D5 and D6. Tablet manufacturing Flashcards
Oral drug formulationsmain considerations & challenges?
-oral administration restricts formulation size and appearance:
eg size to swallow, taste and palatability (children medicines)
-formulation must disintegrate in GI tract in appropriate time:
use of optimized excipients (disintegrants) and fabrication technology (coating)
-formulation must make drug available for absorption:
drug needs to be in dissolved state during its transit through the gastrointestinal tract for absorption to occur | consider appropriate drug solubilisation approaches
-formulation needs to address drug sensitivity to environment in GI tract:
eg protection by enteric coating, local pH buffering or enzyme inactivation
-formulation needs to address drug absorption properties from GI tract:
eg use of absorption enhancers and gastroretentive formulations to overcome absorption window issues
tablet requirements for an ideal oral solid dosage form
-uniform drug content (reproducible dose)
-drug must remain stable during production and storage
-drug must be bioavailable (formulation reliably releases drug in GIT)
-formulation is robust during handling (by patient as well)
-easy and cost effective to mass produce
-pleasant to take – appropriate to patient group
what can be achieved by tablets?
-accuracy in dosing
-stability (in comparison to liquid formulations)
-release of drug in GIT
-robust on handling
-ease of manufacture (‘mature’ technology in pharmaceutical industry)
-convenient administration and high patient compliance
Schematic of tableting process?
one note
requirements for Schematic of tableting process?
-uniform flow of the powder (prerequisite for uniform tablet weight)
-no powder segregation (prerequisite for uniform drug content )
-die cavity uniformly filled (prerequisite for uniform drug content)
-powder compressibility (to remain as tablet once the pressure is removed)
-lubricability (no sticking to the die cavity and punches under pressure)
volume of powder filling die cavity determines?
tablet weight & drug dose
most powders cannot be compressed into tablet, why?
they do not posses the required properties – compressibility – hence need excipients with compressibility properties
ways to make tablets?
one note
what is granulation?
build up of small particles into a larger aggregates with the aid of a binding agent or mechanical force
benefits of granulation?
-spherical and free-flowing granulate particles
-more uniform size distribution
-improved flow
-reduced segregation
-allows volume dispensing
-improved compression
-binder introduction
improved strength of final granule can be achieved by addition of?
binding agent (e.g. binder excipient)
Unit operations in tabletting via wet granulation?
one note
advantages of spray granulation / fluid bed wet granulation?
one step procedure - includes granulating and drying | control of spraying and drying rate critical
ONE NOTE
what is dry granulation (also called dry compaction) ?
powder blend is compacted by applying mechanical force onto the powder
Compaction force applied in: either specialized tabletting machine (‘slugging’) or by roller compaction equipment
ONE NOTE
Dry granulation (also called dry compaction) used for?
moisture sensitive materials
heat sensitive materials. wet granulation process cannot be used for moisture sensitive or heat sensitive materials.
Disadvantages of dry granulation (also called dry compaction)
-can result in granules with low porosity
-dust creation
-special equipment required
Describe direct compression
direct compression process is based on availability of an excipient that has physicochemical properties required for tabletting called: DIRECT COMPRESSION EXCIPIENTS
ONE NOTE
desired properties of direct compression excipients to satisfy requirements:
-good flow
-good compression properties
-particle size similar to that of active drug – to avoid segregation during processing (an issue)
-high bulk density – otherwise thin tablet is produced
-physically and chemically stable in contact with moisture, heat and air
-chemically inert
Describe compressibility
-most powders cannot be compressed into tablet – they do not posses the required properties – compressibility
-typically 20-30% of poorly compressible drug can be incorporated into tablets made by using direct compressible excipient
Describe directly compressible excipients
-Commercially available, speciality ingredients developed by supplier (by patented processes)
-Examples: Ludipress, Emdex, Avicel, Tabbletose - different forms of lactose, cellulose, or starch – modified through processing to acquire required properties for direct compression
ONE NOTE
SUMMARY OF DIFFERENT PROCESSES IN TABLET PRODUCTION
ONE NOTE
Compression stages of powders into tablet
ONE NOTE
Describe compression
-compaction of powdered material due to applied pressure
-in tabletting granulate in the die is compressed between an upper and a lower punch to consolidate the material into a single solid matrix
subsequent events occurring during compression:
-filling of die
-particle rearrangement
-elastic deformation at points of contact
-fragmentation and/or plastic deformation
-bonding
-plastic deformation of the solid body
-decompression and ejection
Compression force effect on tablet hardness?
