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Dissolution_Technique.ppt
1. HISTORY
INTRODUCTION
NEED OF DISSOLUTION TESTING
BIOPHARMACEUTICS CLASSIFICATION SCHEME
SETTING DISSOLUTION TESTING PROCEDURE
SETTING DISSOLUTION SPECIFICATION
FACTORS INFLUENCING DISSOLUTION TESTING
APPARATUS
2. Definition:
Dissolution is defined as a process by which a solid substance
enters in the solvent to yield a solution.
Fundamentally it is controlled by the affinity between the
solid substances and the solvent.
3. HISTORY:
19th Century- Bernard.S.Proctor
Pill Dissolution is necessary for Drug Absorption
1897-Noyes&Whitney
Dissolution-related to rate of diffusion of saturated
layer around the solid
1930- Attempt to relate invitro testing and Invivo availability
1950’s – focus shifted from physicochemcial aspects to
effect on biological activity
4. 1951- Edward’
Therapeutic efficacy can be controlled by dissolution in GIT
1960 to 1961- Levy & Hayes
Correlated dissolution & Absorption Rates
Late 1960’s
Dissolution Testing became Mandatory requirement in USP
for Several Dosage form
5. INTRODUCTION -Dissolution
Far from being understood perfectly
Not a predictor of therapeutic efficacy
qualitative tool in design, fabrication and evaluation of
dosage form
Most sensitive predictor of bioavailability
Important Quality Control Test
6. DISSOLUTION FROM DIFFERENT DOSAGE FORMS
Solution
Suspension
Capsules
Tablets
Coated Tablets
Dissolution
Absorption
fastest
slowest
Initial mechanical lag
Wetting
Penetration
Swelling process
Disintegration
Deaggregation
Disssolution
7. Solid Dosage Form granules or Fine particles
aggregates
Drug in solution
Drug in Blood, other fluids & Tissues
DISSOLUTION OF SOLID
DOSAGE FORMS
Dissolution
(minor)
Dissolution
(major)
Dissolution
(major)
absorption
8. NEED OF DISSOLUTION TESTING:
Rate Limiting Step
Rate of Dissolution controls rate of absorption
Bioavailability can be correlated with invitro
Dissolution Results
Minimizing use of Human Volunteers as Test
subjects
Ensure Batch-Batch Quality Equivalence
9. Invitro models can be used to screen potential drugs and its
formulations
Post approval changes-effect of modification in Formula Structre
on bioavailability can be addressed.
Minimize cost, Labour etc.
Convenient
STILL…….. The best model also may not be able to mimic the
fate of dosage form in biological system
10. STEPS FOR DEVELOPMENT OF A DISSOLUTION TEST
Reconstructions of conditions in GIT in invitro system
Physico chemical properties of an Invitro dissolution model
may be of significance in the Invivo process once a success-
ful model that adequately mimics the invivo situation is
developed
Rate Limiting Factors of drug absorption
Bio pharmaceutics classification scheme
11. RATE LIMITING FACTORS OF DRUG ABSORPTION
Drug is not delivered from its formulation over an appropriate
time frame in solution form at the site of absorption in GIT
Decomposition of drug in GIT
Lack of effective transport of drug across Gut Wall
First pass Metabolism
12. BIO PHARMACEUTICS CLASSIFICATION SCHEME
Categorized into 4 basic classes based on its solublity & permeability
1. High Solubility- High permeability Drugs
2. Low Solubility – High Permeability Drugs
3. High Solubility – Low Permeability Drugs
4. Low Solubility – Low Permeability Drugs
Covers two potential rate limiting factors
. Solubility through upper GIT
. Drug Transport through Gut Wall
Used as basis for setting dissolution specifications
Basis for predicting successful IVIVC
13. CLASS I DRUGS
Stability in GIT
Formation of insoluble complexes
Secreted directly from the Gut Wall
First Pass Metabolism
Dosage Form Characteristics
Ensure that drug is released rapidly from the dosage form
14. CLASS II DRUGS
Rate Limiting Step – Dissolution
Limitation Equilibrium- insufficient volume of fluid in GIT
to dissolve
e.g. Grisiofulvin
Dose: 500 mg
Solubility: 15 µgml
Dose -solubility ratio: 33 Lts
Kinetic- Drug dissolve too slowly
e.g. Digoxin
Dose: 0.25 mg
Solubility: 20 µgml
Dose -solubility ratio: 12.5 ml
strong correlation between IV test & IV absorption possible
Testing at Multiple Sampling Time
Testing at different dissolution medium
15. CLASS III DRUGS
Rate Limiting Step – Permeability
. Rapid Dissolution from Dosage form is desirable
. Increased Contact time between dissolved drug &
absorbing mucosa.
