2. 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.
2
4. • Initial mechanical
lag
• Wetting of dosage
form
• Penetration of
dissolution
medium
• Disintegration
• Deaggregation
• Dissolution
• Occlusion of some
particles
4
5. 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.
5
6. 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 - DDiiffffuussiioonn ccooeeffffiicciieenntt, m2/s
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
6
8. Theories of Drug Dissolution
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.
9. I. Diffusion layer model/Film Theory :-
• It involves two steps :-
a. Solution of the solid to form stagnant film or
diffusive layer which is saturated with the drug
b. Diffusion of the soluble solute from the stagnant
layer to the bulk of the solution; this is r.d.s in
drug dissolution.
10.
11. • The rate of dissolution is given by Noyes and
Whitney:
= k (Cs- Cb) dc
dt
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
12. Modified Noyes-Whitney’s Equation -
dC
dt
DAKw/o (Cs – Cb )
Vh
=
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.
13. 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.
13
14. • Dissolution rate under sink condition follow zero
order dissolution rate.
Conc of disslove drug
Time
Zero order dissolution
Under sink condition
First order under non
sink condition
14
15. 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.
15
16. 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 16
17. • This is first order dissolution rate process, for
which the driving force is concentration gradient.
• This is true for in-vitro dissolution which is
characterized by non-sink conditions.
• The in-vivo dissolution is rapid as sink conditions
are maintained by absorption of drug in systemic
circulation i.e. Cb=0 and rate of dissolution is
maximum.
18. • Under sink conditions, if the volume and surface
area of the solid are kept constant, then
dC
dt
= K
• This represents that the dissolution rate is
constant under sink conditions and follows zero
order kinetics.
19. II. Danckwert’s model/Penetration or
surface renewal Theory :-
• Dankwert takes into account the eddies or
packets that are present in the agitated fluid
which reach the solid-liquid interface, absorb
the solute by diffusion and carry it into the bulk
of solution.
• These packets get continuously replaced by
new ones and expose to new solid surface
each time, thus the theory is called as surface
renewal theory.
20.
21. • The Danckwert’s model is expressed by
equation
dC
dt = dm
V = A (Cs-Cb). γ D
dt
Where,
m = mass of solid dissolved
Gamma (γ) = rate of surface renewal
22. III. Interfacial barrier model/Double barrier or
Limited solvation theory :-
• The concept of this theory is explained by
following equation-
G = Ki (Cs - Cb)
Where,
G = dissolution rate per unit area,
Ki = effective interfacial transport constant.
23. 3) Interfacial layer model
S
Film boundary
Bulk solution
Cs
C
Stagnant layer
In this model it is assumed that the reaction at solid surface is not
instantaneous i.e. the reaction at solid surface and its diffusion across the
interface is slower than diffusion across liquid film.
therefore the rate of solubility of solid in liquid film becomes the rate
limiting than the diffusion of dissolved molecules
equation : dm/dt = Ki (Cs – C ) K = effective interfacial transport rate
constant
24. Biopharmaceutical Classification System
High Solubility
(Dose Vol. NMT
250 mL)
Low Solubility
(Dose Vol. >250
mL)
High Permeability
(Fract. Abs. NLT
90%)
CLASS І
e.g. Propranolol
metoprolol
CLASS II
e.g. piroxicam,
naproxen
Low Permeability
(Fract. Abs.
<90%)
CLASS III
e.g. ranitidine
cimetidine
CLASS IV
e.g. furosemide
hydrochlorothiazide
25. Drug release mechanism in CDDS
Slow zero order release
Slow first order release
Initial rapid release followed by slow zero order
release
Initial rapid release followed by slow first order
release
26. • Zero order kinetics
• First order kinetics
• Hixoncrowell cube-root model
• Higuchi model
• Korsmeyer peppas model
27. • The equation for zero order kinetics is
Qt=Qo+Kot
Qo=initial amount of drug
Qt=cumulative drug released at t
Ko=zero order release constant
t= time in hours
• It describes the system where the drug release rate is
independent of its concentration of the dissolved
substance.
28. • A graph is plotted between the time taken on x axis
and cumulative percentage of drug release on y axis
and it gives straight line
Time(hours)
Cummulative %of drug release
29. • First order release equation is
logQt=logQo + Kt/2.303
Qt=cumulative amount of drug released at time t
Qo= initial amount of drug
K= first order rate constant
t= time in hours
• Here the drug release rate depends on concentration
( unimolecular reaction)
30. • A graph is plotted between time taken on x- axis and
log cumulative percentage of drug release on y- axis
will give a straight line
Time(hours)
Log % of drug release
31. • THE HIXSON-CROWELL RELEASE EQUATION IS
∛Qo-∛Qt=KHCt
Qo=initial amount of drug
Qt= cumulative amount of drug released at time t
KHC= hixson crowell release constant
t= time in hours
• It describes the drug releases by dissolution and
with the change in surface area and diameter of
particle.
