Dissolution

PREPARED BY : NILESH S.JAWALKAR
M.PHARM
PHARMACEUTICS

LIST OF CONTENT
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Introduction
Importance and applications
Theories of Drug Dissolution
Factors affecting Drug Dissolution
Various official dissolution test apparatus
Dissolution of newer dosage form by
unconventional method and equipment
Question bank
References

2

INTRODUCTION


DEFINATION :

•

Dissolution rate may be defined
as amount of drug substance that goes in
the solution per unit time under standard
conditions of liquid/solid interface, temperature
and solvent composition.
It can be consider as a specific
type of certain hetrogenous reaction in which
mass transfer results as a net effect between
escape and deposition of solute molecule at a
solid surface.

•

3

The processes involved in dissolution of solid dosage forms:

4

MECHAMISM OF DISSOLUTION
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Initial mechanical
lag
Wetting of
dosage form
Penetration of
dissolution
medium
Disintegration
Deaggregation
Dissolution
Occlusion of
some particles

5

Intrinsic dissolution
2
rate


Intrinsic dissolution rate (IDR), which is
the rate of mass transfer per area of
dissolving surface and typically has the
units of mg cm-2 min-1.



IDR should be independent of boundary
layer thickness and volume of solvent.
Thus IDR measures the intrinsic properties
of the drug only as a function of the
dissolution medium, e.g. its pH, ionic
strength, counters ions etc.
6

Rate of dissolution
Where:
 m - Amount of dissolved material, kg
 t - Time, seconds
 A - Surface area of the interface between the dissolving
substance and the solvent,m2
 D - Diffusion coefficient, m2/s
coefficient
 d - Thickness of the boundary layer of the solvent at the
surface of the dissolving substance, m
 Cs - concentration of the substance on the surface,
kg/m3
 Cb - concentration of the substance in the bulk of the
solvent, kg/m3
7

Importance and Application


3

Importance:

1. Results from in-vitro dissolution rate experiment
can be used to explain the observed difference
in invivo availability
2. Dissolution testing provides the means to
evaluate critical parameters such as adequate
bioavailability and provides information
necessary to formulator in development of
more efficacious and therapeutically optimal
dosage forms.
3. Most sensitive and reliable predictors of in-vivo
availability.
8

4. Dissolution analysis of pharmaceutical dosage
forms has emerged as single most important
test that will ensure quality of product.
5. It can ensure bioavailability of product between
batches that meet dissolution criteria.
6. Ensure batch-to-batch quality equivalence both
in-vitro and in-vivo, but also to screen
formulations during product development to
arrive at optimally effective products.
7. Physicochemical properties of model can be
understood needed to mimic in-vivo
environment.
9

8. Such models can be used to screen potential
drug and their associated formulations for
dissolution and absorption characteristics.
9. Serve as quality control procedures, once the
form of drug and its formulation have been
finalized.

10

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PRODUCT DEVELOPMENT
Important tool during development of dosage form.
Aids in guiding the selection of prototype
formulations and for determining optimum levels of
ingredients to achieve drug release profiles,
particularly for extended release formulations.
Also guides in selection of a “market-image”
product to be used in pivotal in-vivo bioavailability
or bioequivalence studies.
QUALITY ASSURANCE
D.T. performed on future production lots and is
used to assess the lot-to-lot performance
characteristics of drug product and provide
continued assurance of product integrity/similarity.
12

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PRODUCT STABILITY



In-vitro dissolution also used to assess drug
product quality with respect to stability and shelflife.
As product age, physicochemical changes to the
dosage form may alter dissolution characteristics
of drug product over time. For some products,
polymorph transformations to more stable, and
hence less soluble crystalline forms may result in
reduced dissolution rates.

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13

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COMPARABILITY ASSESSMENT
Also useful for assessing the impact of pre- or
post- approval changes to drug product such as
changes to formulation or manufacturing
process. Thus, in-vitro comparability
assessment is critical to ensure continued
performance equivalency and product similarity.
WAIVERS OF IN-VIVO BIOEQUIVALENCE
REQUIREMENTS
In-vitro dissolution testing or drug release
testing may be used for seeking waiver of
required product to conduct in-vivo
bioavailability or bioequivalence studies.
14

Theories Of Dissolution

4

I.

Diffusion layer model/Film Theory

II.

Danckwert’s model/Penetration or
surface renewal Theory

III.

Interfacial barrier model/Double
barrier or Limited solvation theory

15

I.

Diffusion layer model/Film Theory



It is a simplest model where dissolution of crystal,
immersed in liquid takes place without involving
reactive or electrical forces. Consist of two
consecutive steps:

1.

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).

2.

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
drugdissolution. The model is depicted in following
fig.
16



The rate of dissolution is given by Noyes and
dc
Whitney:
k (C - C )
dt

s

b

Where,
dc/dt= dissolution rate of the drug
K= dissolution rate constant
Cs= concentration of drug in stagnant layer
Cb= concentration of drug in the bulk of the
solution at time t
18


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Brunner & Tolloczko incorporated surface area
„A‟ in Noyes & Whitney equation.
dc/dt = k1A ( Cs – Cb )
Afterwards Brunner, incorporated Fick‟s law of
diffusion & expanded his given eq to include
diffusion coefficient „D‟, thickness of stagnant
diffusion layer „h‟ & volume of dissolution
medium „v‟.

