1
The Apparatus
Paddle or Basket
2
3
Paddle v. Basket
Weaknesses of Paddle Method
• • • Problems with floating dosage units •
Weaknesses of Basket Method
Poor mechanical stability. Hindered visual inspection. Disintegration-dissolution interaction (slower disintegration keeps the dosage unit in a site of higher agitation, thus increasing dissolution). • Poor homogeneity of the bulk fluid due to insufficient stirring or agitation. • Sensitivity against external vibration, eccentricity and the presence of baffles such as thermometer or sampling tube. • Inconvenience for cleaning the set-up after testing.
70 60 50 40 30 20 10 0 0 10 20 30 40 50
70 60 50 40 30
center (n=3) off-center(n=3)
Time (min)
60% - 72% Dissolved at 30 min. 66% ± 4%
Dissolution Time (Minutes)
1 2 3 4 5 6 60
20 10 0 0 10
89% – 99% Dissolved at 30 min. 95% ± 4%
20 30 40 50
1 2 3 4 5 6 60
Dissolution Time (Minutes)
Note: The use of sinkers and type used is part of the dissolution validation protocol
GENERAPHARM
THE PHARMACOPIAL STATUS OF DISSOLUTION TESTING
Compendial testing equipment Factors affecting test results Harmonization USP v EP v JP Calibration, chemical or mechanical Automation a blessing and a curse
The baths and vessels have always been the same
The J.P. had slight differences in basket mesh size
All three had different instructions regarding sinkers
11
Agitation
Analysis of dissolution rates suggests a significant contribution from free convection in regions of low velocity at the base of the vessel of the basket apparatus.
Байду номын сангаас22
Harmonization
There are three pharmacopeias to be considered in ICH,
USP. Ph. Eur. and J.P.
Individual pharmacopias such as the BP now refer to the Ph. Eur.
20
Variations on a theme
21
Variability with Sinkers
Paddle, 50rpm, DI water, off-center 10mm
110
PERCENT DISSOLVED PLOT
PERCENT DISSOLVED PLOT
110 100 90 80
8
Cone effect
change of rpm
75 rpm 50
CONE
9
Paddle design improvements
USP Paddle
Pitched blade
10
The peak vessel
The Peak vessel may seem to be a good solution. However it can give very irreproducible results because there are many possible tablet orientations ranging from simple alignment in the trough through to tablets actually rolling round like a race track. Due to this it is possible to see significant differences in dissolution results when making slight changes in tablet geometry
4
Problems with sticking dosage units • Use of spiral for holding capsules is subject to variability with operators. •
•
The phenomenon of cone formation that results from nondispersion of disintegrated tablets can lead to nonreproducibility of test.
Hydrodynamics and cone effects
5
Cone effects
But it can also occur with the basket The cone effect is often seen with the paddle
6
The cone effect
7
Heavy granulate
Eroding tablet
16
Granule density
paddle 50 rpm
Formulation based on microcrystalline Cellulose Density 1.56g/ml
50 rpm paddle
Formulation based on Calcium phosphate Density 2.80g/ml
75 rpm paddle
18
Sinkers
Floating tablets and capsules Sticky and heavy tablets
19
Reasons for sinkers
• Floating products
– Some modified release products – Capsules
High density granulate
Disintegrating tablet
This is related to excipients and does not necessarily reflect the dissolution of the drug
Low density granulate
– Note: Except for Apparatus 1 and 2, apparatus numbers are not consistent in the three pharmacopoeias. Accordingly, other apparatus should be referred to in the dossier by an unambiguous descriptive title or compendial reference
And JP sinker is now accepted
24
ICH Q4-Not quite harmonised
• 1. (2.1.1) The declaration of interchangeability applies to the Basket Apparatus (Apparatus 1), the Paddle Apparatus (Apparatus 2), and the Flow-Through Cell. The Flow-Through Cell should be referred to in the dossier by an unambiguous descriptive title or compendial reference because it is referred to by different numbers in the three pharmacopoeias.
17
Granule density
paddle 75 rpm
Formulation based on microcrystalline Cellulose Density 1.56g/ml 50 rpm paddle Formulation based on Calcium phosphate Density 2.80g/ml