301 Solid Dosage Forms Flashcards
What are the steps in making a tablet?
- Milling (making smaller/consistently sized particles) & mixing of ingredients
- Granulation to bind ingredients together
- Tableting - compression of ingredients
- Testing to ensure consistency within & between batches
Excipients (what goes into a tablet and why?)
‘Ingredients’ in tablet that are not API
Powder API formulated into tablet by granulation & then compression methods
Significantly influence stability & bioavailability of API in tablet
Types of excipients
Diluents/fillers
Binders
Disintegrants
Glidants
Lubricants
Coating materials
Colouring agents
Stabiliser
Sweeteners & flavouring agents
Other
What do tablets need to weight for patient use?
Minimum of 50mg
Very low dose drugs require diluent/filler/bulking agents to bring tablet weight up to 50mg
Soluble examples of diluents/fillers
Lactose, sucrose, dextrose & mannitol
Insoluble examples of diluents/fillers
Why can lactose not be used for drugs with amine groups?
- Dicalcium phosphate, starches, microcrystalline cellulose (MCC), sodium chloride
- Due to Maillard reaction -> mannitol used instead
What is maillard reaction?
Chemical between amino acids & reducing sugar to create melanoidins, compounds give browned food its flavour
When are binders/adhesives added in the tableting process?
Either dry or liquid to promote formulation of cohesive agglomerate (granule) or to promote cohesive compacts during direct compression
What do binders do in dry granulation?
Binders can be added to dry powder for preparing tablets by direct compression
What can binders do in wet granulation?
And what are examples of these binders?
As solution to mixed powders
Binders for wet are usually polymeric (example: starch, gelatin, PVP, alginic acid derivates, cellulose derivatives, glucose, sucrose)
What do disintegrants do in the tableting process?
- Facilitate breakup or disintegration when tablets come into contact with fluids in GI tract
- Increases effective SA & promotes rapid release & dissolution of drug
- Burst the tablet open and/or promote rapid water ingress into centre of tablet or capsule
Should occur in 15 minutes
Examples of disintegrants
Starch, cationic exchange resins, cross-linked PVP, celluloses, modified starches, alginic acid & alginates, magnesium aluminium silicate, cross-linked sodium carboxymethyl cellulose (CMC)
What is microcrystalline cellulose (MCC)?
Mild disintegrant which acts by capillary action through pores to allow water ingress
Disintegrant mechanisms
- Increase porosity and wettability of compressed tablets to enhance penetration & GI fluid uptake (starch & MCC)
- Swelling of disintegrant, increases internal pressure of tablet matrix leading to disintegration (sodium starch glycolate & croscarmellose)
Glidants
- Improve flow properties of granulations
- Act by reducing inter-particulate friction
- Hydrophobic so adversely affect disintegration, so amount in tablet should be carefully monitored
- Low levels used but have very low bulk density
Examples of glidants
Fumed/colloidal silica (silicon dioxide), starch, talc
Effervescent tablets - disintegrants
Alternative mechanism
Tablets contain acidic and CO2 generating component
Acidic: taratic or succinic acid
Basic: sodium carbonate or bicarbonate
API must be compatible with acidic & basic components & should be soluble and easily dispersible in water
What happens with disintegrants in effervescent tablets?
In water presence, additives react liberating CO2 which rapidly disintegrates tablets and produces effervescence
Flow properties of a tablet
Powders to move within hopper & into tablet die in tablet press
Packing of particles is also reproducible (property variation result in mass differences of powder filled into tablet)
No clumping of powders
Flow property assessment: angle of repose
Angle that powder makes with horizontal plane
Passed through funnel until angle of inclination of powder is too small to overcome cohesive forces between particles
Measure of cohesion within powder mass
Cohesive powder will form an irregular heap, non-cohesive will form a regular conical heap
Tangent of angle of repose
Referred to as measure of internal friction of powder bed
If measured angle exceeds 50 degrees, flow properties of powder are poor
25 degrees indicates powder that would be expected to exhibit suitable flow for manufacturing process
Functions of lubricants in tableting
Prevent adherence of tablet to die faces and punches
Reduce inter-particle friction and improve flow
Facilitate smooth ejection from die cavity
Reduce wear on dies and punches
Example of lubricant
Magnesium stearate
But is chemically incompatible with many drugs - talc or stearic acid are substituted
Amount of lubricant used may adversely affect disintegration and dissolution of tablets
Why are soluble lubricants used and why is it controversial?