19

Modified Noyes & Whitney equation
dc/dt =DAKw/o (Cs- Cb) /Vh

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Where,
D= diffusion coefficient of drug.
A= surface area of dissolving solid.
Kw/o= water/oil partition coefficient of drug.
V= volume of dissolution medium.
h= thickness of stagnant layer.
(Cs – Cb )= conc. gradient for diffusion of drug.
20



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This eq describes a first – order dissolution
kinetics. It represents dissolution under non-sink
conditions.
If volume is relatively large such that
Cs>>>Cb so,
dc/dt =AKw/o Cs/Vh
Cs & D are constant for each specific chemical
substance so dc/dt =k1 A /Vh
(k1= Kw/o D Cs)
V & A are kept constant during dissolution so
dc/dt =k
21

Sink condition
A Sink conditions describe a dissolution system that is sufficiently dilute so that
the dissolution process is not impeded by approach to saturation of the
compound of interest.
Sink conditions affect the production of the sample but not the condition of the
solution upon sampling.

In vivo condition, there is no conc. build up in the bulk of the solution and
hence no retarding effect on the dissolution rate of the drug i.e. Cs>>Cb
and sink condition maintain.

22

Dissolution rate under sink condition follow zero
order dissolution rate.
Zero order dissolution
Under sink condition
Conc of disslove drug



First order under non
sink condition

Time

23

For obtaining IVIVC sink condition can be
achieved by:
1) Bathing the dissolving solid in fresh solvent
from time to time.
2) Increasing the volume of dissolution fluid.
3) 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.
4) Adding a water miscible solvent such as alcohol
to the dissolution fluid.
5) By adding selected adsorbents to remove the
dissolution drug.
 In vitro sink condition is so maintain that Cb
always less than 10% of Cs.
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24

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HIXON-CROWELL CUBE ROOT RELATIONSHIP
Major assumptions in Noyes-Whitney relationship is that the S.A.
(A) term remains constant throughout dissolution process. This is
true for some formulations, such as transdermal patches.
However, size of drug particles from tablets, capsules and
suspensions will decrease as drug dissolves.
This decrease in size of particles changes the effective S.A.
Thus, Hixon & Crowell modified the eq to represent rate of
appearance of solute by weight in solution by multiplying 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

25



DANCKWERT’S MODEL (PENETRATION OR
SURFACE RENEWALTHEORY)



This theory assumes that solid-soln equilibrium is
achieved at interface and mass transport is slow step in
dissoln process.
The model could be visualized as a very thin film having
a conc. Ci which is less than saturation, as it is
constantly being exposed to fresh surfaces of liquid
having a conc. much less than Ci. 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.
Since turbulence actually extends to surface, there is no
laminar boundary layer and so no stagnant film exists.
Instead, surface continually being replaced with fresh
liquid.

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26



Interfacial barrier model (double barrier or
limited salvation theory)
Based on salvation mechanism & 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
In this theory, the diffusivity D may not be independent
of saturation conc. Cs .
The interfacial barrier model can be extended to both
diffusion layer model and the Dankwert’s model.

28

FACTORS AFFECTING DISSOLUTION RATE 4
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Factors related to Physicochemical Properties
of Drug
Factors related to Drug Product Formulation
Processing Factor
Factors Relating Dissolution Apparatus
Factors Relating Dissolution Test Parameters
Miscellaneous factors

29

FACTORS RELATED TOPHYSICOCHEMICAL
PROPERTIES OF DRUG

1) DRUG SOLUBILITY
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Solubility of drug plays a prime role in controlling its
dissolution from dosage form. Aqueous solubility of drug
is a major factor that determines its dissolution rate.
Minimum aqueous solubility of 1% is required to avoid
potential solubility limited absorption problems.
Studies of 45 compound of different chemical classes
and a wide range of solubility revealed that initial
dissolution rate of these substances is directly
proportional to their respective solubility.
Ex. Poorly soluble drug :griseofulvin, spironolactone
hydrophilic drug :neomycin
30

2 ) SALT FORMATION
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

It is one of the common approaches used to increase drug solubility
and dissolution rate. It has always been assumed that sodium salts
dissolve faster than their corresponding insoluble acids. Eg.sodium
and potassium salts of Peniciilin G, sulfa drugs, phenytoin,
barbiturates etc.
While in case of Phenobarbital dissolution of sodium salt was
slower than that of weak acid. Same is the case for weak base
drug, strong acid salts, such as hydrochlorides and sulphates of
weak bases such as epinephrine, tetracycline are commonly used
due to high solubility. However, free bases of chlortetracycline,
methacycline were more soluble than corresponding hydrochloride
salt at gastric pH values, due to common ion suppression.

31

3) PARTICLE SIZE

There is a direct relationship between surface area of drug and its
dissolution rate. Since, surface area increases with decrease in
particle size, higher dissolution rates may be achieved through
reduction of particle size.


Micronization of sparingly soluble drug to reduce particle size is by
no means a guarantee of better dissolution and bioavailability.



