What are some tablets quality control evaluations we would look at?
- chemical: assay, stability
- biological: bioavailability, drug performance
- physical: dimensional, weight, hardness, friability, disintegratability, dissolution
What are some pharmacopeia tests for tablets evaluation?
- content
- mean weight and weight variation
- dimension
- friability
- hardness
- disintegration test
- dissolution/release studies
What is the tablet dimensions specifications for tablet thickness?
< or = 5% of standard value (20 tablets)
What are some causes of thickness variation?
- compressive loads
- die fill --> factors: ~ raw materials ~ punch length ~ machine operation ~ granule properties
What is the purpose for manufacturer’s production to check for tablet thickness?
- important for packaging
- should be part of in-process quality control (thickness, diameter)
Why should tablets should comply to tablet weight test?
- compliance with this test helps to ensure uniformity of dosage is achieved (of biopharmaceutical consequence)
- not required for tablets/capsules that have to comply with the test for uniformity of content for all active ingredients
What could be some variations to tablet weight?
- dimensions of die cavity
- amount of fill
- density of material: determines tablet weight
What is the methodology (pharmacopeia) for tablet weight?
weigh 20 tablets individually and determine average mass
Not more than 2 of the individual masses should deviate from the average mass by more that the percentage deviation shown
none should deviate by more than 2x
What are the % deviation acceptable for Tablets (uncoated and film coated)?
BP pharmacopeia:
Average mass
80mg or less: 10%
>80 & <250mg: 7.5%
250mg or more: 5%
What are the % deviation acceptable for Capsules, granules and powders?
BP pharmacopeia:
<300mg: 10%
300mg or more: 7.5%
Capsule: weigh, subtract weight of shell, for weight of content
What are the % deviation acceptable in USP?
130mg or less: +/- 10%
>130mg and <325mg: +/- 7.5%
325mg and more: +/- 5%
What is friability?
Determine friability, abrasion properties
- tumble in container, may contain beads to increase abrasion
- originated as Roche friabilator
- let it drop 100 time?
What is the friability test?
Compliance ensure tablets can withstand mechanical shocks and abrasion during manufacturing, packaging and transportation processes
Specified amt of tablets being subjected to a tumbling action for a specified time, tablets then collected, dusted and weighed again
USP: each tablet weight should be about = or < 650mg. take as near as possible to 6.5g
if weight more than 650mg, take 10 tablets
Run once, tablets visually damaged –> is a fail
Loss, not greater than 1.0% (=< 1%) –> is a pass
If >1%, repeat twice or more and mean of 3 tests, should not be greater than 1%
Why the word ‘hardness’ is misleading?
It’s rather a breaking force; not crushing strength and not about hardness
hardness has different meaning from “breaking” which is: resistance of a surface to penetration or indentation by a small probe
What is the hardness test?
Tablets are tested either across the diameter or parallel to the longest axis. –> Provides info about strength along the weakest point in the structure
If flat-faced round tablets (right circular cylinders) FAIL in tension, as indicated by a CLEAN SPLIT into HALVES under diametric compression, the breaking force maybe used to compute the tensile strength by (Applies only to cylindrical tablets):
sigma x = 2F / (pi X D X H) where sigma x is tensile strength F is breaking force D is tablet diameter H is tablet thickness
What are the pharmacopeia BP requirements for hardness test?
- measurement on 10 tablets
- report: mean, minimum and maximum in newtons
Impt: type of apparatus and orientation of shaped particles
Break line is a weak point; would need to specify how you place tablet for testing
Why do we need to comply with disintegration test?
- compliance helps to ensure that tablets / capsules break up after ingestion, to ensure rapid dissolution of drug
- test not required for chewable tablets, lozenges, and modified release capsules or tablets
What is the methodology for disintegration test?
USP
mesh aperture, 2mm (#10 mesh);
cycles: 28-32 cycles/min over 50-60mm;
media: 37oC +/- 2oC
Pass: all particles must pass through the 10 mesh screen in the time specified (15min). If any residue remains, it must be a soft mass without core (e.g. hydrogel)
if hard core that is visible - tablets have not disintegrated –> fail
If 1 or 2 tablets or capsules fail, repeat with additional 12 units; pass only if not less than 16 out of the 18 tablets/capsules tested have disintegrated.
(16-18/18 –> pass)
What are the reasons for doing release testing?
- optimise manufacturing processes
- reassure constant manufacturing quality:
~ within lot
~ lot-to-lot
meeting compendial/regulatory requirements, if any
design extended/ delayed release products
predict biopharmaceutical performance
Many pharmacopeia methods available but apparatuses 1-4 are most commonly encountered for solid dosage forms.
What does an In Vitro Dissolution apparatus consists of?
- an inert vessel which contains the dissolution solvent
- a rotating spindle which provides the hydrodynamic flow of the solvent across the surface of the dosage form
What are USP Apparatus 1 and 2?
Apparatus 1: Basket Method (can keep hydrophobic molecules from climbing up the spindle)
Apparatus 2: Paddle method (most popular)
What is Apparatus 3 (Bio-Dis II)?
Reciprocating cylinder
- versatile apparatus
- for in-vitro assessment of release characteristics of product by subjecting to different dissolution media and agitation speeds in a single run
- different pH aq media; keep water bath temp at 37oC +/- 0.5oC
- moves from one vessel to another in different pHs
- However, cumbersome (difficult to carry out), there is no specified duration that vessel stays in media; settings to be adjusted accordingly; can also check whether drug can be available for control release product
What is USP Apparatus 4?
- Flow-through cell
- consists of reservoir containing dissolution/release medium, a pump that forces medium upwards through the vertically positioned flow-cell, and a water bath to control temp in cell
- medium can be changed during experiment (change pH with time)
- can be used for testing tablets, powders, supp, hard and soft gelatin capsules, implants, semisolids and drug-eluting stents
- using different types of cells, if needed
What is the driving force fore release kinetics by Noyes-Whitney Equation?
Diffusion gradient
Cc (saturated drug conc at core) = S (Solubility)
Hence, Cs ~= S
Solubility Cs is also the driving force
