Tablet formation and preparation Flashcards
what is a tablet?
- compressed solid w single/more active(s)
- circular w flat beveled or biconvex faces
how is a tablet prepared?
- medicinal/active w or wo diluents
- prepared by compression or moulding/3d print
- moulding/3d print = small scale
- compression = large scale
properties of oral compressed tablets?
- for swallowing
- disintegrate in stomach
- can be enteric, modified release, effervescent etc
- other forms: solution tablets (solvelle), hypodermic, implants
how to prepare effervescent tablets?
alkali metal carbonate/bicarbonate + organic acid (e.g. tartaric/citric acid)
- liberate CO2 in water
(1) wet fusion
- citric acid moistened, add sodium carbonate —> then granulate (form citric acid fuse powders)
(2) heat fusion: powders blended dry where citric MONOHYDRATE is used; apply heat
- water of crystallization is liberated which AIDS in GRANULATION
- water of crystallization forms the bridges
which method to prepare effervescent tablets is preferred?
(heat fusion more preferable as it minimises moisture)
what are the important properties tablets need to have?
- exact dosage of active principle(s)
- maximum stability
- suitable mechanical properties
- contain inert excipients/additives
- suitable for its intended purpose
advantages of tablets?
- convenient for administrating
- delivery of accurate dose
- small and compact
- stable
- easy to handle and pack
- high production throughput
disadvantages of tablets?
- poor compressibility (due to its elastic component)
- poor wetting
- slow dissolution
- high dose
- bitter taste/ bad odour
- sensitive to moisture
what are some excipient requirements for the solid dose formulation?
for:
- low dose drug - filler used
- strength = binder used
- bioavailability = disintegrant/wetting agent is used
- tabletability = lubricant
- identity = colorant used
what are the major excipients?
- diluent/filler
- binder/adhesive
- disintegrant
- lubricant
what are the minor excipients?
- absorbent
- wetting agent
- stabiliser
- colorant
based on functional classification of excipients, which excipients affect compaction properties?
- diluents/fillers
- binders/adhesives
- lubricants, glidants, anti-adherents
based on functional classification of excipients, which excipients affect bioavailability, stability and market considerations?
- disintegrant
- lubricant
- colours, flavours, sweeteners
examples of diluents/fillers; and what to take note of diluents/fillers?
(1) sugar
- lactose - hydrate/anhydrous forms, directly compressible (e.g. spray dried)
- sucrose based
(2) starches
- corn starch
- pregelatinized starch
(3) cellulose
- microcrystalline cellulose
(4) inorganic salts
- dicalcium phosphate
note: diluents/filler are inert, inexpensive, good flow, good compactibility
examples of binders/adhesives (used for strength)
(1) cellulose
- microcrystalline cellulose (MCC) –> high strength, low friability, self-lubricant
- dry binder
(2) modified cellulose
- HPMC
(3) synthetic polymers
- polyvinylpyrrolidone (PVP)
(4) gums
- sodium alginate, acacia, gelatin
examples of disintegrant
- starch
~ swelling, wicking - microcrystalline cellulose (MCC)
~ wicking, H-bonding - sodium starch glycolate
~ swelling - modified cellulose gum
~ swelling - cross-linked PVP
~ wicking, strain recovery (memory polymer)
5 different mechanisms of disintegrant action
(1) swelling
- starch, sodium starch glycolate, modified cellulose gum
- increase in size, expand their vol
(2) wicking (capillary action)
- MCC, cross-linked PVP, starch
- intraparticulate bonds are broken
(3) strain recovery
- cross-linked PVP
- swell back to ORIGINAL state (unlike the swelling mechanism where disintegrant swells more than its original size)
(4) interruption of particle-particle bonds (H-bonding)
- MCC
(5) heat of interaction
- enthalpy changes as water enters, expansion and contraction happens
what do we have to ensure at least moderate dissolution of the drug?
- disintegration has to occur
what do we have to ensure FAST dissolution of the drug?
- disintegration
- and deaggregation (primary particles released) has to occur
types of colorant
- dyes (soluble or insoluble pigment types)
- lakes (lake pigments contain soluble dyes deposited onto carrier particles, usually metallic salts)
~ ensure dye dont migrate
purpose of colourant?
- provide colour to tablet
- often added wet, with granulation liquid
- may be added dry (but this needs more dye to be added)
- color used in film or sugar coating processes
for the definition of lubricants, what are the 3 diff types of ‘lubricant’?
- glidant
- lubricant
- anti-adherents
what are glidants, and some examples?
- improve flow properties of granules/powders by reducing friction BET PARTICLES, provide ‘BALL-BEARING’ effect
glidants aka flow aids (running powder)
e.g.: silicates, fused silica, starch, talc, MgSt, CaSt, Zn St
what are Lubricants, and some examples?
