1. DRUG DISSOLUTION
Presented by:
M.Bhavani
256213885012
M.Pharmacy(analysis)
1
GUIDED BY
Mrs. YASMEEN BEGUM
ASST PROFESSOR
(M.pharm)
MALLA REDDY COLLEGE OF
PHARMACY
Maisammaguda, Dhulapally (post via
Hakimpet),
Sec-bad-14

2. CONTENTS
• Definition
• Theories of Drug Dissolution
• Mechanism of dissolution
• Factors affecting Drug Dissolution
• Intrinsic dissolution rate and its factors
• In-vitro dissolution testing models
2

3. 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.
3

4. 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.
4

5. The rate of dissolution depends on:
• nature of the solvent and solute
• temperature (and to a small degree
pressure)
• degree of under saturation
• presence of mixing
• interfacial surface area
• presence of inhibitors (e.g., a substance
adsorbed on the surface).
5

6. 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.
6

7. 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.
7

8. 8

9. • 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
9

10. 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.
10

11. • 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.
11

12. • 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.
12

13. Dissolution rate under non-sink and
Conc. of dissolved drug
Time
sink conditions.
zero order dissolution
under sink condition
first order dissolution under
non-sink condition
13

14. • Hixon-Crowell’s cubic root law of
dissolution takes into account the particle
size decrease and change in surface area,
W0
1/3 – W1/3 = Kt
Where,
W0=original mass of the drug
W=mass of drug remaining to dissolve at
time t
Kt=dissolution rate constant. 14

15. 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.
15

16. 16

17. • 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
17

18. III. Interfacial barrier model/Double barrier or
Limited solvation theory
• Based on solvation mechanism, and it is function of
solubility rather than diffusion
• When considering dissolution of the crystal have
different interfacial barrier , given by the following
equation
• This model can be extended to both the diffusion layer
model and danckwert’s model
18
G = Ki (Cs - Cb)
Where,
G = dissolution rate per unit area,
Ki = effective interfacial transport constant.

19. Mechanism of dissolution
Dissolution test determines the cumulative
amount of drug that goes into solution as a
function of time
Steps involved
 liberation of the solute or drug from the
formulation matrix (disintegration)
 dissolution of the drug (solubilization of the
drug particles) in the liquid medium
The overall rate of dissolution depends on the
slower of these two steps

20. Mechanism of dissolution
First Step
Cohesive properties of the formulated solid dosage
form drug play a key role disintegration and erosion
semi- solid or liquid formulations, the dispersion of
lipids or partitioning of the drug from the lipid phase
is the key factor
If the first step of dissolution is rate-limiting, then
the rate of dissolution is considered to be
disintegration controlled

21. Mechanism of dissolution
Second Step
Solubilization of the drug particles depends
on the physicochemical properties of the
drug such as its chemical form (e.g., salt,
free acid, free base) and physical attributes

22. • Factors affecting Drug
Dissolution :-
1. Factors related to apparatus and test
parameters
2. Factors relating to the physicochemical
properties of drug.
3. Factors relating to the dosage forms.
22

23. A.FACTORS RELATED TO APPARATUS
AND TEST PARAMETERS
1.Temperature
2.Agitation
3.Dissolution medium,pH
23

24. B. Factors relating to the physicochemical
properties of drug-i.
Solubility-
• Solubility plays important role in controlling
dissolution from dosage form.
• From Noyes-Whitney equation it shows that
aqueous solubility of drug which determines its
dissolution rate.
24

25. 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. 25

26. • Effective surface area is directly related to the
dissolution rate.
• Greater the effective surface area, more intimate
the contact between the solid surface and the
aqueous solvent and faster the dissolution.
26