Minimise adverse effects of insoluble lubricants on tablet disintegration & dissolution
Yet, soluble lubricants are not as effective as insoluble
What are coating materials?
Provide physical barrier coating on surface of compressed core tablets
Protect API from environment (humidity or acidic stomach) or to offer different release profiles
Examples of coating materials
Polymers like hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (EC), poly(vinyl alcohol) (PVA)
Plasticisers like PEG
Opacifier like titanium dioxide
Colourants like iron oxide red and/or yellow
What do colouring agents do?
Improve the aesthetic appeal of final product
Colour added to binding solution or sprayed onto granules, dye mixed with dry powder blend before wet granulation
Colouring agents: key messages
Red, yellow, & orange drug formulations are perceived as stimulant & blue & green as tranquillising
Colour of drug influences effectiveness, but consistent trends not apparent
Examples: iron oxide red and/or yellow, FD&C Blue #6
What are stabilisers? And examples
Stabilise the API in the tablet from stresses such as oxidation
Antioxidants such as ascorbic acid, butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT) & α-tocopherol
What are sweeteners and flavouring agents used for?
Overcome drug taste and/or improve palatability for some types of tablets
Sweeteners but not sugars often used reduce the bulk volume
Available as oils or spry-dried beadlets to spray onto dry granules or incorporate in lubricant
Examples of sweeteners
Aspartame, saccharin sodium, sucralose, acesulfame potassium
Examples of flavourants
Proprietary flavours such as orange, pineapple
Other excipients: adsorbents
Capable of holding fluids in an apparently dry state
Oil-soluble drugs or fluid extracts are mixed with absorbents to develop a solid form for compression into tablets
Examples of adsorbents
Fumed silica, MCC, magnesium carbonate, kaolin, bentonite
What are moistening agents? And examples
Liquids used for wet granulation
Water, industrial methylated spirits, isopropanol (all solvent traces must be removed during drying process or tablets will have an alcoholic odour)
What does granulation ensure?
Good flow properties
Compressibility to form compacted tablet
Lubricant properties to eject from tablet die
What is granulation?
Wet (liquid required) or dry process
Drug & other excipient powders are prepared in larger, spherical granules to improve their flow & metering solids into a tablet die
Optimal size of granules are 500 & 800 μm
Improve flow of mixture & enhance compression properties
Enlarges particle size of powdered ingredients
Choice of granulation method is dependent on what?
- Physical & chemical stability of therapeutic agent during manufacturing process
- Availability of necessary processing equipment
- Cost of manufacturing process (extra drying & extra equipment to dry tablet for wet granulation)
- Excipients used to formulate product
Dry vs wet granulation
Powder flow, cohesion and/or segregation need improving (compactibility OK)
Poor compactibility and improved flow, cohesion and/or segregation of powder blend
Dry granulation (slugging)
Compacts components of tablet & milling compact to form granules
Compaction is done via slugging or roller compaction
No water or heat required
Compactibility is not problem, only powder flow
Preferred for moisture and/or heat sensitive APIs
Steps of dry granulation
- Milling of API ad excipients
- Mixing of milled powders
- Compression into large hard tablets (slugs)
- Screening of slugs
- Mixing of lubricant & disintegrant
- Tablet compression
Dry granulation advantages
Uses less equipment and space
It eliminates need for binder solution, heavy mixing equipment and costly and time-consuming drying step required for wet granulation
Dry granulation is useful for:
Moisture sensitive material
Heat sensitive material
Improved disintegration
Improved blending
- No binder liquid required
- No drying step required
- Powder particles are not bonded together by binder solubility
- No migration of soluble materials to surface
Dry granulation disadvantages
- Requires specialised equipment such as heavy duty tablet press to form slug
- Does not permit uniform colour distribution as can be achieved with wet granulation where dye can be incorporated into binder liquid
- Process tends to create more dust than wet granulation, increasing potential contamination
What is roller compaction?
