2. Overview of Presentation
• Definition of dissolution
• Process of Dissolution for Solid Dosage Forms
• Theory of dissolution
• Various influencing parameters
• Regularotary Guidance
• Method Development(Chromatography and analysis)
• Key insights to investigations during sample Analysis.
4. Dissolution as a processTablets Disintegration Granules Deaggregation Fine
Or Aggregates Particles
Capsules
Dissolution
Drug in Solution
Wetting of the dosage forms
Penetration of the dosage from by the dissolution medium
Solid dosage form-- DT - Granules-disaggregation- fine
partcles -- dissolution
Disintegration
Disaggregation of dosage form and dislodgment of the granules.
Dissolution
Occlusion of some particles of the Particle
5. Noyes whiteney equation for dissolution
dC D .A X (Cs-Cb)
dt = h
Where dC/dt=Rate of drug dissolution at time “t”
D= diffusion coefficient of compound in the medium
A= surface area of the particle
h= Thickness of the stagnant film layer
Cs = saturated solubility of compound at the particle
media interface
Cb = Concetration of compound in the bulk medium
Cb <<< Cs dependancy is only on Cs
6. Influencing Parameters
- Wetting speed - surface tension- contact angle.
-Addition of surfactant - Air bubble trapping
- Hydrophobic lubricant like talc, mg sterate in formulations
- For capsule gelation is hydrophilic
- Wetability of powder bed inside cap.
- Disaggregation -- compactability
- Tablets - pore volume is small- addition of
disintegraters.-- strain and rupture.
Normally
Solutions > suspensions> capsules > tablets > coated tab
7. Instrinsic Dissolution
Instrinsic dissolution rate can be defined as
rate of dissolution pure pharmaceutical
active when conditions such a pH , Surface
area , Temparature, Agitation Rate and
ionic strength of dissolution media kept
constant.
mg/cm2/min
9. Litterature information
SBOA, PDR, PIL, pK data
Study the Drug Absorption characteristics.
• RLD’s.
•Classification.
•Tmax.
•Absolute bioavailability and
relative bioavailability.
•Food affect.
10. Solubility Study
What do we Get From Solubility
Study ?
Rate Determining Step
Selection of Media For Dissolution
Study
Type of Solubility
1) BCS-Highest Unit Dose in 250
ml of Dissolution media .
2) Saturated Solubility –Shake
Flask method
11. BCS Guidance Summary
BCS takes into account three major factors that govern
the rate and extent of drug absorption from IR solid
oral dosage forms: solubility, intestinal permeability,
and dissolution.
4 BCS classes are: 1 = HS, HP; 2 = LS, HP; 3 = HS,
LP; 4 = LS, LP
Different formulations of rapidly dissolving BCS class 1
product can be given biowaiver if they show rapid and
similar dissolution profiles over the physiological pH
range.
BCS defines rapid dissolution, i.e., 85% in 30 minutes.
If dissolution is this rapid across the pH range,
absorption not dissolution rate limited.
13. Solubility Study
Media Selection :
If the drug is highly hydrophobic and insoluble,
• Buffers with Added surfactants can be
used.
Note : Effect of surfactant shall be studied.
– Not more than 1% is preferable,
– Beyond 2% shall be justified.
– (look for alternate surfactants which gives
better dissolution with less concentration).
14. Solubility Study
Media Selection :
• Based on solubility, The Media are selected for
profile comparison.
• If the T max is Less than 2 hours : Acidic
Media is preferred for the release testing.
• Look for discrimination in the relavant pH
range.
• IF food affects bio-availability, then Simulated
media study is very important.
• Use always pure grade of reagents for
Simulated media preparation.
15. Sink condition
Minimum amount of drug to be dissolved
in order to select as a dissolution media.
3 times the unit dose is taken for study.
NLT 1.5 times the unit dose is the acceptance
criteria.
First : at 25°C using API.
Next : at 37±0.5°C using API.
Next : at 25°C using API+Placebo (processed)
Next : at 37±0.5°C using API+Placebo (processed)
Next : at 37±0.5°C using drug Product (final formula)
16. Seven Steps to Become a Expert for
Dissolution Method Development
Step-1
Single Peak Chromatographic Method/UV scan
Successful Method Development
-No blank Inteferance
-No placebo Inteferance
-Peak Shape/ Tailing
-Shortest Run Time
-Major Degradant Seperation
21. Step-5
-Media Preparation
-Dissolved Oxygen/ Degassing of Media
-Temperature of Media
-Volume of media
-pH of Media
-Setting of Right Parameters for Auto
Samplers.
-Use suitable sinkers or no sinkers.
24. Investigations– During Analysis of
Samples
Possible errors :
•Media preparation.
•Standard preparation.
•Filters.
•Stability of solutions (std/test).
•Sampling / replacement.
•Interference
(Chromatography/UV).
25. Investigations– During Analysis of
Samples
•Always take additional sample at higher
RPM ,10 minutes after the last time interval.
•Alternatively, Perform the assay of the
residue
•Always record the physical observation and
tablet to tablet variation.Involve Formulation
scientist for physical observation.
•Verify and establish the role of sinkers.
•Measure the Volume of media at the end of
the run for ER samples.
26. Investigations– During Analysis of
Samples
• Clean the filters and lines thoroughly
before starting the run.
•Verify the filters (compare with Manual
sampling and centrifuge).
•Standard May absorb moisture. Preserve
Properly. Check the validity dates and
storage condition.
•Extra / additional peaks shall be
investigated and the root cause shall be
known.
•Observe peak distortions between standard
and test.
27. Investigations– During Analysis of
Samples
• If the drug is degrading, we shall also know
what type of degradation it undergoes.
•Inject dissolution sample in RS method and
find out if possible what is the degradant.
•Assess whether method is specific to the
extent that it avoids interference.
•Are we stabilizing the solution or degrading
further and stabilizing.
•Timing of stabilization is also very
important.
29. Request For Biowaiver
Data Supporting :-
Rapid and Similar Dissolution
High Permeability
High Solubility
Biowaiver: Class III compounds are eligible
biowaiver if they dissolve within 15 minutes in
buffer media pH 1.2 –6.8 (75 rpm)
Biowaiver: Class II acids with D:S ratio < 250
ml at pH 6.8 and > 85 % dissolved within 30
minutes at pH 6.8 (75 rpm)
