Dissolution

The rate of solution of solid in a solvent.

It is the transfer of solute molecules from the surface of solid into the bulk of solvent.

Dissolution is the process by which a solid solute with relatively low solubility enters
into a solution in the presence of solvent

The rate of dissolution, is the Amount of active ingredient in a solid dosage form
dissolved in unit time under standardized conditions of liquid/solid interface,
temperature, and media composition
• Mechanisms of dissolution
• Three dissolution models :-
1. Diffusion Layer Model or Film Theory
2. Interfacial Barrier Model or Limited Solution
Theory
3. Danckwerts Model or Surface renewal theory.

These models can be used either alone or in

combination to describe the dissolution rate.
Suspension Tablet or Capsule

Fine particles Granules

Dissolution

Solution Drug in Solution Absorption

1. Diffusion Layer Model or Film Theory

 Simplest Model
 A static liquid film adjacent to the solid surface.
 Rapid reaction occurs between solid and liquid
film interface.
 Rapid mixing occurs and conc. Gradient is
destroyed.
• The rate at which the dissolution takes place
from a particle into its fluid, then the model is
expressed the Noyes-Whitney Equation
Noyes-Whitney Equation:-
• The rate of dissolution (dm/dt)can be
dm/dt=DA(Cs-Cg)/h
Where :-
 dm/dt- rate of the dissolution of the particles
 D- diffusion coefficient
 A-effective surface area
 h-the thickness of the diffusion layer
 Cs-saturation solution solubility of the drug in diffusion layer
 Cg –conc. Of the drug in solution in the bulk of GI Fluids
• The dissolution of drug takes place, the particle size
and surface area are also changed.

• These changes during dissolution is known as

Hixson and crowells cube root law of
dissolution…..
W0 1/3-Wt 1/3 = k t

where :

 W0 = original mass of the drug

 Wt = mass of the drug remained at time t
 k= dissolution rate constant.
2.Interfacial Barrier Model or Limited Salvation
Theory
 The reaction at the solid surface is not rapid , due to
high free energy of activation required for solubility of a
solid.
• So the rate of solubility of solid in the liquid film
becomes rate limiting rather than diffusion of dissolved
molecules.
• The equation for describing the dissolution rate of solid
is
md/dt=Ki(Cs-Cg)
• Where :-
• Ki – the effective interfacial transport rate constant.
3.Danckwerts Model or surface renewal Theory
 Used for the existence of a saturated diffusion layer
and proposed that transport of a solute away from the
solid surface adsorb the solute by normal diffusion.

 The turbulence present in the dissolution medium at

the solid and liquid interfacial responsible for the
rapid movement of solvent.

 The drug conc. never reaches Cs because rapid

movement of solvents.
Factors affecting the rate of dissolution
1.particle size and effective surface area.
 Smaller the drug particle, greater the SA.
 Reduce the particle size, can increase the
bioavailability of certain drugs like griseofulvin,
digoxin and benoxaprofen.

 Micronisation of drugs can also increase the rate and

extent of adsorption by reducing the particle size.

 The addition of surface active agent can leads the

increase the dissolution of drugs.
• In Addition to size reduction, others factors also contribute
to the improvement of the rate of dissolution by solid
dispersion.

• An increase in aqueous solubility of the drug due to the

presence of drug particles in small size.

• Improvement solubility of the drug in diffusion layer.

• Prevention of aggregation and agglomeration of the drug
particles.

• Excellent wettabillity
• Possible formation of metastable polymeric forms.
 2.satuartion solubility of the drug, Cs

• It affect both patient and pharmaceutical parameters.

• It also depend on physical and chemical properties of

drug like partion coefficient, MW and Melting point of
drugs.

• It can be modified by increasing and decreasing its

saturation solubility.
• The pH effect
• The solubility of weak acidic drugs is
• Cs= [HA] + [A-]
• Where, Cs = total solubility of drug in the fluid
[HA]=the intrinsic solubility of unionized drug
[A-] = the conc. of its anion
Total solubility of weak acidic drugs
Cs =Co+CoKa/[H+]
= Co(1+Ka)/[H+]
For weak basis drug
Cs= Co+Co[H+]/Ka
= Co(1+[H+])/Ka
• The rate of weak acidic drugs increases with
increasing pH (i.e. decreasing [H+]).