Micronization of hydrophobic powders can lead to aggregation and
floatation. when powder is dispersed into dissolution medium. So,
mere increase in S.A. of drug does not always guarantee an
equivalent increase in dissolution rate. Rather, it is increase in the
“effective” S.A., or area exposed to dissolution medium and not the
absolute S.A. that is directly proportional to dissolution rate.
Hydrophobic drugs like phenacetin, aspirin shows decrease in
dissoln. rate as they tend to adsorb air at the surface and inhibit
their wettability. Problem eliminated by evacuating surface from
adsorbed air or by use of surfactants. So these drugs in-vivo exhibit
excellent wetting due to presence of natural surfactants such as
bile salts
Eg. therapeutic conc. of griseofulvin was reduced to half by
micronization

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32

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4) SOLID STATE CHARACTERISTICS

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Solid phase characteristics of drug, such as amorphicity,
crystallinity, state of hydration and polymorphic structures have
significant influence on dissolution rate.
Anhydrous forms dissolve faster than hydrated form because they
are thermodynamically more active than hydrates. Eg. Ampicillin
anhydrate faster dissolution rate than trihydrate.
Amorphous forms of drug tend to dissolve faster than crystalline
materials. E.g.Novobiocin suspension, Griseofulvin.
Where in the dissolution rate of amorphous erythromycin estolate
is markedly lower than the crystalline form of erythromycin estolate.
Metastable(high activation energy)polymorphic form have better
dissolution than stable form

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5) Co precipitation &/or Complexation
Co precipitation as well as complexation are use for
enhancing the dissolution rate of drug due to,
Formation energetic amorphous drug phase or
Drug being molecularly dispersed or
Formation of co accervates
e.g.1) Hydroflumethiazide – PVP co precipitate has
four times more solubility than crystalline drug.
2) Dissolution rate of sulfathiazole could be
significantly increased by co precipitating the drug
with povidone
34

Factors related to Drug Product
Formulation
1)DILUENTS
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Studies of starch on dissolution rate of salicylic acid
tablet by dry double compression process shows three
times increase in dissolution rate when the starch
content increase from the 5 – 20 %.
Here starch particles form a layer on the outer surface
of hydrophobic drug particles resulting in imparting
hydrophilic character to granules & thus increase in
effective surface area & rate of dissolution

35

Amt of dissolved mg

100
80
60
10% starch

40
20

5% starch
10

20

30

40

50

Time in min.

The dissolution rate is not only affected by nature of the diluent but
also affected by excipient dilution (drug/excipient ratio).
E.g. in quinazoline comp. dissolution rate increases as the
excipient /drug ratio increases from 3:1 to 7:1 to 11:1.

36

2)DISINTEGRANTS
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Disintegrating agent added before & after the granulation affects the
dissolution rate.
Studies of various disintegrating agents on Phenobarbital tablet
showed that when copagel (low viscosity grade of Na CMC)
added before granulation
decreased dissolution rate but if added
after did not had any effect on dissolution rate.
Microcrystalline cellulose is a very good disintegrating agent but at
high compression force, it may retard drug dissolution.
Starch is not only an excellent diluent but also superior disintegrant
due to its hydrophilicity and swelling property.

3)BINDERS AND GRANULATING AGENTS
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The hydrophilic binder increase dissolution rate of poorly wettable
drug.
Large amt. of binder increase hardness & decrease disintegration
/dissolution rate of tablet.
Non aqueous binders such as ethyl cellulose also retard the drug
dissolution.

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Phenobarbital tablet granulated with gelatin solution provide a
faster dissolution rate in human gastric juice than those prepared
using Na –carboxymethyl cellulose or polyethylene glycol 6000
as binder.
In Phenobarbital tablet, faster dissolution rate was observed with
10% gelatinwhereas decrease in dissolution rate with 20% gelatin.
This was due to higherconcentration which formed a thick film
around tablet.
Water soluble granulating agent Plasdone gives faster dissolution
rate comparedto gelatin.

38

4) Lubricants

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

Lubricants are hydrophobic in nature (several metallic stearate &
waxes) which inhibit wettability, penetration of water into tablet so
decrease in disintegration and dissolution.
The use of soluble lubricants like SLS and Carbowaxes which
promote drug dissolution.

39

5)SURFACTANTS
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They enhance the dissolution rate of poorly soluble drug. This is due to
lowering of interfacial tension, increasing effective surface area, which in
turn results in faster dissolution rate.
E.g. Non-ionic surfactant Polysorbate 80 increase dissolution rate of
phenacetin granules.

6)WATER-SOLUBLE DYES
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Dissolution rate of single crystal of sulphathiazole was found to decrease
significantly in presence of FD&C Blue No.1.
The inhibiting effect was related to preferential adsorption of dye
molecules on primary dissolution sources of crystal surfaces. They inhibit
the micellar solubilization effect of bile salts on drug.
Riboflavin tablet decrease when used FD & C Red no.3 dye in film coat

7)Effect of coating component on tablet
dissolution


Coating ingredient especially shellac & CAP etc. Also have significant
effect on the dissolution rate of coated tablet. Tablets with MC coating were
found to exhibit lower dissolution profiles than those coated with HPMC at
37ºC.
40

PROCESSING FACTORS
1) METHOD OF GRANULATION


Granulation process in general enhances dissolution
rate of poorly soluble drug.



Wet granulation is traditionally considered superior. But
exception is the dissolution profile of sodium salicylate
tablets prepared by both wet granulation and direct
compression where the dissolution was found more
complete and rapid in latter case.



