Diffusion and Dissolution

By: Tsegaye N. (B. Pharm., MSc)

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Objectives
 At the end of this chapter you have to
 Describe the difference between diffusion, osmosis and dialysis
 Different factors that affect diffusion rate.
 Fick’s Laws of Diffusion (steady state, diffusion through a membrane)
 Clinical Applications of Diffusion
 Dissolution of particles (Noyes-Whitney Equation of dissolution and
 Intrinsic dissolution rate
 Explain about sink, burst and lag time
 Hixon-crowell equation
 In-vitro dissolution studies

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Introduction

 Diffusion can be defined as a process by which molecules transfer spontaneously

from a region of higher concentration to a region of lower concentration.
 Is a result of random molecular motion
 Diffusion governs the transport of the great majority of drugs across various
biological barriers after administration.
 The theory of diffusion has been used:
 In investigating the mechanism of drug transport
 Applied to the design and development of various controlled or sustained release

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Diffusion…
 The molecules that migrate from one location to another are termed as diffusants,
permeants or penetrants
 The medium in which the diffusant migrates is called the diffusional barrier.
 The concentration gradient is the concentration profile of the diffusant in the
diffusional barrier.
 The concentration gradient is the driving force for diffusion.
 Diffusion of a drug across a biologic membrane is required for a drug
To be absorbed into and eliminated from the body, and
To get to the site of action within a particular cell

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Drug transport system
 Various nutrients (like Carbohydrates, Amino acids, Vitamins) and drugs are
transported and absorbed into the blood by various mechanisms:-
 Passive transport
 Passive diffusion
 Carrier mediated transport
 Facilitated transport
 Active transport
 Vesicular transport

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Drug transport….
Passive Diffusion can be defined as a process by which molecules transfer
spontaneously from a region of higher conc. to a region of lower conc.

 The number of molecules that diffuse through a

unit area of the diffusional barrier in a given time
is termed as flux, J.
 Flux is a measure of the rate of molecular
diffusion
 Diffusion follows Fick’s law
 Rate of diffusion is directly proportional to the
Fig. 1 Schematic representation of a concentration gradient across the membrane
diffusion system

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Factors that influence diffusion rates

 Distance  Steepness of concentrated gradient

 The shorter the distance, the more  The larger the gradient, the faster
quickly gradients are eliminated diffusion proceeds
 Molecular Size  Membrane surface area and
 Ions and small molecules diffuse more thickness
rapidly  The larger the area, the faster diffusion
 Temperature proceed
 Diffusion coefficient of the drug
Temp. ------ Motion of particles
 Related with lipid solubility and MWt

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Solute transport…
Certain characteristic of passive diffusion: -
 Down hill transport
 Greater the surface area & lesser the thickness of the membrane, faster the diffusion
 Equilibrium is attained when the concentration on either side of the membrane become
equal
 Greater the membrane/water partition coefficient of drug, faster the diffusion
 Passive diffusion process is energy independent
 Drugs with mol. Wt. b/n 100 to 400 Daltons can be effectively absorbed passively by
diffusion

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Solute transport…

Dialysis
 Movement of a solute through a selectively permeable membrane .
 The size of the minute pores in the dialysis tubing determines which substances can
pass through the membrane

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Carrier mediated transport mechanism
 Involves a carrier which binds reversibly with the solute molecules to be
transported to yield the carrier solute complex
 Which transverses across the membrane to the other side where it dissociates to yield the
solute molecule
 The carrier then returns to its original site to accept a fresh molecule of solute.

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Facilitated transport…

 This mechanism involves the driving force as concentration gradient

 In this system, no expenditure of energy is involved (down-hill transport)
 Limited importance in the absorption of drugs.
 E.g. Such a transport system include entry of glucose into RBCs & intestinal absorption
of vitamins B1& B2.
 A classical example of passive facilitated diffusion is the gastro-intestinal
absorption of vitamin B12.

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Active transport
 The driving force is against the concentration gradient or uphill transport.
 Since the process is uphill, energy is required
 As the process requires expenditure of energy
 Endogenous substances that are transported actively include sodium, potassium,
calcium, iron, glucose, amino acids and vitamins like niacin, pyridoxine.
 Drugs having structural similarity to such agents are absorbed actively
 E.g. Pyrimidine transport system --absorption of 5 FU
 L-amino acid transport system --absorption of methyldopa and levodopa

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Solvent transport
 Osmosis: Movement of solvent (water) across a selectively permeable membrane
 Down its concentration gradient
 Towards the solution containing the higher solute concentration (hypertonic area).
 This solution has a lower water concentration
 Continues until water concentrations and solute concentrations are the same on either
side of the membrane

