DISSOLUTION STUDY

1
 Contents

Introduction
Objective
Applications
Factor affecting dissolution study
Theories of dissolution
Official dissolution test apparatus
Acceptance criteria
Calibrations of dissolution apparatus
References

2
 INTRODUCTION
Dissolution is 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 is defined as the amount of solid

substance the that goes into solution per unit time
under standard condition of temperature, pH,
solvent composition and constant surface area.

3
4
 Objectives
To predict the bioavailability – surrogate parameter of
the therapeutic efficacy.
To indicate the robustness of the dosage form – drug
product related safety.
Sensitive to variations in the manufacturing process
which have critical influence on the dosage form
performance.
Quality control tool to control the uniformity of drug
product quality.

5
 Applications
1) Dissolution testing evaluated critical parameter such as
1) Predict adequate bioavailability
2) Provide information to formulator
2) Help to avoid batch to batch variation
3) Selection of best formulation &comparison of excipient effect on
dosage form
4) In vitro- In vivo co-relation
5) Regulatory requirement of official test
6) F1 & F2 (dissimilarity and similarity factors) value help to get
comparing dissolution pattern of test with market product
7) I.P.Q.C. & Q.A also required dissolution test for prediction of batch
to batch variation.

6
 FACTORS AFFECTING DISSOLUTION STUDY
I. Physicochemical Properties of Drug
1) DRUG SOLUBILITY-
2) SALT FORMATION-
3) PARTICLE SIZE-
4) SOLID STATE CHARACTERISTICS-
5) CO-PRECIPITATION-
II. Drug Product Formulation Factors
1) DILUENTS-
2) DISINTEGRANTS-
3) BINDERS AND GRANULATING AGENTS-
4) LUBRICANTS-
5) SURFACTANTS-
6) WATER-SOLUBLE DYES-
7) COATING POLYMERS-
III. Processing Factors
1) METHOD OF GRANULATION-
2) COMPRESSION FORCE-
3) DRUG EXCIPIENT INTERACTION-
4) STORAGE CONDITIONS-

7
IV. Factors relating to dissolution apparatus
1) AGITATION-
2) STIRRING ELEMENT ALIGNMENT-
3) SAMPLING PROBE POSITION & FILTER-

V. Factors relating dissolution test parameters

1) TEMPERATURE-
2) DISSOLUTION MEDIUM-

8
 THEORIES OF DISSOLUTION
1) Diffusion Layer Model (Film Theory)

2) Danckwert’s Model (Penetration or

Surface Renewal Theory)

3) Interfacial Barrier Model (Double Barrier

Mechanism OR Limited Solvation
Theory)

9
 1) DIFFUSION LAYER MODEL (FILM THEORY)

• A simplest model.
• Dissolution takes place without involving reactive or electrical
forces.
• Consist of two consecutive steps:

• Solution of the solid to form a thin film or layer at the solid /

liquid interface called as stagnant film or diffusion layer
which is saturated with the drug this step is usually rapid
(instantaneous).
• Diffusion of the soluble solute from the stagnant layer to the
bulk of the solution this step is slower and is therefore the
rate determining step in the drug dissolution.

10
 Proposed by Noyes & Whitney equation

11
Equation (A) is based on fick’s first law of diffusion & constant surface area
Brunner incorporated fick’s first law of diffusion and
modification of the Noyes – Whitney’s equation to

12
• The equation describes a first – order dissolution kinetics means dissolution
under non-sink conditions.
• If volume is relatively large such that it maintains sink condition then

• Dissolution rate under sink condition follow zero order dissolution rate.
❖ IVIVC sink condition can be achieved by:

Bathing the dissolving solid in fresh solvent from time

to time.
Increasing the volume of dissolution fluid.
Removing the dissolved drug by partitioning it from the
aqueous phase of dissolution fluid into the organic
phase placed either above or below the dissolution
fluid for e.g. hexane or chloroform.
Adding a water miscible solvent such as alcohol to the
dissolution fluid.
By adding selected adsorbents to remove the dissolved
drug.