A newer technology called as APOC “Agglomerative
Phase of Comminution” was found to produce
mechanically stronger tablets with higher dissolution
rates than those made by wet granulation. A possible
mechanism is increased internal surface area of
granules produced by APOC method.
41

2)COMPRESSION FORCE


The compression process influence density, porosity, hardness,
disintegration time & dissolution of tablet.

1. tighter bonding
2 . higher compression force cause
deformation crushing or fracture
of drug particle or convert a
spherical granules into disc
Shaped particle
3.& 4. both condition
42

3) DRUG EXCIPIENT INTERACTION
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These interactions occur during any unit operation such as mixing,
milling ,blending, drying, and/or granulating result change in
dissolution.
The dissolution of prednisolone found to depend on the length of
mixing time with Mg-stearate
Similar as increase in mixing time of formulation containing 97 to
99% microcrystalline cellulose or another slightly swelling
disintegrant result in enhance dissolution rate.
Polysorbate-80 used as excipient in capsules causes formation of
formaldehyde by autoxidation which causes film formation by
denaturing the inner surface of capsule. This causes decrease in
dissoln rate of capsules.

4) STORAGE CONDITIONS
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Dissolution rate of hydrochlorothiazide tablets granulated with
acacia exhibited decrease in dissolution rate during 1 yr of aging at
R.T
For tablets granulated with PVP there was no change at elevated
temperature but slight decrease at R.T.
Tablets with starch gave no change in dissoln. rate either at R.T. or
at elevated temperature.
43

FACTORS RELATING DISSOLUTION
APPARATUS 1
1) AGITATION


Relationship between intensity of agitation and rate of
dissolution varies considerably acc. to type of agitation
used, the degree of laminar and turbulent flow in
system, the shape and design of stirrer and
physicochemical properties of solid.



Speed of agitation generates a flow that continuously
changes the liq/solid interface between solvent and
drug. In order to prevent turbulence and sustain a
reproducible laminar flow, which is essential for
obtaining reliable results, agitation should be
maintained at a relatively low rate.
Thus, in general relatively low agitation should be
applied.

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

I. BASKET METHOD- 100 rpm
II. PADDLE METHOD- 50-75 rpm

44

2) STIRRING ELEMENT ALIGNMENT
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



The USP / NF XV states that the axis of the stirring element must
not deviate more than 0.2 mm from the axis of the dissolution
vessel which defines centering of stirring shaft to within ±2 mm.
Studies indicant that significant increase in dissolution rate up to
13% occurs if shaft is offset 2-6 mm from the center axis of the
flask.
Tilt in excess of 1.5 0 may increase dissolution rate from 2 to 25%.

3) SAMPLING PROBE POSITION & FILTER
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Sampling probe can affect the hydrodynamic of the system & so
that change in dissolution rate.
For position of sampling, USP states that sample should be
removed at approximately half the distance from the basket or
paddle to the dissolution medium and not closer than 1 cm to the
side of the flask.
Filter material must be saturated with the drug by repeated passage
to avoid losses that might go undetected during the test sampling.
Accumulation of the particulate matter on the surface may cause
significant error in the dissolution testing.

45

FACTORS RELATING DISSOLUTION TEST
PARAMETERS
1)TEMPERATURE




Drug solubility is temperature dependent, therefore careful
temperature control during dissolution process is extremely
important.
Generally, a temp of 37º ± 0.5 is maintained during dissolution of
oral dosage forms and suppositories. However, for topical
preparations temp as low as 30º and 25º have been used

2) DISSOLUTION MEDIUM
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Effect of dissolution air on dissolution medium
Altering PH
Dissolved air tends to release slowly in form of tiny air bubble that
circulate randomly and affect hydrodynamic flow pattern
Specific gravity decrease thus floating of powder thus wetting and
penetration problem.
Dissolution media composition & PH
Addition of Na – sulfate decrease the dissolution rate.
Addition of urea increase dissolution rate.

46

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Volume of dissolution medium and sink conditions
Volume generally 500, 900 or 1,000 ml.
Simulated gastric fluid(SGF) - pH 1.2.
Simulated intestinal fluid (SIF)- pH 6.8 (not exceed pH 8.0).
The need for enzymes should be evaluated case-by-case like….
(Pepsin with SGF and pancreatin with SIF
If drug is poorly soluble, a relatively large amount of fluid should be
used if complete dissolution is to be expected.
In order to minimize the effect of conc. gradient and maintain sink
conditions, the conc. of drug should not exceed 10-15% of its max.
Solubility in dissoln. medium selected. For most of the drugs about 1 L
is more than sufficient to maintain sink conditions.
However, some insoluble drug present a problem as to handling of
huge volume of dissoln. medium that would be required to maintain the
sink conditions. For these, different approaches have been tried like….
continous flow method where fresh solvent is pumped continuously into
dissoln flask at a fixed flow rate while maintaining a constant volume.
Use of non-ionic surfactant in conc. above CMC.
Use of alcoholic solution (10-30%).
47


1.

Miscellaneous factor
Absorption :
Absorbent increase the dissolution rate under condition
of a decrease concentration gradient applying Nerst–
Brunner film theroy

2.

Humidity :
Moisture has been shown to influence
the dissolution of many drug from solid dosage form.