. Gastric Emptying Time
. Duration of Dissolution Testing should be as stringent
as Class I
16. CLASS IV DRUGS
Rate Limiting Step – Dissolution & Permeability
Poor formulation have additional negative influence in Class IV
Present significant problem for oral drug delivery
In case of Class I & Class III drugs, if 85% of drug is soluble in
0.1 N HCl within15 min, can ensure that bioavailability is not
limited by Dissolution
If Dissolution is slower than Gastric emptying , a dissolution
Profile with multiple time points in multiple media is recommended
In case of Class II drugs, better IVIVC is expected
17. SETTING UP OF DISSOL’N TESTING PROCEDURE
Class I & Class III drugs – ensure immediate release in 0.1 N HCl
(I.R)
For Drugs with Poor water solubility it has been a challenge to
develop procedures for testing
Enzymes in body affect Dissolution(Pepsin, Lipases, Amylases etc
To Mimic the effects of this natural enzymes & surfactants,
- Increase agitation
- Use of Hydroalcoholic Medium
- Large Volume of Medium
- Use of Surfactants like CTAB(cationic), SLS(anionic) &
polysorbate (non-ionic)
18. STEPS FOR DEVELOPING DISSOLUTION PROCEDURE FOR
POORLY WATER SOLUBLE DRUGS
1. Evaluation of Medium ( pH Effect)
solubility in 0.1 N HCl
solubility in USP listed Medium(pH 4.5 sodium acetate buffer,
pH 6.8 phosphate buffer)
Basket & Paddle Method ( 900-1000 ml, 30,60, 90,120 min)
2. Evaluation of surfactant
added to the pre-selected medium from step 1
2% surfactant is used initially
3. Evaluation of surfactant conc’n
lowest amount to achieve greater than 85% dissolution
19. Few Dissolution Procedures developed by FDA field Labs
Danazol Capsules - Paddle 75 rpm, 900 ml, 0.75 %SLS/Water
“Q” = NLT 75%/30 min
Grisiofulvin Capsules – Paddle 50 rpm, 1000ml, .54%SLS/Water
“Q” = NLT 80%/20 min
Prazosin HCl Capsules – Basket 100rpm, 900ml, 2%SLS/0.1 N HCl
“Q” = NLT 80%/60 min
Glyburide Tablets – Paddle 75rpm, 900ml, 0.5%CTAB/pH 9.0
borate Buffer, “Q” = NLT 80%/60 min
21. SETTING DISSOLUTION SPECIFICATION
NDA– Based on acceptable clinical,pivotal bioavailability-
Bio-equivalance batches
ANDA / AADA-Based on perfomance of acceptable bioequivalence
batches
Generic products- usually same as that of RLD
3 categories of dissolution test specifications for IR products
1. Single point specification
2. Two point specification
3. Dissolution profile comparision
SUPAC related changes
To waive bioequivalance requirements for lower strength
To support waivers for other requirements
22. DISSOLUTION SPECIFICATION FOR GENERIC PRODUCT
1. If USP specification available
Should comply with USP specification if available.