Powder compaction of dry powders into solid mass known as ‘ribbon’
Feeds powder through set of directly opposed, counter-rotating rollers
Ribbon broken down into specific granule size via milling system such as oscillating mill
What is wet granulation?
Agglomeration
Wet massing of powder blend with granulating liquid, wet sizing & drying
Need to use wet granulation, both compactibility & powder flow are issues
API needs to be water stable i.e. not hydrolyse upon addition of binder solution
API needs to be heat stable i.e. not thermally degrade during drying
Steps of wet granulation
- Milling of drugs & excipients
- Mixing of milled powders
- Preparation of binder solution
- Mixing binder solution with powder mixture (wet mass)
- Screen wet mass through 6- to 12-mesh (coarse screen) forms granules
- Drying of moist granules
- Screen dry granules through 14- to 20-mesh screen (fine screened)
- Mixing of screened granules with lubricant & disintegrating agents
- Tablet compression
What does a good binder consist of in wet granulation?
- Good distribution throughout powder
- Chemical affinity between binder and host
- Similarity of surface free energy (surface tension) between host and binder for good binding characteristics
Wet granulation mechanism: particle bonding mechanisms
- Adhesive & cohesive forces in immobile liquid films
- Interfacial forces in mobile liquid films
- Solid bridges - partial melting & hardening of binders, crystallisation of dissolved substances
- Interlocking bonds
Wet granulation mechanism: states
- Pendular - granules start to form, 0-14% moisture content
- Funicular - granules 1 to <100% liquid in pores
- Capillary - may be 100% liquid in pores
- Droplet - >100% liquid in pores
Wet granulation advantages
- More spherical granules than powder
- Better flow properties
- Better compressibility
- Lower pressure to form tablet - extends machine life
- Better content uniformity (especially for soluble, low-dose drugs)
- Prevents segregation of components
- Improved dissolution rate of insoluble API with correct choice of solvent and binder
Wet granulation disadvantages
- Cost, expensive because of labour, time, equipment, energy & space requirements
- Loss of material during various stages of processing
- Stability concern for moisture sensitive or thermo-labile drugs
- Multiple processing steps add complexity, make validation & control difficult
- Any incompatibility between formulation components is aggravated
Wet granulation: granulator
- Can be low or high shear dependent on bowl shape, blade orientation & blade movement
- Shear rate can affect porosity, compactibility & density of granules
Wet granulation: fluid bed granulator
- Combines drying step of conventional wet granulation with granulation step
- Granulating fluid is sprayed on to fluidised powder bed
- Granulating fluid evaporates as powder blend is granulated
- Slow but controlled, offers control over porosity, density & uniformity of granules
What is porosity?
Measurement of void/empty spaces of material
Why is a tablet used most commonly?
Easier for patients:
- Non-invasive
- Palatability
- Portability
- Hard to tamper with
Easy to manufacture:
- Accurate dosing
- Established manufacturing methods
- Stable
- Easy to pack/ID/transport/store
What must a good tablet have?
- Stability of API
- Uniformity
- Consistent performance
- Appropriate disintegration & dissolution
- Can withstand packaging, transport & handling without breaking
- Able to mask the taste & odour
- Can make the appearance ‘appealing’
- Production is economically sound
How are tablets made?
API mixed with excipients so accurate drug dose in solid form
Wet or dry granulation
Powders via direct compression or granules can be used
All ingredients need to be dry and uniform
Steps of direct compression
- Milling of drugs and excipients
- Mixing of ingredients
- Tablet compression
Key questions in direct compression
- Is direct compression feasible? - Is granulation going to be required?
- Is the blend cohesive?
- Is there acceptable flow?
- Is the content uniformity acceptable?
- Is the bulk density acceptable?