48

Dissolution Test Apparatus1
I.P.

USP

B.P.

E.P.

Type 1

Paddle
Basket
apparatus apparatus

Basket
apparatus

Paddle
apparatus

Type 2

Basket
Paddle
apparatus apparatus

Paddle
apparatus

Basket
apparatus

Type 3

Reciprocating
cylinder

Type 4

Flow through
cell apparatus

Type 5
Type 6
Type 7

Flow through cell Flow through
apparatus
cell apparatus

Paddle over
disk
cylinder
Reciprocating
holder

49

Solid dosage form (tablet & capsule)
I.P. & E.P.
Apparatus I – paddle apparatus

Apparatus II – basket apparatus
B.P. & U.S.P.

Apparatus I – basket apparatus

Apparatus II – paddle apparatus
B.P. & E.P.

Apparatus III – flow through cell apparatus
Conditions ( for all)
 Temp. - 37±0.50C
 PH - ±0.05 unit in specified monograph
 Capacity – 1000 ml
 Distance between inside bottom of vessel and paddle/basket is
maintained at 25±2 mm.
 For enteric coated dosage form it is first dissolved in 0.1 N HCl &
then in buffer of pH 6.8 to measure drug release. (Limit – NMT
10% of drug should dissolve in the acid after 2hr.and about 75%
of it should dissolve in the buffer after 45 min.


50

USP APP.

DESCRIPTOIN

ROT.
SPEED

DOSAGE
FORM

Type 1

Basket apparatus

50-120rpm

IR, DR, ER

Type 2
Type 3

Paddle apparatus

25-50rpm

IR, DR, ER

Reciprocating
cylinder

6-35rpm

IR,ER

Type 4

Flow through cell
apparatus

N/A

ER , poorly
soluble API

Type 5

Paddle over disk

25-50rpm

TRANSDERMAL

Type 6

cylinder

N/A

TRANSDERMAL

Type

Reciprocating
holder

30rpm

ER
51

APPARATUS 1- BASKET APPARATUS











Dosage form contained
within basket
Dissolution should occur
within Basket
Useful for :
Tablets
Capsules
–Beads
–Floaters
pH change by media
exchange
52



• Drug product
– Solids (mostly floating)
• Monodisperse (tablets)
• Polydisperse (encapsulated beads)
• Agitation
– Rotating stirrer
– Usual speed: 50 to 100 rpm
• Disadvantage
– Formulation may clog to 40 mesh screen
53

USP Apparatus 2 – Paddle


Dosage form should
remain at the bottom
centre of the vessel



Sinkers used for floaters



Useful for :
– Tablets
– Capsules





pH change by media
addition
54



• Drug product
– Solids (mostly non floating)
• Monodisperse (tablets)
• Polydisperse (encapsulated beads)



• Agitation
– Rotating stirrer
– Usual speed: 25 to 75 rpm



Standard volume: 900/1000 ml



Advantages:

1. Easy to use and robust
2. Ph change possible
3. Can be easily adapted to apparatus 5


Disadvantages

– Floating dosage forms require sinker
– Positioning of tablet

55



Limitations of USP Apparatus 1and 2:

1. USP2 (and USP1) Apparatus has plenty of
HYDRODYNAMICS.
2. Complicated 3-dimensional flow generated by
the paddle.
3. Significant impact of convective transport –
Conditions used (50 – 100 rpm) highly
exaggerates flow in the GI.
4. Use of solvents and surfactants non-native to
GI.

57

Apparatus III – Reciprocating cylinder
The assembly consists of a
1)set of cylindrical,
2)flat-bottomed glass vessels;
a 3)set of glass
reciprocating cylinders;
4)stainless steel fittings (type
316 or equivalent) and
screens that are made of
suitable nonsorbing and
nonreactive
material(polypropelene) and
that are designed to fit the
tops and bottoms of the
reciprocating cylinders; and
a motor and drive assembly
to reciprocate the cylinders
vertically inside the vessels

58











The vessels are partially immersed in a suitable water
bath of any convenient size that permits holding the
temperature at 37 ± 0.5 during the test.
The dosage unit is placed in reciprocating cylinder & the
cylinder is allowed to move in upward and downward
direction constantly. Release of drug into solvent within
the cylinder measured.
Useful for: Tablets, Beads, controlled release
formulations
Standard volume: 200-250 ml/station
Advantages: 1) Easy to change the pH-profiles
2) Hydrodynamics can be directly influenced by varying
the dip rate.
Disadvantages: 1) small volume (max. 250 ml)
2) Little experience

59

Apparatus 3 – Reciprocating cylinder

60

USP Apparatus 4 - Flow Through Cell

61










The assembly consists of a reservoir and a pump for the
Dissolution Medium; a flow-through cell; a water bath
that maintains the Dissolution Medium at 37 ± 0.5
The pump forces the Dissolution Medium upwards
through the flow-through cell.
Assemble the filter head, and fix the parts together by
means of a suitable clamping device.
Introduce by the pump the Dissolution Medium warmed
to 37 ± 0.5 through the bottom of the cell to obtain the
flow rate specified in the individual monograph.
Collect the elute by fractions at each of the times stated.
Perform the analysis as directed in the individual
monograph

