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AS A TOOL IN
PHARMACEUTICS
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 liquidphase.
• Dissolution is the rate determining step
for hydrophobic, poorly aqueous soluble
drugs.
E.g. Griseofulvin, spironolactone
Mechanism of Dissolution
1. Diffusion layer model
2. Danckwert’s model
3. Interfacial
barriermodel
1.Diffusion
LayerModel
• Also called ‘film theory’.
• Formation of a thin film at the interface, called
as stagnant layer.
• 2 steps are involved:
1) Interaction of solvent with drug surface toform
a saturated drug layer , called stagnant
layer.
2) Diffusion of drug molecules from
stagnantlayer into bulk of the system.
Diagram Representing Diffusion through the
StagnantLayer
Noyes- Whitney’s
equation:
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
Modified Noyes-Whitney’s
equation
3.Danckwert’s model/Penetration or surface renewal
Theory
The Diffusion layer model and the Dankwert’s model were based
on two assumptions:
1)The rate determining step that controls dissolution is the
mass transport.
2) Solid solution equilibrium is achieved at the solid/liquid
interface.
According to interfacial barrier model, an intermediate conc. can
exist at the interface as a result of solvation mechanism and is
a function of solubility rather than diffusion.
When considering the dissolution of the crystal will have a
different interfacial barrier given by following equation,
G = ki (Cs – Cb)
Where ,
G = dissolution per unit area
Ki = effective interfacial transport constant
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.
FACTORS INFLUENCING DISSOLUTION
AND DISSOLUTION STUDIES
1. Physicochemical Properties of Drug
1) DRUG SOLUBILITY
Solubility of drug plays a prime role in controlling its dissolution
from dosage form.
Minimum aqueous solubility of 1% is required to avoid
potential solubility limited absorption problems.
2) 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.
3)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 Pencillin- G, sulfa
drugs, phenytoin, barbiturates etc.
6) ADSORBENTS:
The concurrent administration of drugs and medicinal products
containing solids adsorbents (eg:antidiarrhoeal mixtures) may
result in the adsorbents interfering with the absorption of such
7)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.
8)CO-PRECIPITATION:
Dissolution rate of sulfathiazole could be significantly
increased by co-precipitating the drug with povidone.
9)COMPLEXATION:
Complexation of a drug in GIT fluids may alter the rate and
the extent of absorption.eg: streptomycin, tetracyclines.
Eg:Diakylamides -prednisone
2.FACTORS RELATED TO THE APPARATUS
Size and shape:
Stirring device:
Vibrations:
Alignment of the stirring elements:
Temperature
Disadvantages
Basket screen is clogged
with gummy particles.
Hydrodynamic „dead zone“
under the basket
Degassing is particularly
important
Mesh gets corroded by HCl
solution.
APPARATUS-2 (PADDLE)
DESIGN:
Vessel: -Same as basket apparatus
Shaft: -The blade passes through the shaft so that the bottom of
the blade fuses with bottom of the shaft.
Stirring elements: -Made of tefflon
For laboratory purpose
-Stainless steel 316
Water-bath: -Maintains at 37±0.5°C
Sinkers : -Platinum wire used to prevent
tablet/capsule from floating
METHOD
It consists of a special coated paddle formed from a blade and
a shaft that minimizes turbulence due to stirring.
The coated material is inert.
The paddle is attached vertically to a variable -speed motor
that rotates at a controlled speed.
The tablet or capsule is placed into a round-bottom dissolution
flask and the apparatus is housed in a constant temperature
water bath maintained at 37°C.
Most common operating speeds are 50rpm for solid oral
dosage forms and 25 rpm for suspensions.
A sinker ,such as few turns of platinum wire may be used
to prevent a capsule or tablet from floating
Used for film coated tablets that stick to the vessel walls or
to help to position tablet/capsule under the paddle.
Advantages
Easy to use
Robust
pH change
possible
Can be easily automated which is important
Disadvantages
Small volume (max.
250 ml)
Little experience
Limited data
APPARATUS-4 (FLOW THROUGH CELL)
DESIGN:
Reservoir : -For dissolution medium
Pump : -Forces dissolution medium through cell
-Holding a sample
-Flow rate 10-100ml/min
-Laminar flow is maintained
-Peristaltic/centrifugal pumps are not recommended
Water bath:- Maintain at 37±0.5°C
USE:
Low solubility drugs ,micro particulates ,implants, suppositories
controlled release formulations
METHOD(Flow through cell):
The flow through cell is transparent & inert mounted
vertically with filters.
Standard cell diameters are 12 & 22.6 mm.
The bottom cone usually filled with glass beads of 1
mm diameter.
Tablet holder used for positioning special dosage form
e.g. inlay
tablets.
Place the glass beads into the cell as specified in the
monograph.
Place one dosage unit on top of the beads or on a wire
carrier.
Assemble the filter head and fix the parts together by
means of a
suitable clamping device.
Introduce by the pump of the dissolution medium warmed to
Advantages
easy to change media pH
pH-profile possible
Sink conditions maintained.
different modes
a) open system
b) closed system
Disadvantages
Deaeration necessary
high volumes of media
labor intensive
Cell types:
Agitation :-Reciprocation
-Reciprocating frequency 30
cycle/sec
Water-bath:-Maintain at 32±0.5°C
USE:
Transdermal patches
METHOD(Reciprocating disk):
The assembly consists of a set of volumetrically calibrated solution
containers made of glass or suitable inert material, a motor , a drive
assembly used to reciprocate the system vertically.
