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Analytical considerations in the dissolution testing of oral modified release products
Graham ClarkeBristol-Myers SquibbMoreton, UK
The British Pharmaceutical Conference, 26th September 2005
Fit for purpose dissolution methods for testing oral modified release products
Graham ClarkeBristol-Myers SquibbMoreton, UK
The British Pharmaceutical Conference, 26th September 2005
Analytical considerations in the dissolution testing of oral modified release products
Presentation Outline Purpose Practicalities Specifications Method Validation Unusual case studies Future
Analytical considerations in the dissolution testing of oral modified release products
Purpose of dissolution test IV/IVC (next Speaker) Safety/Quality requirements
Release profile Integrity of action e.g. enteric coat
Analytical considerations in the dissolution testing of oral modified release products
Selection of test methodology Choice of apparatus
Baskets (1970, USP 18) Paddles Reciprocating Cylinder Flow through cell Other
Choice of medium, deaeration Media switching Adequate sampling Analytical finish
UV, Fast LC, other?
Analytical considerations in the dissolution testing of oral modified release products
Making it practical (avoiding late nights in the lab)
On-line (UV or on-line LC).
Autosampling (off-line)
Analytical considerations in the dissolution testing of oral modified release products
In-situ Fibre-optic (different probes)
Analytical considerations in the dissolution testing of oral modified release products
Developing Specifications Regulatory/Pharmacopoeial guidance Control dose dumping or non-release 3-phase specification
Early – avoid dose dumping Middle – appropriate control Late – demonstrate full release (80% or
plateau)
FDA Guidance for Industry
•ER oral Dosage Forms: Development, Evaluation and Application of In Vitro/In Vivo Correlations (Sept 1997)
•SUPAC- MR: Modified Release Solid Oral Dosage Forms (Sept 1997)
Analytical considerations in the dissolution testing of oral modified release products
USP Extended Release Dosage Forms
LevelNumber Tested Acceptance Criteria
L1 6 No individual value lies outside each of the stated ranges and no individual value is less than the stated amount at the final test time.
L2 6 The average value of the 12 units (L1 + L2) lies within each of the stated ranges and is not less than the stated amount at the final test time; none is more than 10% of labeled content outside each of the stated ranges; and none is more than 10% of labeled content below the stated amount at the final test time.
L3 12 The average value of the 24 units (L1 + L2 + L3) lies within each of the stated ranges, and is not less than the stated amount at the final test time; not more than 2 of the 24 units are more than 10% of labeled content outside each of the stated ranges; not more than 2 of the 24 units are more than 10% of labeled content below the stated amount at the final test time; and none of the units is more than 20% of labeled content outside each of the stated ranges or more than 20% of labeled content below the stated amount at the final test time.
Analytical considerations in the dissolution testing of oral modified release products
Validation of methods (fit for purpose) UV/HPLC ICH Guidance Q2A and Q2B
Analytical considerations in the dissolution testing of oral modified release products
Validation Specificity
UV – Interference from excipients LC – Demonstrate separation
Carryover or binding Tubing, syringes? Not necessary as
concentration increasing.
Analytical considerations in the dissolution testing of oral modified release products
Validation Linearity (range) “evaluate the linear range of the analytical procedure” “for dissolution testing: +/- 20% over the specified
range” General – six points between 20 and 120%
Correlation coefficient Residual sum of squares
Standard alone and also in presence of excipients.
Analytical considerations in the dissolution testing of oral modified release products
ValidationAccuracy
“application of the analytical procedure to synthetic mixtures of the drug product components”
aka “spiking” Over the Range or Worst case scenario Use a minimum of 9 determinations over a
minimum of 3 concentration levels covering the specified range.
Report % recovered and confidence intervals
Analytical considerations in the dissolution testing of oral modified release products
ValidationPrecision
Repeatability 9 determinations over the range
(3 reps at 3 concs) or 6 reps at 100% of the test concentration
Intermediate precision “Establish the effect of random events” Different days, analysts, equipment etc.
Analytical considerations in the dissolution testing of oral modified release products
Robustness Effect of filtration Stability of solutions
Are samples collected/stored before analysis?
Automated procedure Demonstrate equivalence to manual
FDA Guidance for IndustryAnalytical Procedures and Methods Validation (Aug 2000)
Analytical considerations in the dissolution testing of oral modified release products
Floating or Sticking to surfacese.g. hydrophilic polymer matrix
Problem results in reduced agitation in inadequate exposure to medium
Solution Observe and invalidate test Deaerate Baskets vs paddles
Analytical considerations in the dissolution testing of oral modified release products
Degrading active e.g. ER enteric coated beadlets, meadia switch
Acid catalysed hydrolysis product Low dose drug – degradant has different UV response factor. Required LC for sensitivity Response factor and calculate
Analytical considerations in the dissolution testing of oral modified release products
Avoiding evaporation Evident as higher than theoretical
values obtained Accuracy demonstrated
Analytical considerations in the dissolution testing of oral modified release products
Analytical considerations in the dissolution testing of oral modified release products
Avoiding evaporation Evident as higher than theoretical
values obtained Accuracy demonstrated
Solution Tightly fitting lids Parafilm seal
Equipment issues Problem – Extended release product using cross linked
alginates give inconsistent dissolution profiles.
Solution – Copper ions increase the degree of cross linking in alginates. De-aerator had brass fitting.
Analytical considerations in the dissolution testing of oral modified release products
Stability Study Dissolution Rates
0
20
40
60
80
100
120
1 2 3 4 5 6 7 8
Time (min)
% D
iss
olu
tio
n
Initial
2 Month
3 Month
4 Month
Effect of Copper ions
0
20
40
60
80
100
120
60 120 240 360 540 720 900 1080
Time (min)
% D
iss
olu
tio
n
No Cu (II)
3 ppm Ci (II)
6 ppm Ci (II)
Analytical considerations in the dissolution testing of oral modified release products
The Future Alternate technologies ? More physiological media?