62

Tablets 12 mm











Tablets 22,6 mm

Powders / Granules

Implants

Suppositories /
Soft gelatine capsules

Useful for: Low solubility drugs, Micro particulates,
Implants, Suppositories, Controlledrelease formulations
Variations: (A) Open system & (B) Closed system
Advantages:
1. Easy to change media pH2. PH-profile possible
3. Sink conditions
Disadvantages:
1. Deaeration necessary
2. High volumes of media
3. Labor intensive

63

Apparatus 4 – Flow-Through Cell

64

USP Apparatus 5 - Paddle Over Disk

65








Use the paddle and vessel assembly from Apparatus 2 with the
addition of a stainless steel disk assembly designed for holding the
transdermal system at the bottom of the vessel.
The disk assembly holds the system flat and is positioned such that
the release surface is parallel with the bottom of the paddle blade
The vessel may be covered during the test to minimize evaporation.
Useful for: Transdermal patches
Standard volume: 900 ml
Disadvantages: Disk assembly restricts the patch size.
Borosilicate Glass
17 mesh is standard (others available)
Accommodates patches of up to 90mm

66

USP Apparatus 6 - Cylinder

67

• Use the vessel assembly from

Apparatus 1 except to
replace the basket and shaft with a stainless steel cylinder
stirring element
• The temperature is maintained at 32°C ± 0.5°C
• The dosage unit is placed on the cylinder with release side
out
 The dosage unit is placed on the cylinder at the beginning
of each test, to the exterior of the cylinder such that the
long axis of the system fits around the circumference of the
cylinder & removes trapped air bubbles.
 Place the cylinder in the apparatus, and immediately rotate
at the rate specified in the individual monograph.
68

USP Apparatus 7 – Reciprocating Holder

69

The assembly consists of a set of volumetrically
calibrated solution containers made of glas or other
suitable inert material, a motor and drive assembly to
reciprocate the system vertically
• The temperature is maintained at 32°C ± 0.5°C
•



• The dosage unit is placed on the cylinder with release side out
The solution containers are partially immersed in a suitable water
bath of any convenient size that permits maintaining the
temperature, inside the containers at 32 ± 0.5 For Coated tablet
drug delivery system attach each system to be tested to a suitable

70

•For Transdermal drug delivery system attach the system to a suitable sized sample
holder with a suitable O-ring such that the back of the system is adjacent to and
centered on the bottom of the disk-shaped sample holder or centered around the
circumference of the cylindrical-shaped sample holder. Trim the excess substrate with a
sharp blade.

71

Novel Dissolution test
Apparatus for buccal and
sublingual tablets. 13


Buccal and sublingual dissolution differs from
g.i.dissolution in following ways…
smaller volume ( of saliva)
short residence time ( in mouth)
solids transfer
composition of fluid ( saliva composition)
Incomplete dissolution



So, our dissolution apparatus must provide above
conditions for performing dissolution test of buccal
and sublingual tablets.
73

MODEL:-I

It provides all the characteristics described above.
It is given by HUGHES

6ml/min

74



This novel system comprises a single stirred continuous
flow-through cell that includes …
a dip tube
a central shaft with propeller &
a filter along with one inlet for saliva & one outlet for
sample.



A pump is available which pushes the fluid at the rate 6
ml/min. and this will give a residence time in the cell of
approximately 100 secs for 63% of the dosage form & gives
complete removal in about 8 mins.
75

Composition

of saliva:-

Composition of stimulated saliva
KH2PO4

12mM

NaCl
CaCl2

40mM
1.5mM

NaOH

To pH 6.2

76

Composition of sublingual saliva
COMPOUND
CaCl2. 2H2O

mM
0.2

MgCl2 . 6H2O

0.061

NaCl
K2CO3 . 5H2O

1.017
0.603

Na2HPO4 .7H2O

0.20

Na2HPO4.H2O

0.273

Submaxillary fluid 1.0
2.0
α amylase
77



Advantage



It is a rapid, taking only about 20 minutes per test &
repeatable.
This method could be used as a QC test to ensure
dosage uniformity.
This method is particularly suited for evaluating taste
masking.






Application

This dissolution apparatus is used for
-Claritin
-Reditabs
-Zydis system
78

MODEL:-II

International Journal of Pharmaceutics ,October 2006

The device introduced by them is based on the circulation of pre-warmed
dissolution medium through a cell.
Buccal tablet was attached on chicken pouches.
They stated “ the results obtained by this using this apparatus for the
release of drug from bio adhesive tablets concurred with the predicted
patterns.”
79

Method for dissolution testing
In vitro target site – animal buccal tissues or buccal cell cultures

Animal sacrificed just before in
vitro testing

Buccal mucosa removed surgically

cold Krebs buffer Isolated buccal mucosa stored in ice

Mounted between side by side diffusion cells
80

Novel Dissolution test Apparatus for
Floating tablets 8
Ideal qualities for dissolution apparatus for Floating
tablets.
I.
II.

iii)
iv)

Dosage form should not stick on the agitating device.
Therefore, under driven arrangement is more suitable.
The test must try to mimic the gastric juice release
rate
(2-4ml/min).
The sample collection must be easy.
The volume of cell having dosage form in it must have
nearly same volume as compared to in-vivo gastric
volume.
(70 ml).
81

MODIFIED ROSSET –
RICE TEST

82

Better in-vivo-in-vitro correlation shown by
this method.
 It mimics three points.
i) gastric volume
ii) gastric acid secretion
iii) gastric emptying.
which USP-II apparatus fails to
mimic. &
Here, tablet does not stick to agitating device
because it is under-driven.


