Solubility of Drugs

PART - III

Class- S.Y.B.Pharmacy
Semester III
Physical Pharmaceutics
Conducted by- Mr. Sankalp Gharat
Assistant Professor
(Department of Pharmaceutics)
 Diffusion principles in biological
systems.

“Diffusion is the process of

spontaneous migration of solute
molecules from a region of higher
concentration to a region of lower
concentration, until the concentration
is uniform throughout the system”
 • Steady State Diffusion

• Fick’s First Law of Diffusion:

Fick’s first law states that the rate of diffusion of a solute molecule
through a barrier is proportional to the concentration gradient.

J= dm i.e. J = -D dc
dt dx

Where J= Flux of the component, and is given by the rate of diffusion of the
component expressed in terms of amount (dm) transported in time (dt) across
a plane of unit area.

dc/dx is the concentration gradient.

The negative sign indicates that diffusion occurs in the direction opposite to
that of high concentration, i.e. in the direction of decreasing concentration.

D is the diffusion coefficient or diffusivity of the solute expressed in cm 2/sec,

its value is affected by temperature, pressure, solvent properties and chemical
nature of the solute.
• Fick’s Second Law of Diffusion:
Fick’s second law states that the change in concentration
with respect to time at a particular region is
proportional to the change in the concentration
gradient at that point in the system.

dc = D. d2c
dt dx2

Whereas the first law gives the amount of mass transported

across unit area of barrier in unit time, the second law
emphasizes the rate of change in concentration (change in
concentration with time)
• Steady State: Diffusion Cell
Outlet

Donor Receptor
Compartment Compartment

Inlet
Semi-permeable
membrane

• During the diffusion, the solute molecules diffuse through the semi-
permeable membrane to reach the receptor compartment which is kept
under sink conditions by constantly replacing the solution with fresh
solvent to keep the concentration in the receptor compartment at low
level.
• Under the above mentioned conditions, as the
diffusion proceeds with time, the diffusion
concentration falls in the Donor compartment and
rises in the Receptor compartment until the system
attains an equilibrium based on the rate of removal of
the diffusant from the sink.
• When the system has been kept as such for a
sufficient period of time, the concentrations in the
solution at the Donor and Receptor compartment
becomes constant, dc/dt becomes zero.
dm = D. D2c = 0
dt dx2
This condition may be referred as “quasi stationary
phase”
• Time lag: It is defined as the time required for the diffusant to
establish a uniform gradient within the membrane that separates the
donor and receptor compartments, and is given by tL
• The lag time is given by: tL = h2
6D
Where, h is membrane thickness.
Steady
state

Amount
penetrated
Non
steady
state
Lag
time tL

Time
 Simple Diffusion Cell for Diffusion Study

A simple cell for studying diffusion of drugs is shown in above figure. The apparatus
consists of two cells A and B, separated by a diffusion membrane.
The membranes are generally of glass or clear plastics, which allows visualization of
liquids and of the rotating stirrers.
The chambers can be thermostated and automatic sampling devices can also be
attached to them.
The drug solution is in the donor compartment and the solvent is taken in the receptor
compartment. Sample solutions are collected periodically from receptor compartment
and analysed spectrophotometrically.
Franz Diffusion Cell Assembly
 Dissolution of drug
Tablet /
Capsule
Dissolution

Disintegration

Drug in
Dissolution Absorption
Granules/ Drug blood and
Aggregates in solution other body
fluids

Deaggregation

Fine Dissolution
Particles
DISOLUTION APPARATUS
 Dissolution rate of drug:
• It is the amount of drug dissolved in a given solvent with
respect to time.
• Rate of Drug Dissolution is given by:
Noyes- Whitney equation, dc = DS (Cs-C)
dt Vh
Where,
dc/dt is the rate of dissolution
D = diffusion coefficient
S = surface area of the drug
V = volume of the solution
h = thickness of the diffusion layer
Cs = intrinsic solubility of the drug
C = concentration of solubilized drug at time t
Diffusion principles in Biological systems

• Drug Molecules pass through living

membranes either by:

A) Passive transport
B) Active transport
 Passive Transport
• Involves simple diffusion process from a region of
higher concentration to a region of lower
concentration as seen during drug transport in the
gastrointestinal tract.