32. • A linear plot of cube root initial concentration minus
cube root of percent remaining vs time gives straight
line .
• And release is dissolution rate controlled.
• slope gives K value
Time (hours)
∛Qo-∛Qt
33. • Higuchi equation is
Q=[Dt/Ƭ (2A-tCs)Cst]1/2
or Q=Kt1/2
Q=cumulative drug release at time t
D= diffusion coefficient of drug in in matrix
Cs=solubility of drug in polymeric matrix
Ƭ= tortuosity of capillary system
A=total amount of drug in unit volume matrix
K= higuchi release constant
• Higuchi equation suggest s that the drug release is by diffusion
34. • A graph is plotted with square root of time taken on x-axis
and cumulative % of drug release on y- axis
• It gives a straight line, slope gives K value
√Time ( hours)
cumulative % of drug release
35. • Korsmeyer –peppas equation is
F=Mt/M∞ = Ktn
F= fraction of drug released at time t
Mt=amount of drug released at time t
M∞=amount of drug released at infinite time
K= kinetic constant
t= time in hours
n= diffusion or release exponent
• n is estimated from linear regression of (Mt/M∞) vs time(t)
• If n= 0.45 then indicate fickian diffusion
• If o.45<n<0.89 then indicates anomalous diffusion or non-fickian
diffusion
• If n= 0.89 then indicates case-2relaxtaion or super case transport-2
36. • A graph is plotted between log time taken on x-axis
and log of cumulative percentage of drug release at y-axis
it gives a straight line.
Log time
cumulative % of drug release
37.
38. Classification
• There are basically three general
categories of dissolution apparatus :
1. Beaker methods
2. Open flow-through compartment system
3. Dialysis concept
40. to accessing therapeutic efficacy.
Monitoring batch to batch consistency.
High cost of in vitro dissolution test.
Assessment of bioequivalence.
Requirement for regulatory approval for
product marketing and is a vital
component of the quality control program.
40
42. Design:
Vessel:-
Made up of borosilicate glass
semi hemispherical bottom
Capacity: 1000ml
Shaft:-
Stainless steel 316
Rotates smoothly without significance wooble
Basket:-
Stainless steel 316
Gold coatings up to 0.0001 inch
Water bath:- Maintained at 37± 0.5˚c
42
43. • Dosage form contained
within basket
• Dissolution should occur
within Basket
• pH change by media
exchange
• Uses: Capsules,
tablets, delayed
release, suppositories,
floating dosage forms.
43
44. • • 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
44
46. • Dosage form should
remain at the bottom centre
of the vessel
• Sinkers used for floaters
• Useful for :
• – Tablets
• – Capsules
• pH change by media
addition
46
47. • • Drug product
– Solids (mostly non floating)
• Monodisperse (tablets)
• Polydisperse (encapsulated beads)
• • Agitation
– Rotating stirrer
– Usual speed: 25 to 100 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
47
49. Design:
1.vessel: cylindrical flat bottom glass vessel.
2.Agitation type: -reciprocating
-generally 5-35 rpm
3. Volume of dissolution fluids: 200-250 ml
4. Water bath: maintain at 37±0.5˚c
5. Use: extended release
49
50. The assembly consists of a
set of cylindrical, flat-bottomed
glass vessels; a
set of glass reciprocating
cylinders; )stainless steel
fittings (type 316 or
equivalent) and screens that
are made of suitable
nonsorbing and nonreactive
aterial(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
50
51. • 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
3) Limited data
51
55. • 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
55
56. 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
56
58. Design
1. Vessel:
2. Shaft:
3. Stirring elements
4. Sample holder: - Disk assembly that hold the
product in such a way that release surface is
parallel with paddle.
5. Paddle is directly attached over disk assembly.
6. Samples are drawn away b/w the surface of
medium and top of paddle blade.
7. Volume; 900ml
8. Temperature; 32˚c
58
60. • 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 60
61. Design;
1. Vessel: in place of basket cylinder is used.
2. Cylinder : stainless steel 316.
3.Sample: - mounted to cuprophan(inner porous
cellulosic material) an entire system is adhere to
cylinder.