- reduce the friction between granulation and die-wall (equipment) during compaction
e.g.
hydrodynamic (fluid-type) = mineral oil, paraffin
boundary (solid-type)
= water insoluble: MgSt, CaSt, stearic acid, hydrogenated vege oil, waxes
= water soluble: PEG (carbowax), Na benzoate, Na acetate, leucine, Na lauryl sulfate
what are anti-adherents, and some examples?
- prevent sticking or adhesion of the tablet, granules or powders to the faces of the punches
e. g.:
- starch
- talc
- Mg, Ca, Zn St
- silicates derivatives
- leucine
- Na lauryl sulfate
which materials are best for which type of ‘lubricants’ (based on the 3 types)
(1) stearates = excellent lubricant
(2) talc = excellent anti-adherent
(3) stearic acid = good lubricant (no glidant effect)
(4) waxes = excellent lubricant (no glidant effect)
(5) starch = excellent glidant and anti-adherent
note: poor does not mean it doesnt work
2 different machines for tablet press?
(1) single punch tablet machine
(2) rotary or multi-station tablet machine
how does the single punch tablet machine work?
- lower punch in die will move down to create a die cavity for granules
- shoe moves over die, filling the die cavity, scraping excess granules to the level of die table by moving aside
- upper punch descends to compress granules
- upper punch withdraws, lower punch rises to eject tablet
- shoe shift tablet to collection chute
- cycle repeats
how does the rotary/multi-station tablet machine work?
- dies is on a rotating platform (called turret)
- each die has lower & upper punches
- granules from hopper into feed frame covering a number of dies
- lower punch descends, allow die filling to desired weight + EXCESS
- lower punch raises to correct level, where excess granules removed
- punches are brought together to compress granules into tablet
what is one ‘station’ in the rotary tablet machine?
upper punch + lower punch + die
What are some tableting machines to compress granules?
- Tablets are formed by compression using punches of granules fed into dies
- single punch (single station) tablet machine
- rotary (multiple station) tablet machine
What are the two terms important in compaction forces?
What is the formula for strain?
Stress: applied force to produce a deformation
Deformation: change in the relative positions of different parts of body, expressed as STRAIN which is a change in length per unit length or volume per unit volume
Strain (L0 - L)/L0 = change in L / original length
What is the Hooke’s Law and what is the relationship between the variables in the equation?
sigma = Y X e
Y = modulus of elasticity or Young’s modulus
sigma (y) = yield stress, stress at the elastic limit
e = axial strain
For a given load:
smaller the Young’s Modulus, more strain –> greater the amount of elastic recovery and maybe lower compact strength due to structural failure
How to read a stress-strain relationship for consolidation and bond formation?
x axis: displacement (axial strain, e)
y axis: force (axial stress, sigma)
from 0 to sigma (y) (y axis), the slope is linear - ELASTIC. elastic limit has reached at sigma (y)
But beyond sigma (y), VISCO-ELASTIC (+ PLASTIC) occurs.
if stress if removed, the axial stress can go back to zero.
So, from elastic to visco-elastic (+plastic) portion, total recovery is possible
If it is beyond the yield point (fracture, break), deformation occurs (irreversible)
How does the compaction cycle look like?
Bond making (loading): repacking –> elastic deformation –> plastic deformation –> brittle fracture –> visco-elastic deformation
Bond breaking (unloading): Elastic recovery (unloading): elastic recovery –> visco-elastic recovery
What are the events in die during compactive cycle?
- Die filling
- Pre-compression: particle rearrangement
- Main compression: fragmentation, plastic deformation, elastic deformation
- Ejection: elastic recovery
Consolidation state: Bulk density –> Tap density –> Compact –> and becomes tablet
What are some tableting terminologies (there are 3)?
Tabletability: capacity of a powdered material to be made into a tablet of specified strength under the effect of compression pressure
Compressibility of a material: ability to undergo volume reduction when subjected to an applied pressure
Compactibility: ability of a material to produce tablets with sufficient strength under the effect of densification
What are the relationships btw compressibility, tabletability and compactability?
For tabletability: as compression press (compaction pressure) increases, tensile strength inc (upward slope graph)
For compactability: as porosity inc (solid fraction), tensile strength decreases (downward slope)
For compressibility: as compression press (compaction pressure) increases, Porosity (solid fraction) decreases (downward slope)
pg35 for the graphs
What do we need to better understand the process understanding?
triangle cycle: compressibility, tabletability and compactability
Material properties:
- tablet press compaction cycle
- lubrication
- tooling / tablet design
–> proceeds to –>
Tablet microstructure
–> proceeds to –>
Tablet mechanical properties - tablet hardness, friability, dissolution
Tablet formation requires _______
tabletability, i.e. compaction forces can be translated to mechanically strong compacts
Thus, properties of components to form tablets are critical for the formulation requirements for tableting!
