Dissolution testing

DISSOLUTION
TESTING

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CONTENTS
Definition
Factors affecting Drug
Dissolution
Study of various approaches to
improve dissolution of poorly
soluble drug
In-vitro dissolution testing
models
References
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Definition-
 Dissolution is a process in which a solid substance
solubilizes in a given solvent i.e. mass transfer
from the solid surface to the liquid phase.

 Rate of dissolution is the amount of drug
substance that goes in solution per unit time
under standardized conditions of liquid/solid
interface, temperature and solvent composition.

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DISSOLUTION PROCESS OF SOLID DOSAGE
FORMS

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4

 Factors affecting Drug Dissolution :-

A. Factors relating to the physicochemical properties of
drug.

B. Factors relating to the dosage forms.

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A. Factors relating to the
physicochemical properties of drug-

i. Solubility-
 Solubility plays important role in controlling
dissolution from dosage form.

 Aqueous solubility of drug is a major factor for
determines dissolution rates.

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ii. Particle size and effective surface area of the drug –

 Particle size and surface area are inversely
related to each other.

Two types of surface area –
Absolute surface area which is the total surface
area of any particle.
Effective surface area which is the area of solid
surface exposed to the dissolution medium.

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 Effectivesurface area is directly related to the
dissolution rate.

 Greaterthe effective surface area, more intimate
the contact between the solid surface and the
aqueous solvent and faster the dissolution.

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iii. Polymorphism and amorphism –

 When a substance exists in more than one
crystalline form, the different forms are
designated as polymorphs and the phenomenon as
Polymorphism.

 Stable polymorphs has lower energy state, higher
M.P. and least aqueous solubility.

 Metastable polymorphs has higher energy state,
lower M.P. and higher aqueous solubility.

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 Amorphous form of drug which has no internal
crystal structure represents higher energy state and
greater aqueous solubility than crystalline forms.
 E.g.- amorphous form of novobiocin is 10 times more
soluble than the crystalline form.

 Thus,the order for dissolution of different solid
forms of drug is –

amorphous > metastable > stable

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IV. Salt form of the drug-

 Dissolution rate of weak acids and weak bases
can be enhance by converting them into their
salt form.

 With weakly acidic drugs, a strong base salt is
prepared like sodium and potassium salts of
barbiturates and sulfonamides.

 With weakly basic drugs, a strong acid salt is
prepared like the hydrochloride or sulfate salts of
alkaloidal drugs.

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B. Factors relating to the dosage forms –

i. Pharmaceutical excipients –

 Diluents
 Lubricants
 Binders
 Surfactants
 Colorants
 Disintegranting Agents

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ii. Manufacturing processes -

Method of granulation –

Wet granulation

Direct compression

Agglomerative phase of communication (APOC)

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 Compression Force :-
Rate of drug dissolution

A B C D

Compression force

Influence of compression force on dissolution rate of tablet

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 Factors contributing to the faster dissolution rate of a
drug dispersed in eutectic are :-

a. Reduction of particle size.
b. An increase in drug solubility
c. Absence of aggregation and agglomeration between
the fine crystallites of pure drug.
d. Excellent wettability and dispersibility of a drug as
the encircling soluble carrier readily dissolves and
causes the water to contact and wet the particles.
e. Crystallization of the drug in metastable form after
solidification from the fused solution which has
high solubility

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IN-VITRO
DISSOLUTION
TESTING MODELS

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FACTORS TO BE
CONSIDERED WHILE
DESIGNING OF A
DISSOLUTION TEST

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FACTORS RELATING TO THE
DISSOLUTION APPARATUS
 Design of the container
 Size of the container
 Shape of the container
 Nature of agitation
 Speed of agitation
 Performance precision of the apparatus

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FACTORS RELATING TO THE
DISSOLUTION FLUID

 Volume

 Temperature

 Deaeration of dissolution medium
 PH

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CLASSIFICATION

 There are basically three general categories of
dissolution apparatus :

1. Beaker methods

2. Open flow-through compartment system

3. Dialysis concept

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1. BEAKER
METHODS

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ROTATING BASKET
APPARATUS(APPARATUS 1)
 It is basically a closed-compartment, beaker type
apparatus.
 It comprising of a cylindrical glass vessel with
hemispherical bottom of one litre capacity partially
immersed in a water bath.
 A cylindrical basket made of #22 mesh is located
centrally in the vessel at a distance of 2 cm from
the bottom and rotated by a variable speed motor
through a shaft.

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CONTD…..

 All metal parts like basket and shaft are made of
stainless steel 316.

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ROTATING PADDLE
APPARATUS(APPARATUS 2)
 Here, basket is replaced with a stirrer.
 A small, loose, wire helix may be attached to
the dosage form that would otherwise float.
 The position and alignment of the paddle are
specified in the official books.

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THE RECIPROCATING
CYLINDER METHOD
(APPARATUS 3)
 This method adopts the USP disintegration
“basket and rack” assembly for the dissolution
test.
 The disks are not used.
 This method is less suitable for precise dissolution
testing due to the amount of agitation and
vibration involved.
 E.g. Chlorpheniramine ER tablets,
Carbamazepine chewable tablet
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PADDLE OVER DISK METHOD

(APPARATUS 5)
 Modification of Apparatus 2.
 Here, stainless steel disk designed for holding
transdermal system at the bottom of the vessel.
 The disk/device should not , react with, or
interfere with the specimen being tested.
 The disk holds the system flat and is positioned
such that the release surface is parallel with the
bottom of the paddle blade.

