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Questions and Answers
What is the primary role of lubricants in tablet manufacturing?
What is the primary role of lubricants in tablet manufacturing?
Which problem in tablet manufacture is characterized by the upper segment cracking or separating from the tablet?
Which problem in tablet manufacture is characterized by the upper segment cracking or separating from the tablet?
Which of the following is NOT a remedy for sticking during tablet manufacturing?
Which of the following is NOT a remedy for sticking during tablet manufacturing?
What could lead to binding problems during tablet manufacturing?
What could lead to binding problems during tablet manufacturing?
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How can you achieve a uniform rate of drug release in tablets?
How can you achieve a uniform rate of drug release in tablets?
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Which of the following practices can help avoid chipping in tablet manufacture?
Which of the following practices can help avoid chipping in tablet manufacture?
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What factor influences the evaluation of color in tablets?
What factor influences the evaluation of color in tablets?
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Which problem occurs due to the presence of large percentages of fines in granulation?
Which problem occurs due to the presence of large percentages of fines in granulation?
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What is one of the main advantages of tablets over liquid preparations?
What is one of the main advantages of tablets over liquid preparations?
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Which type of tablet is designed to dissolve under the tongue for rapid absorption?
Which type of tablet is designed to dissolve under the tongue for rapid absorption?
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What is essential for achieving uniform weight and drug content in tablet manufacturing?
What is essential for achieving uniform weight and drug content in tablet manufacturing?
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Which of the following is NOT a type of tablet mentioned?
Which of the following is NOT a type of tablet mentioned?
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What property of tablets is critical for their handling during manufacture and shipping?
What property of tablets is critical for their handling during manufacture and shipping?
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Which method involves mixing drugs with a binder solution before compression?
Which method involves mixing drugs with a binder solution before compression?
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What type of agent helps improve the flow of powder during tablet manufacturing?
What type of agent helps improve the flow of powder during tablet manufacturing?
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Which of the following is a crucial step in both wet and dry granulation methods of tablet manufacturing?
Which of the following is a crucial step in both wet and dry granulation methods of tablet manufacturing?
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What impact does too little binding agent have on granules?
What impact does too little binding agent have on granules?
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Which binding agent is known for its strong adhesive properties when used in warm solution?
Which binding agent is known for its strong adhesive properties when used in warm solution?
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Which property must a suitable binding agent possess to be effective in tablet formulation?
Which property must a suitable binding agent possess to be effective in tablet formulation?
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What role do colour additives play in tablet manufacturing?
What role do colour additives play in tablet manufacturing?
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What characteristic of pastel shades makes them preferable for tablets?
What characteristic of pastel shades makes them preferable for tablets?
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Which flavour is considered a good masking agent for bitter tastes?
Which flavour is considered a good masking agent for bitter tastes?
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What is the main consideration for selecting a suitable moistening agent in tablet formulation?
What is the main consideration for selecting a suitable moistening agent in tablet formulation?
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What is evaluated in tablets to determine their total quality?
What is evaluated in tablets to determine their total quality?
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Study Notes
Tablets
- Tablets are a common, pharmaceutical dosage form.
- They are made by compressing active drugs and excipients.
- Tablets are a convenient and stable method of administering medication.
Advantages of Tablets
- Enable accurate dosing; easy to administer.
- Easy for bulk transport and to carry.
- More stable than liquid preparations.
- Drug release can be modified to suit specific purposes, e.g., slow release.
- Mass production is simple and quick, resulting in low production costs.
Types of Tablets
- Swallowed whole tablets
- Effervescent tablets; release gas when added to water
- Chewable tablets
- Sublingual tablets; placed under the tongue for absorption
- Sustained/Controlled release tablets; release drug over time
- Coated tablets; protect from decomposition or mask taste
- Multilayer tablets; multiple layers
Properties of Tablets
- Must be robust; resistant to abrasion during manufacturing, packaging, shipping and use.
- Must have uniform weight and drug content; consistency.
- Must offer an elegant appearance, including colour, shape, and markings.
- Must retain all functional attributes, such as stability.
- Need to be bioavailable.
Unit Processes in Tablet Manufacture
- Properties are affected by formulation and manufacture method.
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Key unit processes include:
- Solid-solid mixing
- Solid-liquid mixing
- Milling (size reduction)
- Drying
- Compaction
- Strict temperature and humidity control crucial.
- Manufacturing areas need to prevent cross-contamination.
Methods of Tablet Manufacture
- Wet granulation
- Dry granulation
- Direct compression
Steps in Different Methods
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Wet Granulation:
- Mill drugs and excipients.