14
 HIXON-CROWELL CUBE ROOT RELATIONSHIP

• Major assumptions in Noyes-whitney is that the

surface area remains constant throughout
dissolution process like transdermal patches.
But in oral dosage form particle size decreases
as the drug dissolves so, decrease in effective
Surface area.
• Hixon & Crowell modified that equation to
represent the appearance of solute by weight in
solution by multiplying the both sides of
volume term….
W01/3 – W1/3 = kt
W0 = original mass of drug
W = mass of drug remaining to dissolve at time t
K = dissolution rate constant 15
 2) DANCKWERT’S MODEL (PENETRATION
OR SURFACE RENEWAL THEORY)

• Acc. to model, the agitated fluid consist of mass of eddies or packets that are
continuously being exposed to new surfaces of solid and then carried back
to bulk of liquid.
• Diffusion occurs into each of these packets during short time in which the
packet is in contact with surface of solid.
3) INTERFACIAL BARRIER MODEL (DOUBLE
BARRIER/LIMITED SOLVATION
THEORY)

• According to this model, an intermediate conc. can exist at the

interface as a result of solvation mechanism and is a function of
solubility rather than diffusion.
• When considering the dissolution of the crystal will have a
different interfacial barrier given by following equation,

G = Ki (Cs – Cb)
Where G = dissolution per unit area
Ki = effective interfacial transport constant

• The interfacial barrier model can be extended to both Diffusion

layer model and the Dankwert’s model.
17
 VARIOUS OFFICIAL DISSOLUTION TESTS
According to I.P. & E.P. for solid dosage forms (tablets and
capsules) dissolution apparatus used are:

Apparatus 1 – PADDLE APPARATUS

Apparatus 2 – BASKET APPARATUS

According to B.P. apparatus used are:

Apparatus 1 – BASKET APPARATUS

Apparatus 2 – PADDLE APPARATUS
Apparatus 3 – FLOW THROUGH CELL APPARATUS

18
According to U.S.P. apparatus used are:

Apparatus 1 - BASKET APPARATUS

Apparatus 2 - PADDLE APPARATUS
Apparatus 3 - RECIPROCATING CYLINDER
Apparatus 4 - FLOW THROUGH CELL
Apparatus 5 - PADDEL OVER DISK
Apparatus 6 - ROTATING CYLINDER
Apparatus 7 - RECIPROCATION HOLDER

19
As per USP…
Apparatus 1 – Basket
Useful for

• capsules
• beads
• delayed release / enteric
coated dosage forms
• floating dosage forms

Standard volume

• 900/1000 ml
• 1, 2, 4 liter vessels
Speed of agitation
• 100 rpm
20
Advantages

• advantageous for capsule as

they tends to float on the
surface.

• full pH change during the test

• can be easily automated

which is important for routine
investigations

21
Disadvantage

• Poor mechanical stability.

• basket screen may be clogged by gummy particles.
• rapid corrosion of stainless steel mesh in the presence of acidic
medium.
• Poor homogeneity of the bulk fluid due to insufficient stirring or
agitation.
• Inconvenience for cleaning the set-up after testing.
• Hindered visual inspection.

22
 Apparatus 2 - Paddle
Useful for
• tablets
• capsules
• beads
• delayed release / enteric
coated dosage forms

Standard volume
• 900/1000 ml

Method of first choice !!!

23
Speed of agitation: 50-75 rpm

Advantages

• easy to use

• robust

• can be easily automated which is

important for routine investigations

24
Disadvantages

• pH media change is often difficult.

• Problems with floating dosage form products.

• sinkers are required for floating dosage forms.

• hydrodynamics are complex, they vary with site of the

dosage form in the vessel (sticking,floating) and therefore
may significantly affect drug dissolution.

25
Apparatus 3 – Reciprocating
cylinder
Useful for

• tablets
• beads
• controlled release formulations
Standard volume

• 200-250 ml per station

Speed of agitation: 25-35 dips/min

26
Advantages

• easy to change the pH

• hydrodynamics can be
directly influenced by
varying the dip rate
Disadvantages

•small volume (max. 250 ml)

27
 Apparatus 4 – Flow-Through Cell

Useful for
• low solubility drugs
• microparticulates
•Powders
• Implants
• suppositories
• controlled release
formulations

volume of dissolution fluid

• 4-16 ml/min
28
Advantages
• easy to change media pH.
• sink conditions can be maintained.

Disadvantages
• Deaeration necessary
• volumes of media required is high
• labor intensive

29
 Apparatus 5 – Paddle over disk

Useful for

• transdermal patches

Standard volume

• 900 ml

30
▪ Consists of paddle and vessel assembly from Apparatus 2, with the
addition of stainless steel disk assembly designed for holding the
Transdermal system at the bottom of the vessel. The temperature is
maintained at 32±0.5. A distance of 25±2mm between the paddle
blade and the surface of the assembly is maintained during the test.

