This presentation discusses the correlation of dissolution with In-vitro In-vivo correlation, Effect of Selection of Dissolution Apparatus and Dissolution Medium on IVIVC, BCS classification and levels of IVIVC.

1. Dissolution Theories and IVIVC.
BY
Dr. Hema Kanekar.
Asst. Professor,
H.K.College of Pharmacy,
Mumbai 400 102.
Incaseof anyqueries,pleasefeelfreetowriteto
EmailId:hemajhaveri@gmail.com

2. Contents
Introduction to Dissolution considering Biopharmaceutical Classification
System (BCS) of drugs.
Dissolution theories –
Diffusion Layer,
Danckwert’s and
Interfacial Barrier Model.

3. Definitions:
Dissolution is defined as a process in which a solid substance solubilizes in a
given solvent i.e. mass transfer from solid surface to the liquid phase.
Dissolution rate:
Dissolution rate is defined as the amount of solute dissolved in a given solvent
under standard conditions of temperature, pH, solvent composition and
constant solid surface area.
 It is a dynamic process.
 The rate of dissolution of drug substance is determined by the rate at which
solvent-solute forces of attraction overcome the cohesive forces present in
solid.

4. Diagrammatic representation of
Dissolution Process.
(Fig. reproduced from www.omicsonline.org)

5. Biopharmaceutical
Classification (BCS)
of Drugs
 All drugs are classified into
four classes based on its
solubility and permeability.
 Figure 1 indicates the BCS of
drugs.
 This figure also makes clear
the requirement of minimum
250 ml of water with dosage
form and a pre-requiste
requirement before drug’s
dissolution process.
(Figure 1 reproduced from www.particlesciences.com)

6. THEORIES OF DISSOLUTION
3 Theories proposed to explain process of dissolution are as follows:
1) Diffusion layer model / Film theory
2) Danckwert’s model (penetration or surface renewal theory)
3) Interfacial barrier model (double barrier or limited solvation theory)
Diffusion layer model
(Figure reproduced from Textbook of Biopharmaceutics & Pharmacokinetics- A treatise)
As per this theory, drug or solid dissolves in two steps:
1. As solid dissolves, there is formation of layer at
interface of dissolving solid and dissolved solid. This
interface represents the stagnant layer or diffusion
layer .
2. From this stagnant layer, diffusion of soluble solute
occurs to the bulk of the solution. Thus, this step is
rate determining step in drug dissolution process.

7. S (dissolving
Solid/drug)
Film boundary
Concentration of
drug in bulk
solution
Stagnant layer
Cs
c
Diffusion layer model can be further explained by above figure, Cs is concentration of dissolving drug in stagnant layer and
C is the concentration of dissolved drug in bulk. These can be further explained by Modified Noyes Whitney Equation:
dC/dt =D.A.Kw/o (Cs – Cb) v.h
dC/dt = dissolution rate of the drug ,
D = diffusion coefficient of the drug,
A = surface area of the dissolving solid,
Kw/o = water/oil partition coefficient of drug,
V = volume of dissolution medium,
h = thickness of stagnant layer ,
Cs–Cb = concentration gradient generated, bringing about the diffusion of drug.

8. Limitations of Diffusion layer theory:
It is based on the assumption that surface area of the dissolving solid/drug molecule
remains constant during dissolution. However, this is practically not possible as
surface area will change as dissolved drug is getting absorbed.
To account for particle size of dissolving drug,
Hixson and Crowell cube root law was studied and Equation is w0
1/3 – w1/3 = k .t
W=mass/amount of drug which is yet to be dissolved at time t,
K=dissolution rate constant,
W0= Original mass/amount of the drug.

9. Danckwert’s model for drug diffusion
(Figure reproduced from Textbook of Biopharmaceutics &
Pharmacokinetics- A treatise).

10. 2) Danckwert’s Model contd:
This Model states that near dissolving solid/drug molecule, there is creation of solid –
liquid interface resulting from turbulence and hence it is difficult to have stagnant layer
near dissolving solid.
Instead of stagnant layer, turbulence will result in generation of small mass or eddies
which will carry dissolved drug to the bulk of solution.
since solvent molecules or dissolution medium is exposed to new eddies or solid
surface each time, the theory is called known as surface renewal theory
Equation: V.dC/dT= dm/dt = A ( Cs-Cb). (γ.D)1/2
M = Mass of solid dissolved
γ = Rate of surface renewal.