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Fick’s law of diffusion
 Fick’s law of diffusion govern diffusion processes in pharmaceutical systems
 A proportional relationship between the flux and the concentration gradient.
Fick’s first law
 Fick’s first law states that the rate of diffusion of solute molecule through a barrier
or flux is proportional to the concentration gradient

 Fick described diffusion of molecules in quantitative terms

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Fick’s law of diffusion
 The flux, in turn, is proportional to the conc., dC/dx:
dC
J  D
dx
 The unit of J is g/ cm2 sec and is positive quantity
 D-diffusion coefficient (the diffusant) (cm2/sec)
 C-concentration in g/cm3
 X- distance in cm of movement perpendicular to the surface of the barrier
 Mass (gram or moles) , S (cm2), time (sec)

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Fick’s law of diffusion…
Fick’s second law
 Concentration of diffusant in the diffusional barrier varies with time or
 In situations where the concentration profile and concentration gradient are
changing over time.
 An equation for mass transport that emphasizes the change in concentration with
time at a definite location rather than the mass diffusing across a unit area of
barrier in unit time is known as Fick's second law.

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Fick’s law of diffusion…
 The concentration of diffusant in the volume element changes with time, that is,
ΔC/Δt, as the flux or amount diffusing changes with distance, ΔJ/ΔX, in the X
direction dC dJ dC
 J  D
dt dx dx
 Differentiating the first law equation, gives;

 Change in concentration of diffusant with time at any distance

Summary,
 Fick’s first law relates to a steady-state flow, whereas
 Fick second law relates to a change in concentration of drug with time, at any
distance, or an unsteady state of flow
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 Steady state and non-steady state diffusion

 Any system is said to be at steady state, if the condition do not vary with time
(constant)
 When the amount of diffusant enter and leave the given space at the same rate, the
concentration of the diffusant in the given volume is a constant and independent
of time.
 The diffusion process that meets this condition is considered a steady state diffusion
 The concentration gradient is a constant for diffusion at the steady state
 Gives a constant flux

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Steady state and non-steady ….
 Non-steady state diffusion refers to a diffusion process in which the
concentration of diffusant in a given space is a function of time or the
concentration of diffusant in the diffusional barrier varies with time.
 In this case Fick’s 2nd law is used to study the diffusion process.
 Mathematically, this condition can be described as

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Steady state and non-steady ….

 The solution in the receptor compartment is constantly removed and replaced with
fresh solvent to keep the concentration at low level .
 This is know as “ Sink condition” .
 The donor compartment is source and receptor compartment is sink.
 E.g. when transdermal patch is applied to the skin, the conc. in the skin at any
time will be very low compared with the conc. in the patch
 B/c the drug in the skin is absorbed to blood stream, distributed to the site action and
eliminated from the body

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Steady state and non-steady ….

 When Conc. of drug in the receptor compartment is approx. equal zero, this state
is defined as sink condition
 Occur when the rate of exit of the drug from donor compartment is much greater than
the rate of entry to the receptor compartment.
 The concentration of drug in the membrane can be calculated using the partition
coefficient (K) and the concentration in the donor and receptor compartments.
 where
 C1 and Cd are the concentrations in the donor compartment (g/cm3) and C2 and Cr are
the concentrations in the receptor compartment (g/cm3).
 K is the partition coefficient of the drug between the solution and the membrane

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 We can then write as
dM/dt = [DSK(Cd − Cr)]/h
 Or in sink conditions,

 The permeability coefficient (centimeters per second) can be obtained by

rearranging to:
P = DK /h

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Example 1
1. A drug passing through a 1-mm-thick membrane has a diffusion coefficient of 4.23 ×
10−7 cm2 per second and an oil–water partition coefficient of 2.03. The radius of the
area exposed to the solution is 2 cm, and the concentration of the drug in the donor
compartment is 0.5 mg/ml. Calculate the permeability and the diffusion rate of the
drug?.
Given D=4.23 × 10−7 cm2/s, K=2.03, Cd=0.5 mg/ml, h=1mm=0.1cm, A=4ℿcm2
A. P=D*K/h
B. Dc/dt=J=P*(Cd-Cr)*A
2. Succinic acid (0.15 g) dissolved in 100 ml of ether was shaken with 10 ml of water at
37ºC. After equilibrium was achieved, the water layer contained 0.067 g of succinic
acid. What is the partition coefficient (K) of succinic acid?