What are attributes of a “good tablet” (there are 4)?
- contain correct amt of active(s)
- must possess good mechanical properties: hardness, friability
- chemically stable, and
- correct biopharmaceutical pprty: content, disintegration, dissolution
granules for tableting must confer the necessary requisites, and thus the judicious choice of excipients is essential
Need to ensure correct brittle-plastic balance, flow, moisture content, granule porosity, lubrication, etc.
Mechanical strength of tablets depends on?
- particle size, distribution, shape
- granule porosity
- moisture content
- fragmentation and visco-elastic deformation
- applied load (compaction force)
- time of loading (Strain rate sensitivity)
- time of unloading (strain rate sensitivity)
- elastic stress release upon ejection
What are the material requirements for tableting in mechanical strength of tablets?
- Ideal brittle-plastic balance for good compressibility
- adequate granule porosity for compressibility
- sufficient moisture content for correct compressibility
- good powder flow for ideal tabletability
- correct level of lubrication for good compactibility
What are the causes of capping?
- air entrapment
- mechanism of volume reduction
- compression speed
- viscoelastic recovery
- stress and density distribution
- internal shear stress
What are the remedies for capping?
- lower compression force
- reduction compression speed
- decreasing ejection path in the die
- tool design change
- extend dwell time
What to take note of brittle-plastic balance?
Under compressive forces, plastic material will deform irreversibly whereas brittle or fragmenting material will deform by breaking down into small fragments
How is the compact strength like for plastic and brittle material?
Plastic: stronger
Brittle: Weaker
How is capping propensity like for plastic and brittle material?
plastic: higher
brittle: lower
How is the turret speed sensitivity (tableting speed) like for plastic and brittle material?
Plastic: higher
Brittle: Lower
How is lubricant sensitivity (mixing time of amt) like for plastic and brittle material?
Plastic: higher
Brittle: Lower
How do we classify tabletability?
Deformation behaviour: plastic, elastic, or brittle
Looks at bond area
Plastic is normally high bond area
Elastic/brittle is normally low bond area
- Low compactability (low surface energy compounds and weak bonds formed) –> bond strength is low
- High compactability (high surface energy compounds and strong bonds formed) –> bond strength is high
note: high bond area = plastic
low bond area = elastic
- When bond area is high and bond strength is high –> high tabletability
- When bond area is high and bond strength is low –> high or low tabletability
- When bond area is low and bond strength is low –> low tabletability
- When bond area is low and bond strength is high –> low or high tabletability
How to improve plasticity by granulation?
Powder at first –> API (elastic) + Binder (plastic) –> wet granulation (provides plasticity) –> becomes granules
What are some segregation challenges in compaction?
- trying to achieve good content uniformity
~ substantial risk of segregation at different steps of feeding process from hopper to feeder (Transferring process)
~ tendency of tablet feed to segregate inc with large differences in form, size and/or density of the particles/granules
Powder flow with segregation is critical during tableting
Flow must be free and uniform, into the die to ensure:
- tablet weight uniformity
- tablets with consistent and reproducible properties
Must always ensure good feed flow and thus, powder flowability
(I wrote: To do granulation to improve flow w/o segregation
- as in granulation lec; granulation is done as it can improve flowability, reduce segregation tendency, improve compactibility)
why is continuous manufacturing popular/preferred?
- cost reduction - overall & unit product cost
- efficient & robust process development
- improved product quality
- flexibility
- reduced environmental impact
why is the CM process combination flexible?
- multiple processes are possible
e. g. after blending can do diff types of granulation or pelletisation
e. g. after blending can go straight to compression
how does CM work?
(1) materials are preblended with various excipients
(2) granulating liquid is added
(3) drying (segmented dryers) is done
(4) PAT (process analytical technology) is done
(5) granulating –> tableting done
(6) coating done
- processes are repeated
what is the compact CM facility used for?
- for direct compression, wet and dry granulation
- facility is portable
what does the CM granulation skid consists of?
- hopper with preblended feed powder
- twin-screw extruder + granulation liquid = granulation unit
- segmented dryer unit
- granule conditioning unit
Fluid bed, high shear, roller compaction - which method has the best compressibility?
Fluid bed»_space; high shear»_space; roller compaction
Air spaces removed; shear involved
Roller compact - particles already precompacted
Fluid bed granules snowflake formation - the best compressibility
What kind of deformation area refers to low bond area?
Elastic and/or brittle
What kind of deformation area refers to high bond area?
Plastic