-Dosage unit is place in cylinder and
released from outside.
4. Water bath : maintain at 32±.0.5˚c
Use : transdermal patches can not be cut into small
size.
61
63. • 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.
63
66. • The assembly consists of a set of volumetrically
calibrated solution containers made of glass 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 Sample holder 66
67. •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.
67
68. Advantages of the Beaker
Methods
The basket method is the most widely used
procedure which confines the solid dosage
form to a limited area which is essential for
better reproducibility.
It is advantageous for capsules as they tend
to float at the surface thus minimizing the
area exposed to the dissolution fluid.
69. Limitation of the Beaker Methods
Clogging of the basket screen by gummy particles.
Tendency of the light particles to float.
Sensitivity of the apparatus to variables such as
vibration, eccentricity, etc.
Rapid corrosion of the SS mesh in presence of
HCl.
Sensitivity of the apparatus to any slight changes
in the paddle orientation.
Non-reproducible position of the tablets at the
bottom of the flask.
70. 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
71.
72. 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.
73. 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.
74. 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 rugs and dosage form such as
ointments, creams and suspensions.
75.
76.
77. THE ROTATING FILTER METHOD
It consists of a magnetically driven rotating
filter assembly and a 12 mesh wire cloth
basket.
The sample is withdrawn through the
spinning filter for analysis.
78. ROTATING FLASK DISSOLUTION
METHOD
This consists of a spherical flask made of
glass and supported by a horizontal glass
shaft that is fused to its sides.
The shaft is connected to a constant
speed driving motor.
The flask is placed in a constant
temperature water bath and rotates about
its horizontal axis.
79. ROTATING AND STATIC DISK
METHODS
The compound is
compressed into non
disintegrating disc
Mounted – One surface
is exposed to medium
Assumption – Surface
area remains constant
Used to determine the
intrinsic dissolution rate
80. Types of dosage form Release method
Solid oral dosage forms(conventional) Basket,paddle,reciprocating cylinder,
or flow through cell
Oral suspension Paddle
Orally disintegrating tablets Paddle
Chewable tablets Basket,paddle,reciprocating cylinder
Transdermal-patches Paddle over disk
Suppositories Paddle, modified basket, or dual
chamber flow through cell
80
81. FACTORS AFFECTING DISSOLUTION
RATE4
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
81
82. FACTORS RELATED TO PHYSICOCHEMICAL PROPERTIES
OF DRUG
1) DRUG SOLUBILITY
• 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
82
83. 2 ) SALT FORMATION
• 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. 83
84. 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. 84
85. • 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
85
86. • 4) SOLID STATE CHARACTERISTICS
• 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.
86
87. • 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
87
88. 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
88
89. FACTORS RELATED TO DRUG
PRODUCT 1)DILUENTS
• 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
89
FACTORS RELATED TO DRUG
PRODUCT FORMULATION
90. 10 20 30 40 50
Time in min.
100
80
60
40
20
Amt of dissolved mg
10% starch
5% starch
The dissolution rate is not only affected by nature of the diluent but
also affected by excipient dilution (drug/excipient ratio).
90
91. 2)DISINTEGRANTS
• 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.
91
92. 3)BINDERS AND GRANULATING AGENTS
• 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.
92
93. • 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% gelatin whereas decrease in dissolution rate with 20% gelatin.
This was due to higher concentration which formed a thick film
around tablet.
• Water soluble granulating agent Plasdone gives faster dissolution
rate compared to gelatin.
93
94. 4) Lubricants
• 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.
94
95. 5)SURFACTANTS
• 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.
95
96. 6)WATER-SOLUBLE DYES
• 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
96
97. 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.
97
98. 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.
98
99. 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
99
100. 3) DRUG EXCIPIENT INTERACTION
• 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
• Similarly as increase in mixing time of formulation
containing 97 to 99% microcrystalline cellulose or
another slightly swelling disintegrant result in enhance
dissolution rate.
100
101. 4) STORAGE CONDITIONS
• 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.
101
102. 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.
102
103. 2) STIRRING ELEMENT ALIGNMENT
• 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%.
103
104. 3) SAMPLING PROBE POSITION & FILTER
• 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.
• Accumulation of the particulate matter on the surface
may cause significant error in the dissolution testing.
104
105. 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
105
106. 2) DISSOLUTION MEDIUM
• 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 leads to floating of powder which leads to
wetting and penetration problem.
• Dissolution media composition & PH
Addition of Na – sulfate decrease the dissolution rate.
Addition of urea increase dissolution rate.