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Dissolution

 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.
 Dissolution is the rate determining step in the bioabsorption of hydrophobic,
poorly aqueous soluble drugs.
 E.g. Griseofulvin, spironolactone…

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Dissolution

 When a solid dosage form such as a tablet is introduced into water, the drug
contained in the tablet begins to pass into solution.
 Simultaneously, the solid matrix of the tablet disintegrate in to granules and these
granules in turn deaggregate into fine particles
 Dissolution of the drug takes place from tablet, the disintegrated granules and
from the fine particles.

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Dissolution

Fig.-Disintegration, deaggregation, and dissolution stages as a drug leaves a tablet or granular

matrix.

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Dissolution …
 The rate of dissolution is determined by the rate of the slower step
Therefore, diffusion of dissolved solute across the static boundary layer of liquid that
exists at a solid-liquid interface is the rate limiting step.

Theories of Dissolution/mechanism
1. Diffusion layer model/Film Theory
2. Danckwert’s model/Penetration or surface renewal Theory
3. Interfacial barrier model/Double barrier or Limited solvation theory.

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Diffusion layer model

 Also called ‘film theory’.

 Formation of a thin film at the interface of solid and liquid, called as stagnant
layer.
 It involves two steps :-
I. Interaction of solvent with drug surface to form a saturated drug layer, called
stagnant layer.
II. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution.

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Diffusion layer model…..

Fig: Dissolution of a drug from a solid matrix,

Fig: Diffusion layer model for drug dissolution showing the stagnant diffusion layer between the
dosage form surface and the bulk solution
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Diffusion layer model…..

 The rate of dissolution is given by  Modified Noyes and Whitney equation:

Noyes and Whitney:
Where,
D = diffusion coefficient of drug.
Where, A = surface area of dissolving solid.
dc/dt= dissolution rate of the drug Kw/o = water/oil partition coefficient of drug.
K= dissolution rate constant V = volume of dissolution medium.
Cs= concentration of drug in stagnant layer h = thickness of stagnant layer.

Cb= concentration of drug in the bulk of (Cs – Cb)= conc. gradient for diffusion of
the solution at time t drug

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Diffusion layer model…..

 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.
 Under sink conditions, if the volume and surface area of the solid are kept
constant, then

 This represents that the dissolution rate is constant under sink conditions and
follows zero order kinetics.

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Diffusion layer model…..
 Dissolution rate under non-sink and sink conditions

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 Danckwert’s model

 Danckwert did not approve of the existence of a stagnant layer and suggested
that turbulence in the dissolution medium exists at the solid/liquid interface.
 Danckwert 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.
 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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Danckwert’s model

 The Danckwert’s model is expressed

by equation

Where,
m = mass of solid dissolved
γ = rate of surface renewal (interfacial tension)

Fig: Danckwert’s model for drug dissolution

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Interfacial barrier model
 The Diffusion layer model and the Danckwert’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 this model, intermediate concentration exist at the interface as a
result of solvation mechanism and function of solubility rather than diffusion.
 The concept of this theory is explained by the following equation-
G = Ki (Cs - Cb)
Where, G = dissolution rate per unit area,
Ki = effective interfacial transport constant.

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Factors affecting Dissolution

 Dissolution rate is governed by

 Physicochemical properties of API

 Formulation factors

 Physiologic factors

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Factors affecting Dissolution…
Physicochemical properties of API

I. Ionized vs unionized form

 Drug dissolution occur much faster with salt forms.
 Dissolution rate of weak acids and weak bases can be enhance by converting them
into their salt form.
 In some cases, however the conc. of counter ion in the medium affects the
dissolution of drug salts
 The ionization state of the drug is dependent on pH of the environment where
dissolution is expected to occur
 Weak acid – basic environment
 Weak base – acidic environment
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Factors affecting Dissolution…

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:
1. Absolute surface area which is the total surface area of any particle.
2. Effective surface area which is the area of solid surface exposed to the
dissolution medium.
 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.

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Factors affecting Dissolution…
3. Crystal state
 Crystal states tends to dissolve more slowly in water than do the amorphous forms
 Chloramphenicol, corticosteroids and many other drugs can under go changes in
the crystal structure when in suspension or saturated solution
Polymorphic transition can lead to slow dissolving of a drug by changing from faster
dissolving crystal to a slower form
E.g. β crystals of chloraphenicol are more soluble in water than those of the α form
 Anhydrous form of the drugs dissolves faster than crystal form
E.g. Ampicillin trihydrate

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Factors affecting Dissolution…
4. Drug complexes
 Inclusion complexes of hydrophobic drugs in modified cyclodextrins increase the
dissolution rate by increasing solubility in water
 Other polymers materials also can affect the rate of dissolution of hydrophobic
drugs
 E.g. Poly(ethylene glycol) and poly (N-Vinylpyrrolidone)