• The dissolution rate of basic drugs decreasing

with an increasing pH.

• Therefore for weak acidic drugs is more than in

the stomach, whereas weak basic drugs show a
greater dissolution rate in the intestine.
• Salt Forms
• The salt form of weak acidic drug has relatively high
solubility at the elevated pH in the diffusion layer,
dissolution of the drug particles will take place at a faster
rate.
• E.g. penicillin V and its potassium and calcium salts
results peak plasma levels of the drug are best correlated
with their dissolution rates.
• The dissolution of strong alkali salts of weak acids drugs
have been considered to the salt form of drug shows a
rapid dissolution rate than that of its parent drug.
If we look at the dissolution profile of various salts.

Dissolved Drug Concentration versus Time

Salts of weak acids and weak bases generally have much higher aqueous
solubility than the free acid or base, therefore if the drug can be given as a
salt the solubility can be increased and we should have improved dissolution.
 According to the BCS, drug substances are
classified as follows:
Class 1: High Solubility - High Permeability
(Well absorbed orally and no solubility ,permeability problems)

Class 2: Low Solubility - High Permeability

(Slow solubility )

Class 3: High Solubility - Low Permeability

(Slow permeability)

Class 4: Low Solubility - Low Permeability

(Slow permeability)
To improve dissolution of poorly soluble drug

1.Micronisation

2.Nanonisation
3.Supercritical Fluid Recrystallisation
4.Spray freezing into liquid
5. use of surfactant

6.Use of salt forms

7.Solid Dispersion
 In –vitro dissolution testing models

1. Rotating Basket Apparatus (App 1)

2. Rotating Paddle Apparatus (App 2)
3. Reciprocating cylinder Apparatus (App 3)
4. Flow-through Cell Apparatus (App 4)
5. Paddle Over Disc Apparatus (App 5)
6. Cylinder Apparatus (App 6)
7. Reciprocating Disc Apparatus (App 7)
 Dissolution Menology For Immediate Release
product based on BCS

BCS Dissolution
Methodology
I Single point NLT 85 % Q in 15
min.
Multiple Point NLT Q<85% in 15
Min
II Multiple Point

III Same as Class I

IV Same as Class II
• Dissolution Acceptance Criteria
Stage No. of Dosage Acceptance Criteria
Units Tested

S1 6 No. Dosage unit is Less Than 5%

S2 6 Average of the twelve Dosage

units(S1+S2) and No dosage unit is less
than Q=15%

S3 12 Average of the twenty four Dosage

(S1+S2+S3) and not more than two dosage
unit are less than Q=15% and Q=25 %
 In Vitro –In Vivo Correlation (IVIVC)

As the predictive mathematical model that describes the

relationship between an in vitro property (such as the
rate and extent of dissolution) of a dosage form and an
in vivo response (such as plasma drug profile ).
• In vitro-in vivo correlation (IVIVC)
– the correlation between in vitro drug dissolution
and in vivo drug absorption
 CORRELATION LEVELS
 The concept of correlation level is based upon the ability of the
correlation to reflect the complete plasma drug level-time profile
which will result from administration of the given dosage form.

 The correlation between in vitro drug dissolution and in vivo drug

absorption

 The development of new pharmaceuticals to reduce the number of

human studies during the formulation development.

 The optimization of formulations may require changes in the

composition, manufacturing process, equipment, and batch sizes.
 Purpose of IVIVC
• The optimization of formulations
– may require changes in the composition,
manufacturing process, equipment, and batch sizes.

– In order to prove the validity of a new formulation,

which is bioequivalent with a target formulation, a
considerable amount of efforts is required to study
bioequivalence (BE)/bioavailability(BA).
• The main purpose of an IVIVC model

– to utilize in vitro dissolution profiles as a surrogate for

in vivo bioequivalence and to support biowaivers

– Data analysis of IVIVC attracts attention from the

pharmaceutical industry