27. 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.
27

28. • 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
28

29. 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.
29

30. iv. Hydrates/solvates –
• The stoichiometric type of adducts where the
solvent molecules are incorporated in the crystal
lattice of the solid are called as the solvates.
• When the solvent in association with the drug is
water, the solvate is known as hydrate.
• The organic solvates have greater aqueous
solubility than the nonsolvates.
• E.g. – chloroform solvates of griseofulvin is more water
soluble than their nonsolvated forms
30

31. B. Factors relating to the dosage forms –
i. Pharmaceutical excipients –
 Vehicle
 Diluents
 Lubricants
 Binders
 Surfactants
 colorants
31

32. INTRINSIC DISSOLUTION RATE
The intrinsic dissolution rate is defined as
the dissolution rate of pure substances
under the condition of constant surface
area, agitation-stirring speed, pH and
ionic-strength of the dissolution medium.
32

33. • Dissolution is dependent on many factors,
both intrinsic and extrinsic.
• The definition of intrinsic dissolution rate,
IDR is the dissolution rate when extrinsic
factors are held constant for a pure
substance.
• Intrinsic factors are defined by the solid
state properties of the pure substance,
such as;
33

34. • Crystal habit
• Crystallinity
• Amorphism
• Polymorphism
• Pseudo-polymorphism
• Particle size and surface area
The above are predetermined factors which
are different for each substance.
34

35. IDR is the rate of dissolution of pure
substances when extrinsic factors as the
following are kept constant;
• Agitation
• Surface area of tablet or sample
• Temperature
• pH
• Buffer strength
• Viscosity of the dissolution medium
• Ionic strength of the dissolution medium
35

36. IN-VITRO DISSOLUTION
TESTING MODELS
36

37. NON SINK METHODS
• 1) NATURAL CONVECTION NONSINK METHODS
a) Klein solvmeter method
b) Nelson Hanging Pellet Method
c) Levy static Disk Method
• 2) FORCED CONVECTION NON SINK METHODS
a) Tumbling method
b) Levy Method Or Beaker Method
c) Rotating Disk Method
d) Particle Size Method
e) Oscillating Tube Method
f) USP Rotating Basket Apparatus
37

38. SINK METHODS
• 3) FORCED CONVECTION SINK DEVICES
a) Wurster Pollis adsorption method
b) Partition method
c) Dialysis method
d) Rotating disk apparatus
• 4) CONTINUOUS FLOW/FLOWTHROUGH METHODS
a) Pernarowski method
b) Langenbucher method
c) Baun and Walker
d) Tingstad and Reigelman
f) Modified column apparatus
g) Cakiryildiz method
h) Takenaka method
38

39. NATURAL CONVECTION NONSINK
METHOD:
• In this method the density difference is
utilized for replacing the surrounding
dissolution medium.
39

40. Klein solvmeter method:
• carrier device surrounded by float and is immersed in dissolution
medium.
• measuring bar connects float to the to the calibration scale above.
• when dosage form is placed in the boat the bar moves down and as
dosage form dissolves it moves upwards.
• Amount of the dosage from dissolved is revealed from the difference
in the height of the bar movement.
• Dosage form disintegrated cannot be evaluated and concentration
effects on dissolution rate and measuring system is not accountable.
40

41. Nelson Hanging Pellet Method:
• aluminum strip having provision for holding dosage form which is in
turn connected to a perfectly maintained balance arm of strip.
• the dosage form is mounted on the aluminum strip with the help of
wax. since only one part of the dosage form is exposed to the
dissolution, this method can be employed to know the intrinsic
dissolution rate.
• To prevent the disintegration further high pressures can be applied
and also constant surface area can be maintained by reducing
permeability of the compact.
41

42. Levy static Disk Method:
• Acrylic holder containing dosage form is inserted into a known
volume of medium (25ml) through rubber stopper.
• The vial is inverted and is placed in a incubator at 37 C. At specified
time intervals the vial is removed from the incubator and the samples
are analyzed.
• Intrinsic dissolution is possible if the dosage form is mounted on to
the acrylic holder such that only one face of it is exposed.
• disadvantages - effect of concentration on the dissolution medium is
ignored and the surface area of the dosage form while dissolving is
assumed constant which is not impractical.
42