- Mix milled powders.
- Prepare binder solution.
- Mix binder solution and powders until a wet mass is formed.
- Screen the wet mass.
- Dry the moist granules.
- Screen dry granules.
- Mix screened granules with lubricant and disintegrant
- Tablet compression
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Dry Granulation:
- Mill drugs and excipients.
- Mix milled powders.
- Compress into large, hard tablets which are then broken into slugs.
- Screen the slugs.
- Mix with lubricant and disintegrant.
- Tablet compression.
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Direct Compression:
- Mill drugs and excipients.
- Mix milled powders and ingredients.
- Tablet compression.
Wet Granulation Details
- Wet granulation primarily focuses on the transformation of fine powder into larger granules by adding a liquid binder, which leads to enhanced flow properties and improved uniformity. This increased particle size is crucial for ensuring that powders flow smoothly through the hopper into the dies, thus minimizing issues like caking and inconsistent dosage, which can significantly impact the quality of the final product.
Advantages of Wet Granulation
- Improves cohesiveness and compressibility.
- Reduces compression pressure, which extends tooling life and reduces stress on machinery.
- Suitable for drugs with poor flow or compressibility.
- Improves additives distribution.
- Prevents component segregation during processing.
- Potentially improves dissolution rate for hydrophobic drugs.
Limitations of Wet Granulation
- Costly; higher labour and resources.
- This process may not be appropriate for heat-sensitive drugs, as the granulation process often involves moisture and mechanical forces that can degrade, destabilize, or alter the integrity of these delicate compounds, rendering them ineffective.
Direct Compression Details
- Avoids wetting and drying steps; saves money on equipment for these processes.
- Suitable for heat-sensitive drugs.
- Requires a compression vehicle to aid tablet production, which varies based on the specific properties of the formulation, including particle size, shape, and flow characteristics that influence tablet integrity.
Dry Granulation Details
- Used when drugs are sensitive to moisture or heat.
- Mix of powders is forced into a tablet press, creating a compacted mass (slugs).
- Slugs are ground into smaller granules.
- Resultant granules can flow more uniformly due to the improved particle size and shape achieved during the granulation process, enhancing blending and uniform distribution.
- This method is particularly beneficial for compounds that are sensitive to moisture and heat, ensuring stability..
- More expensive than direct compression, due to the process taking longer, and expensive equipment.
Tablet Excipients
- Tablets = Active drug + Excipients.
- Excipients perform many essential roles, not just as fillers.
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Diluents, also known as bulk agents, are substances used in pharmaceutical formulations to increase the volume of the final product without affecting its therapeutic efficacy. They play a crucial role in tablet and capsule production by ensuring consistent dosing of the active pharmaceutical ingredient (API). Common examples include lactose, microcrystalline cellulose, and starch.
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Moistening Agents are substances used to enhance the wettability of solid particles in a formulation. They play a crucial role in ensuring that powders or granules absorb moisture effectively, which can significantly improve the processing characteristics of tablets Common examples of moistening agents include glycerin, propylene glycol, and polyethylene glycol, each chosen for their specific properties and compatibility with active pharmaceutical ingredients.
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Binding agents are crucial components in tablet formulations. They serve the primary function of holding the other ingredients together in a cohesive structure, thereby ensuring the tablet maintains its shape during both manufacturing and handling processes. Commonly used binding agents include starches, cellulose derivatives, and synthetic polymers, each selected based on their properties and the specific requirements of the formulation.
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Glidants are essential excipients utilized in the formulation of pharmaceuticals, specifically to enhance the flow characteristics of powders. By minimizing friction between individual particles, glidants significantly facilitate the manufacturing process. Common examples of glidants include silica and talc.
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Disintegrants are substances that facilitate the breakdown of tablets into smaller fragments upon contact with fluids. Common disintegrants include starch, sodium starch glycolate, and microcrystalline cellulose, each selected for their effectiveness in promoting rapid disintegration, thus enhancing bioavailability.
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Colour and flavour additives are essential ingredients used to enhance the aesthetic appeal and palatability of various products. Common colour additives may include natural extracts, such as beet juice or turmeric, as well as synthetic dyes that are approved for use in pharmaceuticals.
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Lubricants are critical excipients used in the formulation of tablets and other solid dosage forms. Their primary role is to reduce friction between the drug particles and the surfaces of machinery during the manufacturing process, particularly during stages such as mixing, compression, and ejection of the tablets.
Common types of lubricants include magnesium stearate, stearic acid, and talc.
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Diluents (Bulk Agents)
- Used to increase the bulk of the tablet, improving tablet compression.