The samples are placed on the disk shaped holders using cuprophan
supports
The test is carried out at 32°C.
The reciprocating frequency is 30cycles/min.
Advantages:-Convenient method for selecting the volume of the
medium.
-sink conditions can be maintained.
-more sensitivity
Disadvantages: -Investment is high because the design is totally
different from standard equipment already available in industry.
UNOFFICIAL
METHODS
1.ROTATING/STATIC DISK METHOD
Developed by late Eino nelson and described by Levy and Sahli.
In this method ,the drug is compressed in a non-disintegrating
disc without excipients.
The disc is mounted in a holder so that only one face of the disc
is exposed to the dissolution medium.
The holder and disc are immersed in medium and held in a
fixed position as in static disc method and rotated at a given
speed in rotating disc method.
Samples are collected at predetermined times.
Surface area of the drug through which dissolution
occurs is kept constant –intrinsic dissolution rate.
2.BEAKER METHOD:
Reported by Levy and Hayes(1960).
Dissolution medium, 250ml of 0.1N HCl at 37°C placed
in a 400ml beaker.
Agitation by three blade polyethylene stirrer,5cm diameter
and rotates at 60 rpm.
Stirrer immersed to a depth of 2.7 cm in medium and in the
center.
Tablets are placed in a beaker and test was carried out.
Samples are removed and assayed for the content.
3. MECHANISM
7. APPLICATIONS
8. REFERENCES
2
INTRODUCTION
DEFINITION:
Diffusion:
“The movement of particles in a solid from an area of
high concentration to an area of low
concentration, resulting in the uniform distribution
of the substance.”
high low
concentration concentration
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3
INTRODUCTION
C1 C1
Fick’s first law of diffusion
C2
C2 dC
J D dx
x1 x2
6 x D = diffusion coefficient
STEADY- STATE DIFFUSION
dC
J D dx
Where, J is equal to rate of mass transfer across unit
surface area of barrier.
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STEADY-STATE DIFFUSION
SINK CONDITION:
State in which concentration in receptor compartment is
maintained at lower level compaired to its
concentration in donor compartment.
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STEADY-STATE DIFFUSION
Fick´s 1st law:
Mass get transported from 1 compartment to another
over period of time is Flux.
Flux (J) = Rate of mass transfer across unit surface area
of barrier.
J= 1/S (dm/dt) 1)
Where,
dm = change in mass of material.
S = barrier surface area.
dt = change in time.
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STEADY-STATE DIFFUSION
Acc.to Fick‘s law,flux is directly proportional
to conc.gradient.
dC 2)
J D dx
Mechanisms:
Gases & Liquids – random (Brownian) motion.
I. Vacancy diffusion:
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MECHANISM
• atoms exchange with vacancies .
rate depends on:
-- number of vacancies
-- activation energy to exchange.
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Factors that Influence Diffusion
II. Temperature:
Very strong effect on the diffusion coefficient:
D = diffusion
coefficient Do = pre-
exponential
Qd = activation energy
R = gas constant 74
DIFFUSION ACROSS MEMBRANE
75
DIFFUSION ACROSS MEMBRANE
77
DIFFUSION ACROSS MEMBRANE
Active Transport :
Active transport is the energy-demanding transfer of a substance
across a cell membrane against its concentration gradient, i.e.,
from lower concentration to higher concentration.
Special proteins within the cell membrane act as specific protein
‘carriers’. The energy for active transport comes from ATP.
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DIFFUSION ACROSS
MEMBRANE
Passive Transport:
• Passive diffusion is the process by which
molecules spontaneously diffuse from a
region of higher concentration to a
region of lower concentration.
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METHODS & PROCEDURES
Two types:
A) horizontal transport cell:
a. wurester cell
b. Viles chein permeation cell
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Horizontal Transport Cell
wurester cell:
Receptor and donor compartment
made of pyrex glass material.
Animal or human skin acts as
semi permeable cell and barrier
may be supported on a perforated
plate.
Drug sample solution taken in
donor compartment and solvent in
the receptor compartment.
Whole set up placed in constant
temperature bath to maintain the
temp of 37±0.2°C.
The liquid in receptor stirred by
using magnetic beads to obtain
uniform distribution.
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VERTICAL TRANSPORT CELL
Aquair and weiner diffusion cell:
Receptor and donor compartment
made of pyrex glass or plastic
material.
Animal or human skin acts as semi
permeable cell and barrier may be
supported on a perforated plate.
Drug sample solution taken in upper
compartment and solvent in the
lower compartment.
Whole set up placed in constant
temperature bath to maintain the
temp of 37±0.2°C.
The liquid in receptor stirred by
using magnetic beads to obtain
uniform distribution.
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APPLICATIONS
83
REFERENCES
3. www.google.com
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REFERENCES
Aulton M.E. Pharmaceutics “The Science of
Dosage Form Design”, 2nd Ed.; Churchill
Livingstone.
D.M.Brahmankar “Biopharmaceutics and
Pharmacokinetics a
Treatise”
Venkateshwarlu “Biopharmaceutics and Pharmaceutics”,
2nd Ed.
Leon Shargel “Applied Biopharmaceutics and
Pharmacokinetics”,5th Edition.
The Science And Practice of Pharmacy by REMINGTON ,
21 st Edition
C.V.S.Subrahmanyam “Biopharmaceutics and pharmacokinetics”,
-concepts and applications.
http://wiki.answers.com/ http://en.wikipedia.org
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you!!!