• No energy is required for this transport to occur.

• The concentration gradient i.e., difference in the

concentration of the drug across the membrane is
the driving force for passive transport.
 Active Transport
• Drug Molecules are carried across the membrane by
an enzyme or biological carrier.
• Active transport can also occur against
concentration gradient i.e., from a region of low
concentration to that of high concentration.

• The rate of drug transport is influenced by:

1) The physicochemical properties of the drug
2) The nature of the membrane
3)The concentration of drug across the membrane
 Ionic character of drugs
• Most of the drugs are weakly acidic or weakly basic.
• The fraction of drug that exists as unionized or ionized is
determined by the dissociation constant of the drug (pKa) and
pH of its aqueous environment.
• Accordingly, Handerson- Hasselbalch equation for weak acids
and bases is given as follows:
• For Weak acid: pH =pKa + log [A-] (ionized form)
[HA] (unionized from)

For Weak Base: pH = pKa + log [B] (unionized form)

[BH+] (ionized form)
 pH partition principle:
• Biological membranes are lipophilic and are permeable to
unionized species of drug.

• Therefore the rate of passive transport of the weak acid or base

is related to the concentration of the drug that exists in the
unionized form at the sit of absorption. This is known as pH
partition hypothesis.

• The degree of ionization of a drug in a solution can be calculated

using Handerson- Haselbalch equation.

• However this principle is only partly applicable in the biological

systems (as evidenced from in-vivo and in-vitro studies) i.e.
even the ionized species are significantly transported.
Percutaneous Absorption of Topically
Applied Drugs:
• Percutaneous absorption of drugs through skin
generally involves following steps:
• (1)dissolution of drug in vehicle
• (2)diffusion of the dissolved drug from the vehicle
to the surface of the skin
• (3)penetration of the drug molecules through the
skin layer

The rate limiting step is the passage of drug

molecules through skin layers, principally stratum
corneum
Continued……..

factors affecting the permeation of drug

molecules into the skin:
• 1) concentration of dissolved drug
• 2) partition coefficient between the skin and the vehicle
• 3) diffusion coefficients of the drug in the vehicle and
the skin barrier

Diffusion of the drug through skin can be influenced by

the components (surfactants, solvents) of the dosage
form.
Hence, proper choice of vehicle plays an important role
in ensuring bioavailability of topically applied drugs
 Relative Lowering of Vapour Pressure
(Raoult’s Law)
Recap of Raoults Law:

• According to Raoult’s law,

The partial pressure of a component in a liquid mixture is equal to the
vapour pressure in the pure state multiplied by mole fraction of the
component in the solution.
• This implies that the partial pressure of components A and B in a
solution will be:  
• PA = PA0 xA
PB = PB0 xB . 

PA0 and PB0 are respective vapour pressure in pure form

xA and xB are respective mole fractions of components A and B
 Lowering of Vapour Pressure:
• When a non volatile solute is dissolved to a pure solvent- the vapour
pressure of the pure solvent decreases.

• i.e. if Vapour pressure of pure solvent is p, and vapour pressure of the

solution formed after addition of a non volatile solute is ps then,
lowering of vapour pressure= (p-ps)

This lowering of vapour pressure relative to the vapour pressure of the

pure solvent is termed as Relative Lowering of Vapour pressure.

Thus,

Relative Lowering of Vapour Pressure= p-ps

p
• According to Raoult’s law:
The relative lowering of vapour pressure
of a dilute solution is equal to the mole
fraction of the solute present in the dilute
solution.

Raoult’s law can be expressed mathematically as:

p – ps = n .
p n +N
Where, n= number of moles of solute
N= number of moles of solvent
 Determination of Molecular Mass from Vapour
pressure Lowering
• For this calculation, substitute n with w/m and N with W/M in
p – ps = n .
p n +N

• For Concentrated Solutions:

p – ps = w/m .
p w/m + W/M

• For Dilute Solutions:

p – ps = wM .
p mW

Where,
w= grams of solute
W= grams of solvent
m= molecular mass of solute
M= molecular mass of solvent