ability to withstand mechanical handling and transport
Compression forces effect on tablet disintegration
ability to withstand mechanical handling and transport
What holds tablet together?- mechanical theory
-mechanical interlocking of particles
(particularly relevant when powder -particles undergo plastic deformation during compression)
What holds tablet together?- intermolecular theory
-contact between new surfaces close enough so that Van der Waals forces can act
-(particularly relevant when powder particles fracture during compression)
What holds tablet together?- liquid surface film theory
surfaces melt (or dissolve in residual moisture) under applied pressure and upon the release of the pressure the melted (dissolved) material crystallize forming connections between the particles
Describe fillers excipient
-comprise bulk of tablet
-make a tablet size practical for patient
-minimum tablet weight is typically ~50 mg
-at low dose - drug adsorption to filler can be an issue for drug bioavailability
Describe binders
provide cohesiveness required from granule, provide cohesiveness to a final tablet
Describe affect of binders
-granule uniformity
-ease of compression
-hardness of tablet
Describe glidants
-improve powder flow
-some lubricants (magnesium stearate) are good glidants
-flow rate of powder (of granulation) important in tabletting
adequate flow from the hopper into die cavity – see REQUIREMENTS
How do glidants improve powder flow
-act by keeping particles apart as they form a thin film on the particle surface => increase the particle distance and consequently lower cohesion forces
-typically low dielectric constant materials – reduce electrostatic cohesive forces between powder particles
powder flow is function of:
particle size, particle shape, the roughness of the particle surface, the chemical nature of the powder, the moisture content
Describe problems with glidants
-flow problems due to too fine particles can be solved by particle enlargement => achieved by granulation
-most common glidants
colloidal silica dioxide, magnesium stearate, talc (0.1-0.5%)
ONE NOTE
Describe lubricants
-reduce friction between powder particles and die during compression and ejection of tablet
-ease ejection of tablet from die, prevent sticking of tablet to punches, prevent excessive wear of punches/dies
-act by forming an adsorbed lubricant layer around the particles during mixing
-too much can reduce bonding properties of powder particles, disintegration of tablet, and decreased tablet strength
ONE NOTE
Describe colouring agents
-Assist in product visual identification – and provide acceptable appearance
-All colorants used in pharmaceuticals must be approved and certified by the FDA.
-Colorants are often added during coating, but can also be included in the formulation prior to compaction. In the latter case, the colorant can be added as a soluble dye (wet granulation process) or insoluble (direct compression)
Describe disintegrants and tablet disintegration
-aid disintegration and de-aggregation process of tablets
-disintegrants normally cause rapid disintegration of the tablet upon exposure to moisture (conventional tablets)
Describe disintegrants mechanism of action
ONE NOTE
Why are disintegration and dissolution important?
-to be absorbed through GI epithelium a drug must be dissolved in gastrointestinal lumen
-the rate of drug absorption can be determined by the rate of drug dissolution from tablet
-for drugs that need to be absorbed in upper part of GI tract rapid dissolution may be especially important
ONE NOTE
Describe starch
-the most common disintegrant
-cheap
-granular
-native (starch-maize, potato) or pregelled starch (Starch 1500)
-mechanism - predominantly deformation and swelling
-amounts used - 2 to 20%
Describe MICROCRYSTALLINE CELLULOSE – Avicel, Elcema
-more familiar as a compression aid, but also aids disintegration by having good water transport properties
-mechanism - predominantly wicking
-amounts used - 10% and higher
Describe other materials as examples of disintegrants
-Alginic acid - an insoluble polysaccharide
-Carboxymethyl cellulose - a soluble polysaccharide derivative
-Magnesium aluminium silicate - a mineral - Veegum
Describe super-disintegrant- SODIUM STARCH GLYCOLLATE – Explotab, Primojel
-cross-linked, carboxymethylated potato starch
-mechanism – extensive swelling – claimed to swell 100% original volume
-amounts used – 2 to 10%
Describe super-disintegrant- CROSCARMELLOSE TYPE A – Ac-Di-Sol
-cross-linked, carboxymethylated cellulose
-mechanism – fast wicking action and significant fibre swelling
-amounts used – 2 to 10%
Describe super-disintegrant- CROSSPOVIDONE – Kollidon XL, Polyplasdone XL
-cross-linked PVP (polyvinylpyrrolidone)
-mechanism – wicking with virtually no swelling
-amounts used – 5-20%
