Solid Oral Dosage Forms 5 Flashcards
Tablet and capsule testing
Testing related to clinical requirements
Tablet and capsule physical properties to withstand handling during transport from manufacturer to patient
Correct uniform dose
API released from tablet or capsules- disintegration, dissolution
Product handling performance
Measure of integrity of dosage form- ability to survive handling
Capsules- hard: shell fragility, soft: strength of seal
Tablets- breaking force, friability
Tablet strength: breaking force
Often referred to as tablet hardness or crushing strength, which are incorrect terms
To obtain good results, tablet should break into approximately two equal parts (perfect failure)
Result in units of force, N or kg, precision +/- 1N (measure 10 and calculate mean, maximum and minimum)
Tablet friability
% weight loss after standard handling- 25 rpm for 4 minutes, sample size 6.5g or 10 tablets if large, if size or shape causes problems tilt at 10 degrees to bench top
Related to tablet strength
Dose uniformity measurement
Two ways to measure, take samples and test:
Simple Mass Variation- weigh tablets and contents of hard and soft capsules, relies on dosage forms being homogenous in content of APU
Complex Content Uniformity- assay the quantity in each tablet or capsule, involves more laboratory time
Reasons for poor uniformity of weight or content
Poor powder flow into tablet dies or capsule powder hoppers
Worn tabletting tools or mismatch of punch lengths
Powder adhering to dosators or dosing discs and tamping fingers
Segregation
Insufficient powder mixing
Poor choice of lubricant or glidant
Median particle size too large or too small
Particle size distribution too wide
Tablet friability, weak capsule powder plugs
In vitro release of API
Disintegration- measure of how fast capsule/tablet breaks up in water at body temperature
Dissolution- measure of rate at which active dissolves from capsule or tablet
Official methods
European pharmacopoeia, Japanese pharmacopoeia, United States pharmacopoeia, International Conference on Harmonisation
Standardisation of test apparatuses
Disintegration
First stage in releasing the active ingredient from a solid oral dosage form
Types of disintegration:
Tablets- dissolution or rupture of coating, break-up of core into primary granules
Capsules- rupture of shell, disintegration of contents
Disintegration test
Standard apparatus in JP, PhEur, USP
Oscillating tube with wire mesh base (nominal aperture 2.00mm)
End point imprecise because relies on judgement, initial limit is all parts of dosage form must have gone through mesh by specified time
Disintegration apparatus
Standard pharmacopoeial apparatus
Permits the use of discs- to keep floating forms below surface, permitted for soft capsules
Standard tablets and capsules use apparatus A, large tablets and capsules use apparatus B
Disintegration end point
All tests for set time (15 min), then remove tubes from medium and examine
Complete disintegration is state in which any residue of the unit, except fragments of insoluble coating or shell, remaining on the screen of the test apparatus or adhering to the lower surface of the discs, if used, is a soft mass with no palpably firm core
Disintegration testing
Imprecise end-point
Tablets perform better than capsule because easier to see end-point, parts of capsule shell adhere to mesh blocking openings
No IVIV correlation
Good disintegration does not assure product works- primary particles can remain unchanged
Conversely, if it does not disintegrate there is a problem
Disintegration: enteric products
Tablets and capsules with either GR contents or coated tablets and shells
Standard disintegration apparatus
At end of test tablets show no signs of cracks that would allow escape of contents
Change medium, at end all dosage units have disintegrated
Retest allowed if units have stuck to the disc
Dissolution
Measure of how fast an active goes into solution from dosage from
Every material soluble in test medium has an intrinsic dissolution rate
Oral dosage forms are mixtures, and each component can influence rate at which API dissolves
Dissolution: official test methods
Challenge: official tests need to be based on simple readily available apparatuses, using simple reproducible methods with standard reagents. Test needs to be applied to all relevant dosage forms
History; many methods proposed, most are product specific. All originally designed for standard release tablets and used water
Rotating bucket
Standard basket 40 mesh, with 900ml fluid
Useful for solid forms, floaters, beads, modified release and suppositories
Paddle
Standard, paddle stainless steel or Teflon coated, 900 ml fluid, wire spiral for floaters
Useful for solid forms, modified release, transdermal patches
Sinkers
Capsules float, very few have density > 1.0g/ml
USP: small piece, non-reactive material, few turns, validated sinker, copper or platinum wire
PhEur: glass or metal helix
Sink conditions
The volume of test solution must be great enough to allow all the active to dissolve
Challenge: low solubility actives
The quantity is limited by the size of the apparatus
Increasing the size of the flask changes the hydrodynamic conditions
Rationale for dissolution testing
Does not assure bioavailability
BP 2005: once registered required routinely as part of quality control to demonstrate consistency of process before release
No IVIV correlation for many products
In vitro/In vivo correlation
In vivo testing of products carried out during clinical trial phase of development process
In the past making changes to product formulations during product life cycle often required in vivo tests to prove that changes had not altered availability, either decreased or increased
In vitro/In vivo correlation 2
This was slowing down improvements, a US FDA study did a risk assessment on the process and proposed very soluble readily absorbable API were a low risk and did not require a lot of testing and poorly soluble poorly absorbed API were a high risk and required the most. Thus significantly reducing the regulatory load: system called SUPAC- scale up and post approval changes
Taking the medicine
An object longer in one axis than the other is the easiest shape to swallow
The capsule shape has become a popular shape for tablets- the caplet
Swallowing
Central control- some can, some cannot
Swallowers vs. non-swallowers- difference is the way people eat food, chewers and gulpers
Aids for swallowing medicines- gravity, sitting or standing up, lubricant e.g. water
