溶出度方法学验证2
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10
Disintegration
Disintegration Dissolution
X
…..… … ……. … .. .
1934-Switzerland's Pharmacopeia Helvetica was the first regulatory body to introduce a disintegration test for tablets.
90%
4
Why dissolution?
• Quality control
– Two batches of the same product with acceptable assay and content uniformity but -------------------• Batch I releases 90% active substance in 20 minutes
• Levo thyroxine • Carbamazepine • Warfarin
9
“Results of tests conducted by the MHRA’s Medicines Testing Laboratory, suggest that the TEVA product may differ from other products in the amount of levothyroxine that is released over time (dissolution)”
SUB THERAPEUTIC LEVEL
time
6
Therapeutic levels-slow release
TOXIC LEVEL
concentration
90% Release 20 min
60% Release 20 min
THERAPEUTIC LEVEL SUB THERAPEUTIC LEVEL
• There is less than a two fold difference in toxic concentrations and minimum effective concentrations in the blood
– Safe and effective use of the drug products require careful titration and patient monitoring
1
Dissolution
An interplay of three groups of factors
API PROPERTIES
FORMULATION DESIGN
THE TEST PROCEDURE
2
INTRODUCTION
• The need for dissolution testing
time
7
Therapeutic levels - narrow therapeutic range
TOXIC LEVEL
concentrationBiblioteka Baidu
Therapeutic range
THERAPEUTIC LEVEL SUB THERAPEUTIC LEVEL
time
8
What is a narrow therapeutic index?
1950-Disintegration became an official USP Method, USP 14.
11
An historic publication!
“These differences are not detected by the test for disintegration rate given in the British and U.S. pharmacopoeias” (Shaw et al., 1972; Wagner et al., 1973).
Dissolution is everywhere!
Stability testing Formulation Bioequivalence Manufacturing Scale up
Product similarity
Variations SUPAC
Product Quality Assurance
Dissolution studies
Dosage form development
IVIVC Biowaivers
Drug release
Formulation kinetics
regulatory requirements Release mechanisms
In-vivo predictions
• Batch II releases 60% in 20 minutes
5
Therapeutic levels-instant release
TOXIC LEVEL
concentration
90% Release 20 min
THERAPEUTIC LEVEL
60% Release 20 min
– Historical perspective
– Narrow therapeutic ranges – Boundary theory of dissolution – Intrinsic dissolution – The start of modern dissolution testing
• For narrow therapeutic range products this can be an argument against substitution
– It is really an argument against switching suppliers once a therapy has been started
• Drug absorption
– A dissolution technologists view
3
Why dissolution?
• Chemical parameters do not tell the whole story
Which is better?
50%
A tablet with assay of 100% which releases only 50% of the active substance OR A tablet with assay of 90% which releases 100% of the active substance
Disintegration
Disintegration Dissolution
X
…..… … ……. … .. .
1934-Switzerland's Pharmacopeia Helvetica was the first regulatory body to introduce a disintegration test for tablets.
90%
4
Why dissolution?
• Quality control
– Two batches of the same product with acceptable assay and content uniformity but -------------------• Batch I releases 90% active substance in 20 minutes
• Levo thyroxine • Carbamazepine • Warfarin
9
“Results of tests conducted by the MHRA’s Medicines Testing Laboratory, suggest that the TEVA product may differ from other products in the amount of levothyroxine that is released over time (dissolution)”
SUB THERAPEUTIC LEVEL
time
6
Therapeutic levels-slow release
TOXIC LEVEL
concentration
90% Release 20 min
60% Release 20 min
THERAPEUTIC LEVEL SUB THERAPEUTIC LEVEL
• There is less than a two fold difference in toxic concentrations and minimum effective concentrations in the blood
– Safe and effective use of the drug products require careful titration and patient monitoring
1
Dissolution
An interplay of three groups of factors
API PROPERTIES
FORMULATION DESIGN
THE TEST PROCEDURE
2
INTRODUCTION
• The need for dissolution testing
time
7
Therapeutic levels - narrow therapeutic range
TOXIC LEVEL
concentrationBiblioteka Baidu
Therapeutic range
THERAPEUTIC LEVEL SUB THERAPEUTIC LEVEL
time
8
What is a narrow therapeutic index?
1950-Disintegration became an official USP Method, USP 14.
11
An historic publication!
“These differences are not detected by the test for disintegration rate given in the British and U.S. pharmacopoeias” (Shaw et al., 1972; Wagner et al., 1973).
Dissolution is everywhere!
Stability testing Formulation Bioequivalence Manufacturing Scale up
Product similarity
Variations SUPAC
Product Quality Assurance
Dissolution studies
Dosage form development
IVIVC Biowaivers
Drug release
Formulation kinetics
regulatory requirements Release mechanisms
In-vivo predictions
• Batch II releases 60% in 20 minutes
5
Therapeutic levels-instant release
TOXIC LEVEL
concentration
90% Release 20 min
THERAPEUTIC LEVEL
60% Release 20 min
– Historical perspective
– Narrow therapeutic ranges – Boundary theory of dissolution – Intrinsic dissolution – The start of modern dissolution testing
• For narrow therapeutic range products this can be an argument against substitution
– It is really an argument against switching suppliers once a therapy has been started
• Drug absorption
– A dissolution technologists view
3
Why dissolution?
• Chemical parameters do not tell the whole story
Which is better?
50%
A tablet with assay of 100% which releases only 50% of the active substance OR A tablet with assay of 90% which releases 100% of the active substance