12 units of reference and test
Dissolution profile at 15 min intervals prefered
2.If USP test not available, but test for RL- NDA drug available
Dissolution profile at 15 min intervals of test and reference
product prefered (12 units each)
3. If both are not available
Comparative dissolution testing using test and reference
product under different conditions recommended.
pH 1.0 – 8.0
addition of surfactant
use of apparatus I,II etc
23. SPECIAL CASES
1. Two Point Dissolution Testing
2. Two Tiered Dissolution Testing
> In SGF with or without pepsin
> In SIF with or with out pancreatin
MAPPING / RESPONSE SURFACE METHODOLOGY
Determining relationship between CMV and response surface
derived from an invitro dissolution profile and invivo bio-availability
data
Goal is to develop product specification that will ensure the
bio equivalence of future batches prepared with in the limit of
acceptable dissolution specification
24. DISSOLUTION PROFILE COMPARISION
F1 Factor (Difference factor)
% difference between the two curves at each time point
12 units to be used
For curves to be considered similar, value should close to zero.
F2 Factor (Similarity factor)
Measurement of the similarity in % dissolution between two curves
12 units to be used
For curves to be considered similar, value should close to 100
25. FACTORS TO BE CONSIDERED IN COMPARISION
Dissolution time points for both curves should be same
The Reference batch should be most recently manufactured
pre change product
Only one measurement should be considered after 85%
dissolution of both the product
26. SETTING OF DISSOLUTION SPECIFICATION IN
MODIFIED RELEASE DOSAGE FORM
Without IVIVC
1. Should be established from clinical/bioavailability lots.
2. 10% deviation at any time point permitted
3. Above 10% variation can be permitted provided that
range at anytime point doesnot exceed 25% with the
evidence that they are bio-equivalent
4. Above 25% can be acceptable with proven bioequivalence
5. Minimum of 3 time points recommended to set specification
6. The last time point should be at the point where atleast 80%
of drug is dissolved/plateau of dissolution profile reached
7. USP acceptance criteria for dissolution testing recommended
unless alternate acceptance criteria is specified in ANDA/NDA
27. Where IVIVC has been Established:
Specification should be established in such that all lots that
have dissolution profiles within the upper & lower limits of
the specifications or bio equivalent to clinical lot/reference std
Level A correlation Established:
. Specification should be established based on avg data.
. Minimum of 3 time points recommended to set specification
. The last time point should be at the point where atleast 80%
of drug is dissolved/plateau of dissolution profile reached.
. In lots at lowest & highest specification limits should have a
maximal difference of 20% in the predicted Cmax & AUC
28. Multiple Level C correlation Established:
SAME as previous
Level C correlation based on single time point established
. There is NMT a 20% difference in predicted AUC & Cmax
. % dissolved at any time point should be +/- 10% from mean
dissolution profile obtained from clinical/bioavailability lots.
29. FACTORS INFLUENCING DISSOLUTION TESTING
Dissolution Test should give reproducible results even when it is
performed in two different laboratories or with different personel.
To achieve high reproducibility all variables that influence the
test should be controlled
1) Factors related to physicochemical properties of the drug
2) Factors related to drug product formulation
3) Factors related to dosage form
4) Factors related to Dissolution testing Device
5) Factors related to Test parameters
6) Miscellaneous Factors
30. Factors related to physicochemical properties of the drug
a) Solid Phase Characteristics
. Amorphicity, Crystallinity
b) Polymorphism
c) Co-precipitation and /or Complexation
. Hydroflumethiazide-PVP-co-precipitates
d) Particle Characterisitics
. Effective surface area, wetting properties of media,
hydrophilic nature of the drug
31. Factors related to drug product formulation
a) Excipients & Additives
b) Particle Size
c) Granulating agents & Binders
d) Disintegrating agents
e) Lubricant
f) Interfacial tension between drug&media
g) Surfactants
32. Factors related to dosage form
a) Manufacturing Procedure
b) Granule Size
c) Drug – Excipient interaction
d) Compression force
e) De – aggregation
f) Storage of dosage form
33. Factors related to Dissolution testing Device
a) Eccentricity of agitating element
b) Vibration
c) Agitation intencity
d) Stirring element alignment
e) Flow pattern disturbances
f) Sampling probes, position & filters
g) Dosage form design
h) Type of device
34. Factors related to Test parameters
a) Temperature
b) Dissolution medium
. Dissolved gas / air
. Composition of media
. pH
. Viscosity
. Other factors
Miscellaneous Factors
a) Adsorption
b) Sorption