- Inert, can improve binding/flow in tablet properties.
- In the case of high-dose pharmaceuticals, it is often unnecessary to include certain excipients, as these medications require larger tablet weights for efficacy. Specifically, tablets should ideally weigh no less than 70 mg to ensure proper dosing, stability, and patient compliance in administration.
- Common diluents include lactose (pleasant taste, dissolves in water quickly absorbs little moisture) and Dicalcium Phosphate; (insoluble, hard, white granules).
- Other typical diluents include: dextrose, mannitol, microcrystalline cellulose, sucrose.
Moistening Agents
- Required for wet granulation, typically using water.
- If water isn't suitable, e.g., with heat-sensitive drugs, alcohol is used, but absolute alcohol is expensive, and industrial methylated spirits are used instead.
- All traces of alcohol must be removed during the drying process.
Glidants
- Improve the flow properties of granulations.
- Improve the friction between particles.
- Silica is a typical glidant; added in small quantities (0.1%).
Lubricants
- Prevent granules adhesion to punch faces/dies.
- Ensure smooth tablet ejection from the die.
- Enhance flow properties of granules.
- Commonly used in tablets include talc and magnesium stearate, and are blended with the granulations at a concentration of up to 1% w/w.
- Lubricants increase disintegration time, so are used in small amounts and for short mixing periods, as overmixing reduces bonding forces within the tablet matrix.
Disintegrants
- Break up tablets after administration to increase the surface area and enhance drug release.
- Act by swelling when in contact with water, which bursted the tablets open.
- Alternative disintegration mechanism is capillary action; liquid is drawn through the tablet's tiny channels, and interparticle bonds are ruptured.
- Common disintegrant is starch.
Binding Agents (Adhesives)
- Act as adhesives to bind powdered ingredients together into tablet granule form.
- Help bind granules during compression, creating strength in the final tablet form.
- Too little binding agent leads to weak, soft tablet granules.
- Too much binding agent creates hard tablet granules.
- Can be added as a powder (dry granulation) or a solution (wet granulation).
Criteria for Binding Agent Selection
- Compatibility with other tablet components.
- Sufficient cohesion for normal processing should not inhibit normal disintegration/dissolution.
- Should allow the drug to dissolve in a way that is bioavailable for the patient.
- Common binding agents include Starch (good, used in mucilage with H₂O), Gelatin (gel in cold water; used with a warm solution), Polyvinylpyrrolidone (PVP) (dissolves readily in water and alcohol, helps release drug faster)
Colour Additives
- Aesthetic value and distinguishes one product from another.
- Pastel colours are more common, and are less likely to show mottling than darker colours.
- Colours must be certified by the Food and Drug Administration (FDA).
- Colour added to a binder liquid during wet granulation (allows for uniform dispersion).
Flavours
- Mask bitter, sour, and unpleasant tastes in liquid and solid dosage forms, e.g., chewable tablets.
- Salt can overcome excessive sweetness.
- Common flavours include chocolate for bitterness, and raspberry for saltiness.
Evaluation of Tablets
- Chemical, physical, and biological properties evaluated comprehensively.
- The total quality of the tablet formulation after manufacturing is taken into account.
- Evaluation must consider factors arising during manufacture and storage.
Evaluation Tests for Tablets
- Tablet thickness; achieving a consistent tablet thickness is crucial because any discrepancies can lead to difficulties in packaging processes and may ultimately impact patient satisfaction and adherence to medication regimens. Variations could also affect dosage accuracy and overall product quality.
- Hardness; must withstand handling and reasonable consumer use.
- Disintegration; essential to be able to break down into small parts.
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Dissolution; a critical process that facilitates the release of a drug from its solid form, allowing it to become soluble in the gastrointestinal tract (GIT). This is essential for effective absorption into the bloodstream. Factors such as pH, temperature, and the presence of other substances can influence dissolution rates. Includes several tests for analysis, which may involve methods like U.S.P. (United States Pharmacopeia) dissolution testing, assessing how quickly and completely a drug can dissolve under specified conditions.
- These tests help ensure consistent drug performance and support regulatory requirements for pharmaceutical products.
- Colour; must be uniform from tablet to tablet.
- Unique Identification Markings; used for quick identification; includes engraving, embossing, and printing.
- Weight; dimensions/density of mix determine weight; must not vary greatly from batch to batch.
- Friability; another measure of strength; the tablet's ability to withstand shock and abrasion before or after manufacturing, packaging, and shipping.
- Uniformity of content; measures the consistency of active drug content within a tablet sample.