11. In this model it is assumed that the intermediate concentration exists at interface as a
result of solvation mechanism.
Thus, Rate of solubility of solid in liquid film becomes the rate limiting than the
diffusion of dissolved molecules
Equation: G = Ki (Cs-Cb).
G = Dissolution rate per unit area.
Ki = Effective Interfacial transport constant.
All these theories explain the process of release of drug from dosage form In vivo and method to
calculate dissolution rate constant for particular dosage form.
However, it is very important to establish the In vitro Dissolution conditions in such way that it mimics
In vivo dissolution. Results obtained form dissolution testing and its correlation forms basis for In Vitro
In Vivo Correlation (IVIVC).
3) Interfacial layer model

12. Importance of Dissolution in IVIVC
(In Vitro-In Vivo) Correlation.
The US FDA defines IVIVC as “a predictive mathematical model describing the relationship
between an in vitro property of an extended release dosage form (usually the rate or extent of
drug dissolution or release) and a relevant in vivo response, e.g.,plasma drug concentration or
amount of drug absorbed.”
This correlation is applicable to all the dosage forms being developed.
Level A : A correlation represents a point-to-point relationship between in vitro dissolution and
the in vivo input rate (e.g., the in vivo dissolution of the drug from the dosage form).
Level B: IVIVC uses the principles of statistical moment analysis. The mean in vitro dissolution
time is compared either to the mean residence time or to the mean in vivo dissolution time.
Level C: IVIVC establishes a single point relationship between a dissolution parameter, for
example,t50%,percent dissolved in 4 hours and a pharmacokinetic parameter.
(e.g.,AUC,Cmax,Tmax).

13. The best dissolution method for In vivo—In vitro correlation is the method that describes what actually happens in
vivo. All of the factors cannot be easily reproduced in vitro by a simple dissolution method.
Further the factors is not similar if the subject is in fed or fasted state; in the fed state, food also has a direct
influence on the API or formulation behaviour.
Two important factors related to Dissolution and having direct effect on IVIVC is
1. In Vitro Dissolution Media
2. In Vitro Dissolution Apparatus
In Vitro Dissolution Media:
The simplest medium is composed of 0.1 N HCl (pH 1.2) which mimics the pH of stomach.
Simulated intestine fluid (SIF) can also be used as dissolution Medium.
Based on solubility of drug molecule and overall pH of dosage form, media such as acetate or phosphate buffers
are usually used.
For specific applications (e.g.,poorly soluble drugs such as BCS class IV),the pharmacopeias recommend the
addition of either enzymes or surfactant such as Sodium Lauryl Sulfate.
Non-compendial media are used to simulate the fasted and fed states in vivo.
These are known as “fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid
(FeSSIF)”.

14. Any Pharmacopeial method that can discriminate between the formulations may be used, but certain techniques are
preferred (i.e.,paddle,flow-through cell,basket—USP Apparatus 2,4, and 1,respectively).
Following are stages in vivo for any administered dosage form:
(1) sequential use of enzymes in physiological amounts,
(2) Appropriate pH for the enzymes,
(3) Removal of the products of digestion,
(4) Appropriate mixing at each stage of digestion,
(5) Physiological transit times for each step of digestion, and
(6) A peristaltic dynamic approach.
[Currently, there is only one complete dissolution system which measures this i.e. The TNO Gastro-Intestinal Model
(TIM1) is an in vitro system developed at TNO Nutrition and Food Research (Zeist,the Netherlands) that simulates the GI
tract in man.]
So, following things are important in selecting dissolution apparatus for IVIVC:
 Maintenance of “sink” conditions
 Maintenance of agitation to simulate mixing and peristalsis
 Maintenance of temperature to simulate body temperature
 Maintenance of pH based on solubility of drug molecule and enzymes and surfactant based on permeability
characteristics.
In Vitro Dissolution Apparatus

15. Biopharmaceutical Classification System :
All drugs are classified based on solubility and permeability into four BCS (Biopharmaceutical
Classification System) classes.
These are as presented in below figure:
Drug Molecule
Characteristics
High Solubility
(Dose Vol. NMT 250 mL)
Low Solubility
(Dose Vol. >250 mL)
High Permeability BCS CLASS І
e.g. Propranolol, metoprolol
CLASS II
e.g. piroxicam, naproxen
Low Permeability CLASS III
e.g. ranitidine cimetidine
CLASS IV
e.g. furosemide,
hydrochlorothiazide

16. Based on BCS Classes, we can explain IVIVC requirement for these molecules as below:
Three main cases exists
1) BCS Class I : Dissolution rate constant and permeability rate constants are higher and drug is well absorbed from GI Tract.
2) BCS Class II: Dissolution rate constant is lower than permeability rate constant and hence release from dosage form is
controlled or dependant on dissolution.
3) if kd is greater than kp,the drug is permeation-controlled (Class III),and
4) BCS Class III: Dissolution rate constant is higher than permeability rate constant and hence drug release from dosage form
depends on permeability and also referred as “Permeation controlled” .
The dissolution rate constant is in turn dependant on three micro-processes which are as Kr (Release from formulation), Kdd
(Disintegration from dosage form) and Ks ( Dissolution of API, once it is disintegrated and in particulate form).
There are four possibilities:
 if kdd is greater than ks, the apparent dissolution is driven by the dissolution of the API. The Intrinsic dissolution studies is
key step in formulation development ( BCS Class II, IV).
 if kdd is lower than ks, then the formulation is controlled by disintegration, and the formulation excipients and
manufacturing process plays the critical role.
 Also, if kdd is close to ks, then disintegration would be the key factor.
 IF kr is lower than ks, it indicates slow release and the critical attribute is the dissolution.
Thus, Dissolution studies play an important role in establishing and understanding IVIVC.