106
107. • 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.
107
108. • In order to minimize the effect of conc. gradient and maintain sink
conditions, the conc. of drug should not exceed 10-15% of its maximum
Solubility in dissolution medium selected.
• However, some insoluble drug a 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
dissolution 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%).
108
111. DISSOLUTION ACCEPTANCE CRITRIA
STAGE No. of Dosage units
tested
Acceptance criteria
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
than Q-25%
112. Method for comparison of
dissolution profile
• 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
113. • 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 100 113
114. USP SGF (simulated gastric fluid)
NaCl 2.0 g
Purified pepsin 3.2 g
HCl 7.0 mL
Purified water qs. 1000 mL
Media has a pH of about 1.2
USP SIF (simulated intestinal fluid)
Monobasic potassium phosphate 6.8 g in Purified
water 250 mL
NaOH (0.2 N) 77 mL and Purified water 500 mL
Pancreatin 10.0 g
Adjust with either 0.2 N NaOH or 0.2 N HCl to a pH
of 6.8 ± 0.1.
Purified water qs. 1000 mL
115. Oral Drug Absorption
Gastric
Emptying
Transit Permeation
Dissolution
Metabolism
116. In Vivo and In Vitro Relationship:
Scientific Issues
• Limits to oral drug
absorption
– Dissolution-limited
– Solubility-limited
– Permeability-limited
Gastric
Emptying
Transit Permeation
Dissolution
Metabolism
SSoolluubbiilliittyy
Dissolution Permeation
Conc ³ Solubility
118. In vitro-in vivo correlation
• A predictive mathematical model
that describes the relationship
between an in-vitro property of a
dosage form and an in-vivo
response.
119. • Key goal in development of dosage form
and good understanding of in vitro and in
vivo performance of dosage form
• Formulation optimization requires altering
some parameters – bioavailability studies
• Regulatory guidance developed to
minimize the additional bioavailability
studies
120. 120
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.
121. Basic approaches
• By establishing a relationship usually
linear, between the in vitro dissolution and
in vivo bioavailability parameters.
• By using data from previous bioavailability
studies to modify the dissolution
methodology.
122. • In vitro – in vivo correlation can be achieved
using
Pharmacological correlation
Semi quantitative correlation
Quantitative correlation
123. In vitro-in vivo correlations
• Correlations based on the plasma level
data
• Correlations based on the urinary
excretion data
• Correlations based on the
pharmacological response
124. DEFINITION
• USP definition
“The establishment of rational relationship b/w a biological
property or a parameter derived from a biological
property produced by a dosage form and
physicochemical property of same dosage form”
• FDA definition
“It is predictive mathematical model describing the
relationship b/w in vitro property of dosage form and a
relevant in vivo response”
125. IMPORTANCE
• Serves as a surrogate of in vivo and assist in
supporting biowaivers
• Validates the use of dissolution methods and
specification
• Assist in QC during mfg and selecting the
appropriate formulation
126. IVIVC levels
• Level A:
– Point to point correlation is developed between in vitro
dissolution rate and the in vivo rate of absorption
• Level B:
– Utilises statistical moment analysis and the mean in vitro
dissolution time is compared to either the mean residence time
or the mean in vivo dissolution time
• Level C:
– single point correlation that relates one dissolution time point to
one pharmacokinetic parameter
Multiple level C
127. Level A correlation
• Highest category
correlation
• Represents point to
point relationship
• Developed by two
stage procedure
Deconvulation
Comparison
• Purpose – define
direct relationship
120
100
80
60
40
20
0
0 20 40 60 80 100 120
% Drug Dissolved
% Drug
Absorbed
128. Level B correlation
• Utilizes the principle of statistical moment
analysis
MDT vitro is compared with MRT vivo
• No point to point correlation
• Does not reflect the actual in vivo plasma level
curves
129. Level C correlation
• Dissolution time point (t 50%,t 90% ) is
compared to one mean pharmacokinetic
parameter ( Cmax ,tmax ,AUC)
• Single point correlation
• Weakest level of correlation as partial
relationship b/w absorption and dissolution
is established
• Useful in the early stages of formulation
development
130. Multiple level C correlation
• It reflects the relationship b/w one or several
pharmacokinetic parameter of interest and
amount of drug dissolved at several time point of
dissolution profile
• Base on
Early
Middle
Late stage
131. Applications
• Ensure batch to batch consistency
• Serve as a tool in the development of a
new dosage form with desired in-vivo
performance
• Assist in validating or setting dissolution
specifications
