1. PITFALLS TO BEWARE IN IN-VITRO RELEASE STUDIES Presented by: Maneesha Pande Department of Chemical Engineering, Indian Institute of Technology Delhi th World Congress on Biotechnology October 6, 2015

2. CONTENTS INTRODUCTION SIGNIFICANCE OF IN-VITRO DRUG RELEASE STUDIES
METHODS FOR IN-VITRO DRUG RELEASE STUDIES
COMPENDIAL METHODS
NON-COMPENDIAL METHODS
METHOD DESIGN: IMPORTANT FACTORS
PITFALLS TO BEWARE
EXAMPLES/CASE STUDIES
CONCLUSION
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3. IN VITRO DRUG RELEASE STUDIES: SIGNIFICANCE
Objectives of in-vitro drug release studies:
1) At the formulation development stage – to
assess the drug release characteristics of
different formulations and relate them with in-vivo
release pattern
- here, efforts are to mimic maximum
possible physiological parameters
- in vivo – in vitro correlation is done as per
established protocols
2) At the production stage - as a tool for quality control
- after a specific formulation is selected, to
ensure batch-to-batch uniformity
- to establish bioequivalence
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4. IN-VITRO DRUG RELEASE METHODS: COMPENDIAL
USP Apparatus 1: Rotating Basket
USP Apparatus 2: Rotating Paddle
USP Apparatus 3: Reciprocating Cylinder
USP Apparatus 4: Flow Through Cell
USP Apparatus 5: Paddle Over Disc
USP Apparatus 6: Cylinder
USP Apparatus 7: Reciprocating Holder
Franz Diffusion Cell (Non-compendial apparatus)
Apparatus for medicated chewing gums (Non-compendial apparatus)
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5. In-vitro drug release studies at the formulation development stage
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6. IN-VITRO DRUG RELEASE METHODS: NON- COMPENDIAL
Sample and separate method
Useful for microparticulate system
Continuous flow method
Useful for microparticulate systems
Dialysis method
Useful for micro/nanoparticulate system
Useful for semisolid/gel systems
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7. POSSIBLE TO IN-VIVO CONDITIONS
IMPORTANT PARAMETERS
Release medium
Composition
Volume
Maintenance of “sink” conditions
Flow characteristics of
release medium vis-à-vis the shape of container
Stirring speed
Sampling procedure
Volume of sample
Sampling interval
Whether sample is replaced by plain release medium
Concentration of drug
CONDITIONS SHOULD
BE AS CLOSE AS
POSSIBLE TO IN-VIVO CONDITIONS
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8. PITFALLS TO BEWARE
Interference of membrane used for retaining the sample
Incomplete release of drug
Inability of flow pattern to provide thorough mixing of release medium
Causing resistance to mass transfer
Influence of drug concentration
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9. CASE STUDY : EFFECT OF SAMPLE HOLDER AND FLOW PATTERN
Magnetic stirrer blade
Sample enclosed in dialysis membrane
Release
Medium
Baffles
Typical initial experimental set-up for in-vitro drug release studies using dialysis membrane
Inadequate mixing
of release
medium
Thorough mixing
of release
medium

10. MODIFIED EXPERIMENTAL SET-UP
Baffles
Release medium
Sample holder covered with fine nylon cloth (to retain sample)
Stirrer bar
Modified experimental set-up
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11. RESULTS AND DISCUSSION
Comparative release of sulfadiazine from plain solution and through MC-4000 gel (across a dialysis membrane, kDa MW cut-off), at 400C)
Comparative release studies of cisplatin from plain solution in normal saline and from 90:10 castor oil:water biliquid foam (across a dialysis membrane, kDa MW cut-off) at 400C)
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12. RESULTS AND DISCUSSION continued……..
Drug release pattern at different stirring speeds
Eliminating mass transfer resistance

13. RESULTS AND DISCUSSION continued……..
Effect of concentartion of drug (sulfadiazine) on in-vitro release of drug
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14. CONCLUSIONS
Seemingly insignificant factors such as the selection of sample holder and speed of stirring play a very important role
Amount of drug contained in the formulation (whether above or below saturation concentrations) is important
Careful experimental design is of utmost importance in in-vitro drug release studies
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15. THANKYOU

16. QUESTIONS???
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17. IN-VITRO RELEASE STUDIES: REPRESENTATIVE PLOTS OF SOME PUBLISHED WORK
Zheng, et al., Oncology Reports 23:
Shikanov et al. Vol Chemotherapy Research and Practice Article ID
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18. CHEMICAL STRUCTURES Sulfadiazine, C10H10N4O2S MW 250.278 g/mol
Cisplatin, H6N2Cl2Pt
MW g/mol

19. RELEASE KINETICS: DIFFERENT MODELS
Zero order release
First order release
Higuchi Model
Hixon-Crowell Model
Weibull Model
Korsenmeyer-Peppas Model
Hopfenberg Model
Baker-Lonsdale Model
Gompertz Model
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