium stearate, and stearic acid.
• Poor selection may result in 'water-proofing' tablet, poor tablet disintegration, poor dissolution, and decreased stability:

Tablet Ingredients: Glidant

• Improves flow characteristics of powder mixture
• Should be added in DRY state prior to powder compression.
• Examples include talc, and colloidal silicon dioxide (CAB-O-SIL® M-5P, Cabot, Corp) (<1%).

Tablet Ingredients: Disintergrant

• A substance or mixture of substances added to a tablet to facilitate its break-up or disintegration after oral ingestion.
• Disintegrant + 'active' + diluent should be mixed prior to granulation.
• May act by capillary action or swelling.
• Chemical Examples include starches, celluloses (carboxymethyl cellulose, Croscarmellose, sodium carboxymethyl cellulose, microcrystalline cellulose (Avicel®)), and cross-linked polymers.
• Effervescent tablets do not need disintegrant because sodium bicarbonate, tartaric or citric acid effervescence will cause tablets to disintegrate.
• Effervescent tablets need to be kept in a dry atmosphere at all times (thicker aluminum foil instead of a blister pack).

Tablet Ingredients: Coloring Agents

• Gives appearance to tablet.
• Serves as quality control based on particle/granule size, uniformity of granulate, and homogeneity of the powder blend.
• Serves as identification by user.
• Identifies the American Manufacturer's Association (AMA).
• Can be dissolved in the binding solution prior to granulation.
• Can be blended in dry with other ingredients.

Tablet Ingredients: Flavoring Agents

• Masks flavor or strong 'actives'.
• Used in very small quantities
• Examples include cyclamates and saccharine (banned), and aspartame

Tablet Pre-formulation

Characterization of drug and excipients by assessing:

• Purity
• Organoleptic properties
• Physicochemical properties (Solubility, Crystal properties and polymorphism, and Stability, hygroscopicity)
• Particle size, shape, and surface area.
• Density, flow-ability
• Compressibility
• Compatibility (excipients)

Methods to manufacture tablets

• Wet granulation
• Dry granulation
• Direct compression
• Tablet coating

Size Enlargement: Granulation

• Size enlargement process whereby small particles are gathered together into larger permanent aggregates.
• Used to render them into a free-flowing state similar to dry sand.

Dry Granulation

• Dense sheets are achieved through a roller compactor (chilsonator), then a mechanical granulator.
• Slugging achieves granulate to desired particle size through coarse tablets or slugs Flat (d=2.5 mm)

Extrusion

• Type of wet granulation that uses moist powder with a solvent type/volume.
• Extrude through mesh with specific equipment.
• Dry through oven with controlled temperature to size of tray and thickness of slurry layer.

Spray Drying

• Nature of powder collected depends upon Initial Solute Concentration, Size distribution of droplets, Rate of solvent removal.

How to select the appropriate granulation method?

Consider in order of importance:

1. Stability of the drug to Water and Heat.
2. Solubility of the drug and excipients.
3. Type of process and desired size of granule.
4. Type of dosage form

Tablet Manufacture Process

• Pre-formulation
• Granulation - Wet or Dry (GRANULATION METHOD)
• Compression (tableting)
• Coating
• Packaging
• QC (quality control)
• Another method is direct compression after PRE-FORMULATION

Tablet manufacture: Wet granulation (process)

• Sieve all ingredients through USP #40 sieve (reduce size if necessary)
• Mix 'active' and diluent (dry, ~ 30min)
• Prepare binder solution (add disintegrant or color if needed)
• Blend all mixtures
• Pass paste through a screen equivalent to USP#6 or #8 sieve (slurry) compress tablets
• Mix dry granules with lubricant and/or glidant
• Mill and sieve and pass through Sieve USP# 12 -20
• Dry with static bed (tray oven) or fluidized bed

Tablet Manufacture: Dry Granulation (Process)

• Sieve all ingredients through USP #40 sieve (reduce size if necessary)
• Mix 'active', diluent, binder, disintegrant and color (dry, ~ 30min)
• Pre-compress into sheets or slugs (shapes = 3-5 g) by a Roller compactor or chilsonator
• Mill and sieve through Sieve USP# 12 -20
• Ball mill and Hammer mill compress tablets
• Mix dry granules with lubricant and/or glidant and pass through tumbler

Tablet Manufacture: Direct Compression (Process)

• Sieve all ingredients through USP #40 sieve (reduce size if necessary)
• Mix 'active', diluent, binder, disintegrant and color (dry, ~ 30min) using a V-mixer or other tumbling mixer
• Compress tablets

Tablet Manufacture: Compression (Tableting)

• Components of tooling include dice and punches.
• There are single punch tableting machines or presses, rotary tablet machines, and multi-layer tableting machines.

Operation of Tableting Machines

• Step 1: Top punch lowers. Powder fills the die.
• Step 2: Excess powder is scraped off.
• Step 3: Tablet is compressed.
• Step 4: Top punch retracts.
• Step 5: Bottom punch rises, ejecting the tablet.