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CYLINDER METHOD
(APPARATUS 6)
 Same as apparatus 1,except to replace the basket
and shaft with a S.S. cylinder stirring element.
 Temperature - 32 ± 0.5°
 The dosage unit is placed on the cylinder.
 Distance between the inside bottom of the vessel
and cylinder is maintained at 25 ± 2 mm.

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RECIPROCATING HOLDER
METHOD (APPARATUS 7)
 The assembly consists of a set of calibrated solution
containers, a motor and drive assembly to reciprocate
the system vertically.

 Various type of sample holder are used.

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2. OPEN FLOW-THROUGH
COMPARTMENT SYSTEM
 The dosage form is contained in a small
vertical glass column with built in filter
through which a continuous flow of the
dissolution medium is circulated upward at a
specific rate from an outside reservoir using a
peristaltic or centrifugal pump.
 Dissolution fluid is collected in a separate
reservoir.
 E.g. lipid filled soft Gelatin capsule

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ADVANTAGES
 No stirring and drug particles are exposed to
homogeneous, laminar flow that can be precisely
controlled. All the problems of wobbling, shaft
eccentricity, vibration, stirrer position don’t exist.

 There is no physical abrasion of solids.

 Perfect sink conditions can be maintained.

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DISADVANTAGES

 Tendency of the filter to clog because of the
unidirectional flow.
 Different types of pumps, such as peristaltic and
centrifugal, have been shown to give different
dissolution results.
 Temperature control is also much more difficult to
achieve in column type flow through system than in
the conventional stirred vessel type.

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3. DIALYSIS SYSTEM

 Here, dialysis membrane used as a selective barrier
between fresh solvent compartment and the cell
compartment containing dosage form.
 It can be used in case of very poorly soluble drugs and
dosage form such as ointments, creams and
suspensions.

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DISSOLUTION TESTING FOR NDDS
OCULAR DRUG DELIVERY

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SYSTEMS
 A number of methods are used to conduct in-vitro
evaluation of controlled ocular drug delivery
systems.
 (a) Bottle method
 In this method, dosage forms are placed in the
culture bottles containing phosphate buffer at pH
7.4.
 The culture bottles are shaken in a thermostatic
water bath at 37°C.
 A sample of medium is taken out at appropriate
40
intervals and analyzed for drug contents.

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 b) Modified rotating
basket method
 In this method, dosage
form is placed in a
basket assembly
connected to a stirrer.
The assembly is
lowered into a jacketed
beaker containing
buffer medium.
 The temperature of
system is maintained at 41
37°C. A sample of
medium is taken out at

MICROSPHERES
 Beaker method
 The dosage form in this method is made to adhere at the bottom of the beaker

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containing the medium and stirred uniformly using over head stirrer.
 Volume of the medium used for the studies varies from 50-500 ml and the
stirrer speed form 60-300 rpm.
 Modified Keshary Chien Cell
 A specialized apparatus was designed in the laboratory.
 It comprised of a Keshary Chien cell containing distilled water (50ml) at 37 0
c as dissolution medium.
 TMDDS (Trans Membrane Drug Delivery System) was placed in a glass tube
fitted with a 10# sieve at the bottom which reciprocated in the medium at 30
strokes per min.
 Samples are removed at appropriate time intervals and analyzed for drug
content.

42

DISSOLUTION STUDY OF
CHEWING GUM AS A
DOSAGE FORM

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43

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 TEMP-37.c

 Chew Rate-60 chew/min.

 Unspecified buffer (ph close to 6)-20 ml

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DISSOLUTION ACCEPTANCE
CRITRIA

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 Q –Value –

 Define as a percentage of drug
conten dissolved in a given time
period.

45

DISSOLUTION ACCEPTANCE
CRITRIA
STAGE No. of Dosage units Acceptance criteria

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tested
S1 6 No Dosage unit is
less then Q+5%

S2 6 Average Of 12
dosage units (S1+S2)
and no dosage unit is
less then Q-15%
S3 12(6+6+12=24) Average of 24
dosage units >- And
not more than two
dosage units are less
than Q-15% and No
dosage unit is less
46
than Q-25%

METHOD FOR COMPARISON
OF DISSOLUTION PROFILE

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 Difference factor (F1 Value)-
 Define as calculate the % Difference between 2
curves at each time point and is a measurement
of the relative error between 2 curves.
 f1= {[Σ t=1n |Rt-Tt|] / [Σ t=1n Rt]} ×100.

 Values range from 0 to 15

47

 Similarity
Factor (F 2 value)-define as
measurement of similarity in % Dissolution
between two curve.

 Where Rt and Tt = cumulative % dissolved
for reference and test
 Values range from 50 to 100
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REFERENCES
 D.M.Brahmankar, Biopharmaceutics and
pharmacokinetics- A Treatise; Vallabh Prakashan,
page no. 20–31.

 Leon
Shargel, Applied Biopharmaceutics &
Pharmacokinetics; 4th edition, page no. 132-136.

 TheIndian Pharmacist, February 2008, page
no.10-12

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REFERENCES
 United States Pharmacopoeia – 24, page no.: 1942
– 1951.
 “Current perspectives in dissolution testing of
conventional and novel dosage forms”, by Shirazad
Azarmi, Wilson Roa, Raimar Lobenberg, Int. jou.
Of pharmaceutics 328(2007)12 – 21.
 Alton’s pharmaceutics “ The design and
manufacturing of medicines”, by Michael E. Alton,
page no.: 21 – 22.

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