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Factors affecting Dissolution…
II. Formulation factors
 Solid dosage form
 For tablet dissolution is dependent on disintegration and deaggregation to form
fine particles
Tablets disintegration is affected by addition of binding agent during wet granulation
 In some instance polymeric binder such as poly(N-vinylpyrrolidone) and NaCMC
can increase the rate of dissolution of hydrophobic drugs

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Factors affecting Dissolution…
 Some diluents (e.g. starch and lactose) can increase the dissolution rate of
hydrophobic drugs in SDF
 Due to increase in effective surface area available for dissolution
 Lubricants (e.g. stearic acid and magnesium stearate) decrease the dissolution
rate of the drug
 By increasing a hydrophobic layer in the particles that impedes the interfacial
interactions with the aqueous medium

 Compression forces affects the disintegration as well as dissolution process

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Factors affecting Dissolution…

Suspension and emulsions

 Several important factors influences the dissolution of the drugs from the
suspension
 Settling, aggregation and change in the crystal structure up on agitating of the
suspension
 Decrease in the effective particle size up on settling and aggregation will decrease the
dissolution rate

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Factors affecting Dissolution…

 Drug dissolution from O/W emulsion is affected by partitioning from oil into the
aqueous phase and subsequently in to the dissolution medium
 Viscosity of suspensions and emulsion also can affect the dissolution of the drugs
 Semisolid dosage form
 The dissolution characteristics of the drug in semisolid DF are dependent on the
type of base used

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Factors affecting Dissolution…
III. Physiological factors
 Gastric emptying time and intestinal transit time
 GET-time taken for material to pass through the stomach
 Varies from 5 min to 12hr
 Dependent on the type of materials and presence and absence of food in the stomach
 GET has marked effect on the dissolution properties of solid DFs
 Small intestinal transit time : time taken for material to pass through the small
intestine
 SITT also affects the dissolution
 SITT is around 3hr
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Factors affecting Dissolution…
Variability of pH
 pH difference along GIT affects dissolutions
 pH in stomach varies from 1 to 3.5
 In the intestine pH varies from 5.5 to 7
 Weakly basic drugs ionize in the stomach
 Fast dissolution
 Weakly acidic drugs ionize at high pH (intestine)
 Fast dissolution

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Factors affecting Dissolution…
Factors relating dissolution apparatus and test parameters
 Thickness of boundary layer
 Degree of agitation
 Shape, size & position of stirrer
 Volume of dissolution medium
 Shape & size of container
 Viscosity of dissolution medium
 Temperature

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In-vitro dissolution testing methods
 Alternative to in vivo bioavailability determination
 The most widely used apparatus for dissolution study are rotating Basket and
paddle type dissolution apparatus
 Rotating Basket Apparatus (Apparatus 1)
 Consists of a 40 mesh stainless steel basket attached to the end of a stirring shaft
which in turn is attached to a variable speed motor
 A tablet or a capsule is placed within the basket and immersed in the dissolution
fluid contained in a cylindrical glass vessel with hemispherical bottom of one liter
capacity which partially immersed in a water bath

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In-vitro dissolution testing methods…

 The basket is located centrally in the vessel at a distance of 2cm from the bottom
and rotated by a variable speed motor through a shaft.
 The dissolution fluid is water, buffer solution or dilute acid simulating GI pH and
maintained at 37oc
 Samples are withdrawn at different times for analysis
 The volume the dissolution medium is maintained constant by replacing the
amount removed with fresh dissolution fluid

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In-vitro dissolution testing methods…
 All metal parts like basket and shaft are made of stainless steel.

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In-vitro dissolution testing methods…
Rotating Paddle Apparatus (Apparatus 2)
 Here, basket is replaced with a paddle.
 The position and alignment of the paddle are specified in the official books.
 During the operation, the tablet is dropped in the dissolution fluid

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In-vitro dissolution testing methods…

 Other dissolution testing apparatus

 Reciprocating cylinder (apparatus 3)
 Flow through cell (apparatus 4)
 Paddle over disk (apparatus 5)
 Rotating cylinder (apparatus 6)
 Reciprocating holder (apparatus 7)

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Application of Dissolution

1. Product Development
 Important tool during development of dosage forms.
 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.

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Application of Dissolution…

2. Quality Assurance
 DT 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.
3. Product Stability
 In-vitro dissolution also used to assess drug product quality with respect to stability
and shelf life.
 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,
 Hence less soluble crystalline forms may result in reduced dissolution rates
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Application of Dissolution…

4. 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.
5. 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.

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 Thank you!!!
Q???

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