Problems in Tablet Manufacture
- Binding
- Sticking
- Capping/Lamination
- Chipping/Cracking
Binding Problems
- Insufficient lubricant, sticky and adheres to die-wall.
- Excessive binding agent causing hard granules leading to poor handling and ejection problems.
Sticking Problems
- Incompletely dried/improperly lubricated granulation.
- Granulation often sticks to punch faces; leading to chipping and damage to tablets or causing them to pull apart from the punch.
Capping/Lamination Problems
- Air entrapped in the die which is released when pressure is applied to create space; leading to tablet capping.
Chipping/Cracking Problems
- Sticking or damaged punches causing chips or cracks
- Due to inadequate lubrication and granulation hardness
Remedies:
- Binding: Increase lubrication, adjust granule size/moisture, use more efficient lubrication, and adjust binder/wetting concentration
- Sticking: Decrease granulation moisture content, change or reduce the lubricant, increase binder proportion in the granulation, and clean punch faces with a light mineral oil solution
- Capping/Lamination: Remove fines from granules, remove or adjust the lubricant, re-granulation process , adjusting the binder's proportion.
- Chipping/Cracking: Replace punches/reface nicked or chipped punches; adjust granule size, increase wetting and binder; polish punch tips.
Other Compressed Dosage Forms
- Lozenges
- Sublingual and buccal tablets
- Implants
- Effervescent tablets
- Chewable tablets
- Multilayered tablets
- Sustained-release tablets
Lozenges
- Compressed tablets at least 18mm in diameter.
- No disintegrant; meant to be sucked to dissolve in the mouth.
- Flavours are commonly used to improve palatability.
Types of Lozenges
- Local effect: Contains antiseptic or antibiotic; must be palatable and slowly soluble, containing ingredients like sucrose, lactose, and gelatin solution for enhanced taste.
- Systemic effect: Contains vitamin supplements; intended to dissolve in the mouth and provide a palatable delivery method.
Sublingual and Buccal Tablets
- Placed under the tongue or inside the cheek.
- Produce an immediate systemic effect, absorbed directly through the mucosa (drug lining the mouth).
- Examples include isoprenaline sulphate.
- Small and flat tablets with no disintegrant required; compressed lightly to create softer tablets.
- Sucrose used to enhance sweetness.
Implants
- Small pellets (2-3mm) of drug, specifically formulated without any excipients, indicating a pure pharmaceutical preparation. These pellets are created under strict aseptic conditions to ensure sterility and prevent contamination.
- Inserted into body tissues, slowly absorbed over months/years.
- Used to treat conditions for which a steady drug level is desired, like hormones.
- Manual, die-filling method used due to drug properties.
Effervescent Tablets
- Broken up by internal CO₂ release when added to water.
- Used for palatability enhancements.
- Alkali metal carbonates/bicarbonates + tartaric/citric acid → CO₂ liberates in H₂O.
- Water soluble lubricant added to prevent insoluble residue on water surfaces.
Chewable Tablets
- Attractive option for those who struggle swallowing or for children.
- Can be used anytime without water.
- Uses mannitol (flavour) as the diluent to improve palatability.
- Created from wet granulation; granules have to be robust enough to be chewed but also palatable.
- Disintegrant rarely needed; tablet broken down by chewing action.
Multilayer Tablets
- Composed of multiple granulations layered on top of each other.
- Granulations are conveyed using specialized equipment designed to ensure precise dosing, utilizing individual weight control systems. This meticulous approach helps maintain product consistency and uniformity throughout the manufacturing process, enhancing overall quality.
- Suitable for incompatible substances.
- Emphasise dust control during the production process.
Sustained-Release Tablets
- Designed for slow drug release after ingestion.
- Fewer doses required daily, improving patient compliance.
- Extending the activity throughout the night eliminates the need for the patient to wake.
- Benefit use in hospital settings due to time savings or nurses.
- Reduces fluctuation in drug concentration, leading to fewer side effects.
Disadvantages of Sustained-Release Tablets
- Tablets generally much more expensive than normal tablets.
- Increased risk of accidental poisoning.
- Large drug doses lead to the bigger tablet sizes, which can lead to swallowing problems.
- Failure of the drug release mechanism can lead to a phenomenon known as dose dumping, which occurs when the medication is released into the bloodstream all at once rather than being gradually released over an intended duration. This can result in an increased risk of side effects and toxicity, as the spike in drug concentration can overwhelm the body's ability to process it effectively.
Example Formulation Questions
- Listed example formulation questions for practicing the use of the concepts in a practical setting given.
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