43. FORCED CONVECTION NON SINK
METHODS:
• As the name indicates the devices are
agitated to induce relative motion between
dissolution medium and the dissolved
particles. Agitation is implemented by
stirring, rotation or oscillation.
43

44. Tumbling method:
• dosage form with the dissolution medium is placed in test
tube that is in turn clamped to the revolving drum which is
rotated at a speed of 6 to 12 rpm in a water bath at 37 0C.
• The test tubes are removed and the medium is assayed at
regular time points for the dissolved drug amount.
44
Test tube
dosage
Rotating
drum

45. Levy Method Or Beaker Method:
• 400ml beaker is placed in a constant temperature bath kept
at 37 C. A 5 centimeter three blade polyethylene stirrer is
centered and rotated at 59 rpm.
• The tablet is dropped at the side of the beaker and samples
are taken at specified time points for analysis.
• This method is amenable to measure intrinsic dissolution
rate.
45
stirrer
Thermoregulated
dissolution vessel
Wing blade stirrer
Dissolution medium
Dosage form

46. Rotating Disk Method:
• ideally suitable for measurement of the intrinsic dissolution rate with
those which maintain a constant surface area.
• The dosage forms which are prepared by hydraulic press are
mounted onto the Plexiglas holder that is in turn attached to metal
shaft which is stirred at a constant speed.
• This holder is immersed at a depth of 1 inch in a 500ml dissolution
medium that is maintained at 370C and rotated at 555rpm.
46
Thermoregulated
dissolution vessel
Rotating disk
Dissolution medium

47. Particle Size Method:
• primary purpose is to incorporate vigorous agitation so as to suspend
the dissolved particles.
• The changes in the particles size is measured with the help of coulter
counter. The particle size and the surface area
data together will enable to know the dissolution kinetics.
• but, practically chemical analysis outweigh the particle size analysis
and this method is not suitable for dosage forms.
47

48. Oscillating Tube Method:
• Broadbent et.al have employed BP (British pharmacopoeia)
disintegration apparatus for dissolution.
• The difference is that only one tablet is placed instead of five and
immersed in 200 ml of dissolution medium.
• advantage- both disintegration as well as dissolution can be observed
simultaneously.
• With the help of this device only total dissolution rate can be
determined because constant surface area cannot be maintained due
to the extreme agitation and abrasion caused by the mesh.
48
Other limitations.
•Increasing solute concentration
•lack of reproducibility
• intensity of agitation
• constancy of agitation

49. USP Rotating Basket Apparatus:
• The rotating basket of 10 mesh is placed at a
distance of 2.5 cm from the bottom of the vessel,
is centered within 2 mm of the centerline of the
vessel.
• The shaft is rotated at 100 rpm and temperature
of the medium is maintained at 37 C.
• Aliquots should preferably be withdrawn midway
between the surface of the medium and the
bottom of the vessel and midway the cylindrical
edge of the basket and wall of the vessel.
49

50. 50
Speed (25-150rpm)
Shaft
Centering or tilt
eccentricity
Sampling point
flask
basket
basket position

51. Magnetic basket dissolution apparatus:
• it enables reproducible and precise placement of the dosage form.
• It consists of a beaker (800 ml)and a magnetic basket of 50 mm
long and 11 mm inner diameter whose exact placement is ensured
by a magnetic bar placed outside the beaker at the bottom.
• The additional modifications include the basket is constructed of
epoxy resin that inert in both acidic and basic environment.
• the agitation is provided by a three bladed, blades of 18 mm
diameter set at an angle of 60 angle and 45 0 from the vertical shaft
of 7 mm, propeller with a diameter of 51mm.
• The dissolution container, of 600 ml of medium is in turn immersed
in a water bath so as to maintain the desired 37 c. propeller is
immersed at a depth of 41 mm of the beaker
• For the adjustment of the pH electrodes are placed at a depth of 27
mm from the vertical top and 7 mm from the horizontal beaker walls.
With all these the device can be used to characterize inter product
variation of products.
51