Sequential Steps in a Rotary Tableting Machine

1. Adjust the height of the upper and lower punches.
2. The granulate is placed in the tablet feeder.
3. The automated tabling process:
   • As the machine moves, the lower punch descends. The granulate is deposited in the dice cavity.
   • The scrapper removes the excess powder, ensuring homogeneous tablet weight.
   • The upper punch descends; height/strength is adjusted and imparted by the pre-compression and main compression rolls.
   • Powder is compacted between punches.
   • The upper punch is lifted. The lower punch rises so the tablet is ejected from the dice cavity.

Coated Tablets

• 'Coating' is a procedure to cover a tablet with a layer of substances.
• Cover the unpleasant taste, odor and color
• Physical and chemical protection in medicine from environment (light, moisture, and air)
• Control of drug release as in enteric coating or sustained release
• Improve the appearance of tablets
• Assist and facilitate the identification of a certain drug.
• Ease the process of blistering.

Kinds of Tablet Coatings

• Sugar Coated Tablets protect the drug from air and humidity, providing a taste/smell barrier for objectionable actives.
• Warm up uncoated tablets
• Waterproof and seal with ShellacTM.
• Thicken or sub-coat with gelatin, acacia gum, powdered sugar.
• Smooth and final round with dibasic calcium phosphate, titanium oxide, starch.
• Finish, color, and polish with carnauba wax/beeswax.
• Film Coated Tablet uses polymer/ plasticizer that coats the outside.
• The Polymer is often hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (CMC), polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), Eudragit™).
• The Plasticizer is often castor oil, diethyl phtalate, propylen glycol.
• Color the Tablet at the end.

Enteric Coated Tablet (ECT)

• Contain 'Actives' best absorbed in the intestines.
• Contain 'Actives' that cannot withstand the stomach acid.
• Tablet should not be crushed/chewed. Coating includes cellulose acetate phtalate and poly(methacrylic acid-co-methyl-methacrylate, poly(vinyl acetate phtalate).
• At low pH, carboxyl groups remain protonated (not water soluble).
• At high pH, carboxyl group is ionized (becomes water soluble).
• Aquateric®, Caoteric®, Eudragits™ are commercially available.

Specialized Tablets

• Multiple Compressed Tablets allow formulation of different drugs that may be incompatible with each other in the same tablet for controlled/sustained release.
• Scored Tablets are manufactured with punches that imprint line in the middle ('score') to make it easier to break tablet in ½ if there is no smaller dose available.
• *Warning: NEVR split a Coated Tablets.
• Contains lactose or mannitol silica-gel and HPMC and dissolve/erodes slowly to maximize absorption. Chewable Tablets: Smooth, disintegrate rapidly
• Mannitol may account for 50% or more of the weight of the formulation (Flavored).

Specialized Tablets.

• Effervescent Tablets contain Sodium bicarbonate/salts of citric, malic, tartaric, adipic, and fumaric acids (compressed from effervescent granules).
• Sublingual Tablets contain Nitroglycerin and have instant dissolution, formed in a mold for a suitable. temp active and contain Lactose or mannitol,saccharine massed with 60% ethanol.
• Buccal Tablets should be small flat and intended to inserted in buccal pouch where 'active' absorbs directly through the oral mucosa. and dissolve slowly to maximize absorption.

Tablet Manufacture: Possible Problems

• Capping or lamination stems from insufficient binder, too many “fines”, mixing problems, and compression problems.
• Sticking or picking stems from Granules that adhere to equipment by being Insufficiently lubricated with improper binder, and granules/tablet Poorly dried, and Wrong Choice of steel and polish of punches.
• Mottled color stems from Sub-optimal particle size, mixing, blending Improper preparation of coating solution
• Erosion and chipping occur in Soft or friable tablets with Fast pan rotation and Over-wetted tablet surface.
• Twining stems fromInadequate drying and Inadequate pan rotation.

Quality Control of Tablets

• Size (diameter and thickness)
• Weight and weight variation
• Color
• Hardness (or breaking strength)
• Friability
• Disintegration
• Dissolution
• Content uniformity
• Weight and Weight Variations lead adjust compression parameters process to make sure there are 5-10% of weight variation allowed per batch

Quality Control - Thickness (hardness & diameter)

• Thickness, hardness, and diameter should be measured in process. This may lead to adjustment in compression parameters.
• Final product measurements indicate accuracy of the dose and disintegration time, and sturdiness for subsequent coating/packaging.

Friability Testing - Quality Control

• Use (USP) to test how well tablets will stand up. to coating/packaging and shipping, and other processing conditions
• Add 10 duster tablets and weigh then on the analytical balancer.
• Add tablet to section and rotate 100 duster times.
• Re- duster weight to tablets than to tablets should not lose more than 1 % of their total weight.

Disintegration and Dissoultion

• Disenigration a USP test that estimates the time of tablet distringention of GI tract, the active become available for dissolution and obsortion .
• It is affected by thickness and hardness of the tablet.