Advantages

• standard equipment (paddle) can be used, only add a stainless steel

disk assembly.

Disadvantages

• disk assembly restricts patch size.

31
USP apparatus 6 – Rotating cylinder
USP apparatus 7 – Reciprocating
holder

32
Acceptance criteria
1) For Immediate release dosage forms

level No. Criteria

Tested
B1 6 Each unit is not less than Q+5%.
B2 6 Average of 12 units (B1 +B2) is equal
to or greater than Q and no unit is less
than Q-15%.
B3 12 Average of 24unit (B1 +B2 +B3) is
equal to or greater than Q, and not
more than 2 units are less than
Q-15%, and no unit is les than
Q-25%. 33
2) For Extended release dosage forms
level No. Criteria
Tested
L1 6 No individual value lies outside each the stated range
and no individual value is less than stated amount at the
final test time.
L2 6 Average value of the 12 units (L1+L2) lies within each
of the stated range and not less than stated amount at the
final test time. None is more than 10% of labeled content
outside each of the stated range. And none is more than
10% of labeled content below the stated range at the
final test time.
L3 12 Average value of the 24 units (L1+L2+L3) lies within
each of the stated range and not less than stated amount
at the final test time. Not more than 2 of the 24 units are
more than 10% of labeled content outside each of the
stated range. Not more than 2 of the 24 units are more
than 10% of labeled content below the stated amount at
the final test time.
34
3) For Delay release dosage form

level No. Criteria

Tested
B1 6 No individual value exceed 10% dissolve.

B2 6 Average of 12 unit (B1+B2) is not more than

10% dissolve. And no individual unit is
greater than 25% dissolve.

B3 12 Average of 24 unit (B1+B2+B3) is not more

than 10% dissolve. And no individual unit is
greater than 25% dissolve.

35
 FOR CALIBRATION OF USP DISSOLUTION APPARATUS…..

•CALIBRATOR TABLETS….( For apparatus 1&2)

1) Prednisone Tablets, ( Disintegrating type)
2) Salicylic Acid Tablets, ( Non-Disintegrating type..)

FOR APPARATUS – 3…….

3) USP Chlorpheniramine Maleate Extended Release Tablets

36
 USP Dissolution apparatus suitability test

PERCENT DISSOLVED AT 30 MINUTES

Apparatus 1 (Basket) Apparatus 2 (Paddle)

CALIBRATOR 50 (RPM) 100 (RPM) 50 (RPM) 100 (RPM)

Salicylic acid 6-23 43-63 46-59 58-69

prednisolone 14-21 23-29 13-22 16-27

37
Dissolution test apparatus used for different dosage
forms are:
Type of dosage form Release method

Solid oral dosage form Basket, paddle, reciprocating cylinder, flow through
(conventional) cell

Oral suspension Paddle apparatus

Oral disintegrating tablets Paddle apparatus
Chewable tablet Basket, paddle, reciprocating cylinder
Transdermal patch Paddle over disk apparatus
Powder/granules Flow through cell apparatus
Micro particulate Modified flow through cell apparatus
formulation
Implants Modified flow through cell apparatus

38
 References

•Physical pharmacy by Alfred martin, James swarbrick ,

third edition ,pg no:408-411
•Text book of physical pharmaceutics by CVS Subramanyam,
second edition, pg no : 85-109
•Theory and practice of industrial pharmacy by Leon lachman,
third edition, pg no:301-303
•Biopharmaceutics and pharmacokinetics by D.M.Bramankar ,
sunil B. Jaiswal, first edition, pg no:19-50
•Dissolution, Bioavailability & Bioequivalence by M. Abdou,
Pg no: 56-58, 73-84,145-146,165-156

39
•The official compendia of standards , USP 24 NF 19
US pharmacopoeia & National formulary ,
pg no: 1941-1951
• Indian pharmacopoeia 1996, volume -2, apendix-8.2
• British pharmacopoeia 2008, volume-4
• Encyclopedia of pharmaceutical technology,3rd edition
edited by James swarbrick, page no.908-927.
•Remington “The science and practice of pharmacy”,
21 st edition, vol-1, page no. 672-688.
•www.dissolutiontech.com

40
THANK YOU….

41