52. 52
Sampling port
stirrer
Magnetic basket
magnet

53. Modified USP Basket apparatus:
• It is known fact that the flow of the medium should be sufficient for
the dosage form such that the disintegrated particles during the
dissolution should be swept by the medium from the basket screen.
• in order to fulfill this, the effort done was to change the direction of
the basket by the angle of 90 0 by bending the stirring rod so as to
get L- shaped configuration.
• a cylindrical SS screen of 24-mesh was seam welded and fitted
over the Teflon holder so as to hold the tablet firmly.
• This device facilitates the increase in the dissolution rate because of
the enhanced flow of the medium.
• wandering of the dosage form within the basket is the major
disadvantage while the advantages include economically feasible
and simple construction, dual functionality i.e. both holding the
dosage form as well as stirring of the holder.
53

54. 54
Dissolution
vessel
USP basket

55. Rotating Filter-Stationary Basket Apparatus:
• This device consists of stationary basket, a fluid
container and filter assembly with an external magnetic
stirrer.
• the dissolution medium is contained in a fluid container
of 1.5 l volume capacity.
• There are a total of 4 ports: For sample, for glass tube to
favor the withdrawal of the aliquots, another for
replacement of the fresh medium and other for
thermometer to check the temperature.
• the basket is of 12 mesh which is kept stationary held at
2 to 5 cm from the bottom of the fluid container. the
dosage form is placed in the filter providing different
intensities of agitation.
55

56. 56
Sampling port
thermometer
Rotating
Stationary filter
basket

57. USP Paddle method:
It is also called USP apparatus-2, the paddle should be centered
within 0.2 cm of the centerline of the vessel, 2.5 + 0.2 cm from the
bottom of the vessel.
• the shaft should rotate at a speed of 100 rpm with a temperature of
about 37 0 C. the dosage form should experience some movement
under the paddle till disintegration progresses.
• once disintegration occurs, aliquots should be drawn preferably from
midway upper edge of the paddle and the surface of the medium
between the wall of the vessel and stirrer shaft.
• the lower portion of vessel should be hemispherical and uniform in
all aspects of weight, inside diameter and curvature.
• In case of floating dosage forms stainless steel or glass helix is
attached to the dosage form. in this case excess abrasion and wear
of the dosage forms due to the friction from the inner surfaces is
observed, affecting the micro environment adversely.
57

58. 58
Speed 25-150rpm
shaft
Centering or tilt
eccentricity
Sampling point
flask
paddle
Paddle position
Stainless or glass helix

59. • Forced Convection Sink Devices:
An ideal dissolution process is one which will mimic the invivo
conditions by maintaining perfect sink conditions. these perfect sink
conditions can be maintained by either of the following systems:
a) Fixed fluid volume.
b) Multiple phase
c) Continuous fluid flow
• a) Fixed fluid volume: in this system the fluid volume is kept fixed
such that the volume is sufficient to maintain the drug concentration
below 10-20% of its solubility. fro example USP apparatus I and II.
b) Multiple phase: upon dissolution, the drug is either partitioned into
water immiscible phase or adsorbed onto the solid interface.
c) Continuous fluid flow: this system helps to know the solubility
irrespective of its solubility or dosage strength. the dissolved drug
along with the medium is removed constantly and is replaced by
fresh medium.
59

60. Wurster-Polli Adsorption Method:
• in this method the dissolved drug is
adsorbed by charcoal or bentonite.
• care should be taken regarding the
adsorbent, adsorbent should not alter the
viscosity of the medium
60

61. Partition Method:
• In this device organic phase is employed to
remove the dissolved drug such that the drug
would partition between the lipophilic and
hydrophilic phases.
• selection of organic phase plays a critical role.
61