83

Dissolution study of Lipid –filled soft gelatin
capsules. 15

(International Journal of Pharmaceutics ,October 2006.)
84




MECHANISM
It is one type of flow through cell.



Lipid content due to its lower density rises up in the
cell after rupturing of the capsule.



When lipid phase reaches the triangular area top of
the left side cell, it stays there.
thus ,dissolution medium continuously extracts
the drug from the lipid layer as it flows through the
cell.
The dissolved drug can now be determined using a
fractional collector and be analyzed in the medium.



85

Pillay & Fassihi model for Lipid –filled
soft gelatin capsules.

I = organic phase, i.e., 100 ml
II = aqueous phase
III = ring/mesh assembly
IV = position of capsule

86

Dissolution study of chewing gum as a
dosage form. 11

87



European Pharmacopoeia published a monograph
describing a suitable apparatus for studying the in
vitro release of drug substances from chewing gums.



A study was carried out to explore differences in the
release of nicotine from the directly compressible
gum base compared with a conventional nicotine gum
using the European Pharmacopoeia chewing
apparatus described in the European Pharmacopoeia.

88



The gums were placed in the chewing chamber with 40
ml of artificial saliva.



The temperature of the chewing chamber :37±1°C
chew rate : 60 chews/minute
unspecified buffer (with a pH close to 6) : 20 ml



The machine was run without chewing gum for the first
two minutes and then the buffer removed to ensure that
i) any residues from the extensive washing and
cleaning procedure were removed &
ii) to allow equilibration of chew rate and
temperature.
89

Artificial Saliva Formulation Components:-

90

Dissolution study of the bio-degradable
microspheres.

91

Mini Paddle Apparatus- for dissolution
study of Immediate-Release Dosage
Forms10

92



The mini paddle is based
on the USP paddle setup
but scaled down exactly
1/3 with respect to the
dimensions.



250 ml volume used in
the mini paddle
apparatus.



A stirring rate of 100
rpm in the mini paddle
apparatus appears to be
the most favorable.

93



Mini paddle apparatus might be a useful tool in characterizing
drug release profiles under “standard test conditions.”



Due to the possibility of using smaller sample sizes and
smaller volumes of media ,
it offers various advantages in terms of substance,
analytical, and material cost savings.



The mini paddle set-up is also a promising alternative in the
case of highly potent drugs.
The mini paddle should preferably be used for…
powders,
multiparticulate dosage forms,
small tablets or capsules
(i.e., where the paddle apparatus would be the usual method



94

TDDS Dissolution Test12


Apparatus used:



Franz diffusion apparatus
Paddle over disk
Cylinder method
Flow through diffusion cell





95

Animal skin – hairless mouse , guinea pig , rabbit
But no animal skin mimic human skin so human skin is preferred &
use is based on availability.
 Temp 32c +/- 1c
pH 5-6
Stirring rate – 100
rpm.
 Enzymes for oxidatn, reductn, hydrolys,conjgtn
Skin lipids
Microbial flora ( difficult to reproduce

96

Semisolid dissolution test

12



Apparatus used



USP paddle over disk
Franz diffusion apparatus
Flow through apparatus
Unconventional apparatus
a) designed by chouhan12
Commonly used membranes
Polysulphone (Tuffryn, 0.45 μm size): Most suitable syn.
membrane for ointments.
Cellulosic acetate plus.
Nylon
Teflon and polycorbonate











97

A = Constant temp. water
bath
B = 250 ml beaker
C = Teflon disk
D = Layer of ointment
E = sink
F = Magnetic stirring bar
G = Motor

98

Parentral Depot dissolution
14
test
IN VITRO DISSOLUTION TESTING FOR
DEPOTS
 DEPOT
Dissolution
DRUG IN SOLUTION
Partition
DRUG IN TISSUE FLUID
Factors need to be controlled.
1) nature & site of absorption of drug
2) physiological pH of tissue fluid


100

DIAGRAM OF ROTATING DIALYSIS CELL
IT USED FOR
PARENTERAL DEPOTS
Dialysis membrane
provides well defined
surface area.
Dissolution medium pH =
pH of site of absorption.
E.g NAPROXEN – IN
COCONUT OIL
VOLUME – 1000ML ,
37C+/_ 0.5C
Stirring rate 50rpm
Dissolution media
pH 3 ± 0.01 (0.05 M
phosphate buffer)
pH 5 ± 0.01 (0.05 M
Acetate buffer)
pH 7 ± 0.01 (0.05 M
phosphate buffer)

101

Dissolution Test of
15
Suspension
APPARATUS
Rotating Paddle
 MEDIA
Aqueous medium
Rotationg speed 50rpm
Temperature 37oc +/- 5


102











Method parameters such as
sample introduction and
agitation rate should be
established on the basis of
the viscosity and composition
of the suspension matrix. .
For low-viscosity
suspensions, an accurate
dose can be delivered to the
bottom of the dissolution
vessel using a volumetric
pipette.
A slow agitation rate of 25 rpm
is generally recommended for
less viscous sus-pensions.
For high-viscosity samples,
the dose may need to be
determined by weight with a
quantitative sample transfer to
the dissolution vessel to
ensure ac-curacy of the
sample size introduced.
High-viscosity suspensions
may also require a faster
agitation rate such as 50 or 75
rpm to prevent sample
mounding at the bottom of the

103

Dissolution Test of Inhaler16
A USP Apparatus 2,
Hanson SR8-Plus
dissolution test station
was employed to
conduct the dissolution
study.