Direct compression advantages
- Fewer processing steps (cost effective)
- Can often save labour, time, equipment & space
- It doesn’t require either heat nor moisture (fewer stability issues)
- It is ideal for simple formulation (lubrication performed in same vessel as powder mixing, reduction in transfer losses & contamination)
Direct compression disadvantages
- Not suitable for high-dose drugs with poor compression & flow properties
- Specialist (more expensive) excipients required
- There is often non-homogeneous distribution of low-dose drugs due to segregation after blending & if particles not of similar particle size/distribution properties
- Drugs with extremely low bulk density have issues flowing correctly & compressing directly due to air entrapment
- Formulations are sensitive to over-lubrication
- Softer tablets tend to be produced by direct than those produced by wet granulation (Issue for film coating)
- Cannot be used if a colourant is required (will produce mottled appearance)
Definitions:
Compression
Compaction
Tablet formation
- Apply force to
- Packing closely together
- Compressing sample of powdered material to form compact
Stages of tablet manufacture:
Filling die
Compression
Tablet decompression & ejection
- Dies can be various shapes & sizes
Filled by volume not weight from a hopper by gravity requires good powder flowability - Upper punch enters die, compression/compaction
- Upper punch leaves die, decompression
Tablet ejected
Tablet porosity - deformation of particle bed under compression
Particles undergo rearrangement to produce less porous structure
Further increase in force induces particle fragmentation/deformation leading to further decrease in porosity and increase in inter-particulate contact
Tablet presses: single-punch press
Uses 1 die and punch set
Produces 200 tabs/min
Used in pilot-scale manufacture and granulation for slugging
Tablet presses: rotary press
Large-scale manufacture
10,000 tabs/min
Powder/granule bed compressed between 2 punches
Upper & lower punches (up to 60/machine) within circular die table rotating circularly
Powder/granules fed from hopper to upper surface die table
Tablets removed by chute & collected
Tablet defects:
Pitting
Capping
Lamination
- Pit marks (dings) on surface due to insufficient lubricant at tablet/punch interface or punches with rough surface
- Mechanical splitting, tablet fractured
- Mechanical splitting, fracture occur within main body
How do capping and lamination occur?
Defects during ejection stage of manufacturing process & are attributed to stress-induced fracture due to radial & axial expansion - elastic recovery (go back to original shape after releasing stress (compression))
Post compression stage
Elastic recovery - heat released (bond may break during elastic recovery)
Heat can cause re-crystallisation
Polymorphism can be a problem (e.g. ranitidine when made into tablet causes side effects due to polymorphism)
Powdery surfaces can result – impair coating process
Flaws apparent straight after compression (but sometimes hours/days later)
Tablet testing: pharmacopoeia
Provide standards for pharmaceutical substances and medicinal products
Standards are an important tool in the regulation of the quality of medicines
We use BP
BP testing: pharmacopoeial tests
- Uniformity of weight
- Uniformity of content
- Tablet disintegration
- Tablet dissolution
BP testing: non-pharmacopoeial tests (not required in testing)
- Crushing strength
- Friability
- Tablet thickness
What are the benefits of modified drug delivery?
Promote therapeutic benefits while at same time minimising toxic effects
Types of release: immediate
Instantaneously available for pharmacological action
Dissolve with no intention of delaying/prolonging dissolution
Types of release: modified release (MR)
Delayed - release drug at time other than administration
Extended - release drug over extended period after administration
Types of release: controlled
Both extended release and pulsatile
Pulsatile - release finite amounts (pulses) of drugs at distinct, pre-programmed time intervals
What is disintegration?
Breaks tablet into granules & particles
Evaluated to ensure drug is fully available for dissolution & absorption from the GI tract
Only oral tablets not chewable or buccal (manually disintegrated)
Disintegration steps
Facilitate disintegration when in contact with GIT fluids, burst tablet and promote rapid water ingress to centre
Liquid penetration (water ingress), swelling, internal stress - microfracture, disintegration
What is swelling in disintegration?
Omni-directional enlargement of particles which builds pressure, pushing apart adjoining particles leading to exertion of stresses on overall systems = tablet breaks
Disintegration testing
Only indirectly linked to drug bioavailability and product performance
What is friability in the context of tablets?
A measure of tablet durability and resistance to breaking or crumbling under stress
Outline the stages of a drug leaving a tablet
Disintegration, deaggregation, dissolution, and absorption
Which properties affect a tablet’s disintegration, dissolution, and absorption?
Physicochemical properties, stability, compatibility with excipients, and site of absorption
What is required for a tablet to allow drug absorption?
It must disintegrate, dissolve, and then be absorbed in the GI tract
Why is crushing strength important in tablets?
Tablets must be hard enough to withstand processing but not so hard that they pass through the GI tract intact