62. Dialysis Method:
• In this method dialysis membrane having
minimal equilibrium time, adequate physical
strength and solid particle retention is employed.
• in this device dissolution medium is placed on
one side of the membrane and the next side is
dosage form and the assembly is rotated at 15
rpm speed.
• aliquots are withdrawn at the distal end.
• the advanced method included baffled rotating
round bottomed flask at 37 0C such that sloshing
action is provided.
62

63. 63

64. Rotating Flask apparatus:
• In this method a flask containing dissolution medium is rotated around
its horizontal axis in a water bath kept at a temperature of 37 C.
• The flask has a provision of sampling such that aliquots can be
withdrawn and the fresh medium can be replaced back.
• This apparatus is best suited for oral solid dosage forms like tablets and
capsules since they do not require much agitation.
64

65. Flow Through Devices:
• For the drugs which saturate rapidly in
large volumes of medium, USP apparatus
will not serve the purpose.
• For this the suitable device is flow through
device. In this device unlimited quantity of
fresh dissolution is available.
• A dosage form is placed in a small cell
and is subjected to a stream of fresh
dissolution media.
65

66. Continuous Flow Apparatus by Pernarowski et.al.-
• It consists of 10 mesh stainless steel basket stirrer assembly with an
adjustable stirrer.
• the chamber is 3 necked flask of 33 mm and the rest two of 20 mm
diameter.
• 1L of medium is employed within the flask. the dissolution characteristics
are dependent upon the amount of medium pumped through the
dissolution chamber.
66
Type 1 fluid
Type 2 fluid
Two way stopper
Glass tube
Stirring shaft
Suction to
sampling
basket

67. Langenbucher Column-type flow through Method:
• This device is according to the dissolution basic
design .
• The screen is constructed such that the medium
flows equally through the entire cross section in a
laminar pattern.
• This is again closed by a secondary screen, filter
which prevents the undissolved drug from being
eluted.
67

68. 68
(b)
(c)
(a) B-particle bed, C-cell, F1&F2-screens, H-heat exchanger, h-height of
the cell, P1,P2-volumetric pumps, R-liquid reservoir, x-circulatory factor,
Q,xQ,(1-x)Q=volumetric flow rates,
(b) And (c) =designs of flow through cells

69. Continuous Flow apparatus by Baun and walker:
• Also called as constant- circulation apparatus.
• This consists of a cell, holding dosage form, a reservoir
with dissolution medium, a pump and water bath.
• there is a constant circulation apparatus that can be
altered depending upon the dosage form.
69
Oscillating
pump
Dissolution cell reservoir
Water bath

70. Continuous flow apparatus by Tingstad and Riegelman:
• a cylindrical glass cell of 6.1 cm long and 1.9 cm in diameter constructed
with two glass filter funnels is used.
• The dissolution cell has filter membranes which prevents the solid
particles from being analyzed.
• There are also external valves to control the excess flow of solvent into
the system. the air trap averts air bubbles.
• The complete assembly is immersed in a temperature bath kept at 37 C.
70

71. Flow-Through Modified Column apparatus:
• The device consists of filter of 14 M -size made of nylon.
• the tubing from the pump is connected to the dissolution cell.
• the Teflon faced stainless steel supports the screen resting on the
bottom half of the filter holder.
• The direction of the flow is such that the particles do not fall through the
screen. the rest of the process is the same.
71

72. Continuous flow apparatus by Takenaka et.al.:
• The release of drug is measured with the aid of in vitro
simulator device consisting of flow type dissolution
container.
• The dosage form is placed in the basket rotating at 94
rpm with 300 ml of medium.
• then the medium is removed by collecting reservior using
peristaltic pump.
• aliquots are withdrawn using syringe and then filtered
using Whatman filter paper and the same volume is
replaced immediately with fresh medium.
72

73. 73

74. 74