in vitro: dissolution and drug release testing

1. IN-Vitro DISSOLUTION TESTING &
DRUG RELEASE
Prepared by
Dr. Anumalagundam Srikanth
Dept. of .Pharmaceutical analysis

2. DISSOLUTION
A process in which a solid substance is solubilized in a given solvent i.e.,
mass transfer from solid surface to liquid phase. (i.e., from solid to liquid)
(or)
 It is a process by which drug released from solid dosage form and
immediately goes into molecular solution.
It is a Rate Determining Step
 If the drug is hydrophilic with high aqueous solubility then dissolution is
rapid and rate determining step in the absorption of such drugs is rate of
permeation through the bio membrane.
Absorption of such drugs is said to be permeation rate limited or Tran’s
membrane rate limited.

3. Dissolution process of solid dosage Forms :
TABLETS OR
CAPSULES
GRANULES OR
AGGREGATES
FINE PARTICLES
DRUG IN SOLUTION
(IN-VITRO OR IN-VIVO)
DRUG IN
BLOOD,OTHER
FLUIDS,AND
TISSUES
DISINTEGRATION
DISAGGREGATION
DISSOLUTION
ABSORPTION
IN-VIVO

4. Theories of Dissolution
1. Diffusion Layer Model/ Film theory
2. Danckwerts’s Model/ Penetration or Surface Renewal Theory
3. Interfacial Barrier Model/ Double Barrier Theory

5. Diffusion Layer Model/ Film theory
• Solution of the solid to form a thin layer at the solid/liq. interface is called Stagnant film or Diffusion layer
which is with saturated drug.
• This step is Rapid Soluble solute form diffuses from the stagnant layer to the bulk of the solution. This
step is slower and rate-determining step in drug dissolution.
• This rate of dissolution if the process is diffusion controlled and invovles no chemical reaction.
• It can be explained by Noyes – Whitney Equation .
dC/dt = k(Cs-Cb)
where dC/dt = dissolution rate of drug
Cs = conc. Of drug in stagnant layer
Cb= conc. Of drug in bulk of the solution at time t.
k = dissolution rate constant. (First order)

6. Danckwert’s Model
• This model suggest that turbulence in dissolution medium exists at the solid/liquid
interface.
• As a result, agitated fluid consisting of macroscopic mass of eddies or packets reach the
interface in random fashion due to eddy currents, absorb the solute by diffusion and
carry it to bulk of the solution.
• Such solute containing packets are continuously replaced with new packets of fresh
solvent due to which drug conc. At S/L interface never reaches Cs and has lower limiting
value of Ci
• This theory is also called as Surface Renewal Theory.

7. Interfacial Barrier Model
• According to the interfacial barrier model: An intermediate concentration can exist at the interface as
result of solvation mechanism and function of solubility rather than diffusion. When considering the
dissolution of a crystal, each face of the crystal will have a different interfacial barrier such a concept is
given by the following equn.
G =Ki (cs - cb )
• where G= dissolution rate per unit area.
• Ki =effective interfacial transport constant.
• Cs = Concentration of drug in the stagnant layer
• Cb =Concentration of drug in the bulk of the solution at time t
In this theory, the diffusivity D may not be independent of saturation concentration cs.
Therefore the interfacial model can be extended to both diffusion layer model and Danckwerts model.

8. IN-VITRO DISSOLUTION TESTING
• Dissolution and drug release tests are in-vitro tests that measure the rate and extent of
dissolution or release of the drug substance from a drug product, usually aq.medium under
specified conditions.
• It is an important QC procedure for the drug product and linked to product performance in-vivo.
NEED FOR DISSOLUTION TESTING:
• Evaluation of bioavailability.
• Batch to batch drug release uniformity.
• Development of more efficacious and therapeutically optical dosage forms.
• Ensures quality and stability of the product.
• Product development, quality control, research and application.

9. IN-VITRO DISSOLUTION TESTING MODELS
Non-Sink methods
1) NATURAL CONVECTION NON SINK METHODS:
a) Klein solvmeter method
b) Nelson hanging pellet method
c) Levy static disk method
2) FORCED CONVECTION NON SINK METHODS:
a) Tumbling method
b) Levy or Beaker method
c) Rotating disk method
d) Particle size method
e) USP Rotating basket apparatus
f) USP Paddle apparatus

10. SINK METHODS
3) FORCED CONVECTION SINK DEVICES:
a) Wurster pollis adsorption method
b) Partition method
c) Dialysis method s
d) Rotating disk apparatus
4) CONTINOUS FLOW/FLOW THROUGH METHODS:
a) Pernarowski method
b) Langenbucher method
c) Baun and Walker
d) Tingstad and Reigelman
e) Modified column apparatus
f) Takenaka method

11. Conditions that May Affect Drug Dissolution and Release:
Drug and formulation related:
• Drug substance
• Particle size
• Polymorph
• Surface area
• Chemical stability in dissolution media
Formulation of drug product :
• Excipients (lubricants, suspending agents, etc)

12. • Conditions that May Affect Drug Dissolution and Release: methodology related
• Medium
• Volume
• pH
• Molarity
• Co-solvents, added enzymes/surfactants
• Temperature of medium
• Apparatus
Hydrodynamics
Agitation rate
Shape of dissolution vessel
Placement of tablet in vessel
Sinkers (for floating products and products th at stick to side of vessel)

13. Dissolution Apparatus

14. Apparatus 1–7 refer to compendial dissolution apparatus in USP-NF (United
States Pharmacopeia)

15. Rotating basket (Apparatus 1)
 In case of none-disintegrating dosage forms this apparatus is superior
to apparatus 2 since it constraints the dosage form in a steady state fluid
flow
 It is inferior for testing dosage form s which contains gums due to
clogging of screen matrix
 In the case of floating dosage forms this method performs well, but care
should be taken that excipients do not clog the basket mesh

16. Rotating Paddle (Apparatus 2)
 This apparatus is identical to apparatus 1 except that the paddle is
substituted for the rotating basket
 Frequently used for both disintegrating and non-disintegrating dosage
forms

17. Reciprocating cylinder (Apparatus 3)
 One advantage of the reciprocating cylinder is that the gastrointestinal
tract conditions can be easily simulated, as it is easy to make time
dependent pH changes
 This apparatus is most suitable for n on disintegrating (extended
release) or delayed release (enteric coated) dosage forms

18. Flow cell (Apparatus 4)
 The advantage of flow through cell apparatus is the ability
to test drugs of very low aqueous solubility and t he ability
to change the pH conveniently during the test

19. Paddle over disk (Apparatus 5)

20. Cylinder (Apparatus 6)
• The cylinder method for testing transdermal preparation is modified
from the basket method (Apparatus 1). In place of the basket, a
stainless steel cylinder is used to hold the sample.

21. Reciprocating Disk Method (Apparatus 7)
 In the reciprocating disk method for testing transdermal
products, a motor drive assembly (Apparatus 7) is use d to
reciprocate the system vertically, and the samples a re placed
on disk-shaped holders using cupophan supports