A schematic diagram of
modifications to the
dissolution apparatus is
shown in Figure 1. The
two main components of
the dissolution setup
include
1) dissolution test station
(FigureA)
2) a newly designed
membrane holder
(Figure B).


104









The membrane
holder assembly was
customized, it
consists of
NGI dissolution cup
(a),
removable
impaction inset (b),
a securing ring (c),
two sealing o-rings,
a PC membrane to
function as a highly
porous diffusional
powder retaining
layer.

105







To select suitable particle size
cutoff ranges for the
subsequent dissolution study,
aerodynamic particle
separation was achieved
using the NGI. Either the
Ventolin HFA device or the
Pulmicort Flexhaler device
was actuated five times to
obtain a quantifiable amount
of drug.
The NGI was operated at a
flow rate of 30 L/min for the
Ventolin HFA and 60 L/min for
the Pulmicort Flexhaler.
For the dissolution studies,
the dissolution cup assembled
with the impaction insert was
placed in the NGI, as shown
in Figure 2. Following
actuation, the impaction insert
was removed from the NGI
dissolution cup for the

106







Dissolution Media
Simulated lung fluid (SLF),
0.2 M phosphate buffer(pH 7.4),
phosphate-buffered saline (PBS),
modified PBS(mPBS) containing
dipalmitoylphosphatidylcholine(DPPC),
and PBS containing polysorbate 80
(tPBS) were used in the dissolution
studies.
107



Dissolution Apparatus



The membrane holder was
placed at the bottom of each
vessel, release-surface side
up, with the distance between
the bottom edge of the paddle
and the surface of the
membrane holder maintained
at 20 ± 2 mm( Figure 2)



The distance between the
paddle and the surface of the
membrane holder can be
adjusted within a range that
allows the paddle to
effectively remove released
drug from the exposed
membrane surface and
provides continuous
circulation to the media in the
vessel.
109








MECHANISM

The mechanism of this dissolution method can be
explained by a dissolution–diffusion-controlled drug
release from the membrane holder. During the
dissolution process, the dispersed drug within the
membrane holder undergoes dissolution as dissolution
medium migrates through the pores on the membrane
surface, and the dissolved drug then releases out to the
reservoir by diffusion
DIFFUSION MEMBRANE
A PC membrane was selected as the diffusion barrier .
The PC membrane surface constitutes a perfect sink for
the released drug when used in this manner.
A PC membrane do not swell, do not create air
bubbles, have a well-defined uniform pore size (17, 18),
and consist of homogeneous 0.05-μm non-tortuous
cylindrical pores on the surface that allow free diffusion
of dissolved drug and dissolution medium
110

List Of Reference
1. Pharmaceutical dissolution testing by Umesh V. Banakar.
2. Remington 20th edition, 654.
3. Dissolution, Bioavailability & Bioequivalence by M. Abdou.
4. Biopharmaceutics & Pharmacokinetics by D.M.Bramankar, 20-29.
5. Generic Drug Product Development, vol-143 by Shargel.
6. Current concepts in pharmaceutical sciences & biopharmaceutics by
James Swarbrick.
7. Advanced Drug Delivery Reviews,(46), 75-87, 2001.
8.A Novel Multi compartment Dissolution Apparatus for Evaluation of
Floating Dosage Form Containing Poorly Soluble Weakly Basic Drug Dr.
Rajesh K. Parikh1,2,Dhaivat C. Parikh1,Renish R. Delvadia1, and
Sanjay M. Patel Dissolution Technologies ,FEBRUARY 2006.
9.A More Relevant Dissolution Method for Evaluation of Floating Drug
Delivery System Mukesh C.Gohel, Pavak R.Mehta, Rikita K. Dave2 and
Nehal H. Bariya. Dissolution Technologies | NOVEMBER 2004.
111

10.The Mini Paddle Apparatus–a Useful Tool in the Early Developmental Stage?
Experiences with Immediate-Release Dosage Forms. Dissolution Technologies |
NOVEMBER 2006.
11.in Vitro Release of Nicotine From Chewing Gum Formulations. Dissolution
Technologies | MAY 2004.
12.Current perspectives in dissolution testing of unconventional and novel dosage forms
semisolid Shirzad Azarmi, Wilson Roac, Raimar L¨obenberg , International Journal of
Pharmaceutics ,October 2006
13.A new method of characterising buccal dissolution of drugs. Dr.L.Hughes.Rohm &
Haas research laboratories.feb.2004.
14.FIP/AAPS Guidelines for Dissolution/In Vitro Release Testing of Novel/Special
Dosage Forms . Dissolution Technologies | FEBRUARY 2005
15. 14.FIP/AAPS Guidelines for Dissolution/In Vitro Release Testing of Novel/Special
Dosage Forms (suspension) march 2010
16.Invitro dissolution testing for inhaler ,dissolution technology ,november 2010
112

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