PRINCIPLES OF PHARMACEUTICS

DIFFUSION AND DISSOLUTION

IN
(15/06/21)

By
Leticia Lariba Duut
(Department of Pharmaceutics)
U.D.S
1
02/03/2023
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Importance of diffusion in pharmaceutical sciences

1. Drug release Dissolution of drugs from its dosage form.

2. Passage of gasses, moisture, and additives through the packaging

material of the container.

3. Permeation of drug molecules in living tissue.

4. Drug absorption and drug elimination

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+ Diffusion

 Diffusion: is a process of mass transfer of individual molecules

of a substance as a result of random molecular motion.

 The driving force for diffusion is usually the

concentration gradient.

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The movement of molecules from a area in which
they are highly concentrated to a area in which they are less
concentrated.
Define Diffusion

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 Diffusion
The passage of matter through a solid barrier can occur by:

1. Simple molecular permeation or

2. By movement through pores and channels

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 Molecular diffusion or permeation through nonporous media depends

on the solubility of the permeating molecules in the bulk membrane
 The passage of a substance through solvent-filled pores of a membrane
and is influenced by the relative size of the penetrating molecules and
the diameter and shape of the pores
 Diffusion or permeation through polymer strands with branching and
intersecting channels. Depending on the size and shape of the diffusing
molecules, they may pass through the tortuous pores formed by the
overlapping strands of polymer. If it is too large for such channel
transport, the diffusant may dissolve in the polymer matrix and pass
through the film by simple diffusion.

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+ Pharmacokinetics of
drugs (ADME)
 Absorption
 Distribution
 Metabolism
 Excretion of drugs

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+ Drug Absorption and Elimination
Passage of Drugs Through Membranes

 Passive diffusion

 Transcellular diffusion (through the lipoidal bilayer of cells)

 Paracellular diffusion (passage through aqueous channels)

 Using membrane transporters

 Facilitated diffusion (energy independent)

 Active transport (energy dependent)

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 + How to get other molecules across
membranes??
There are three ways that the molecules typically move through the membrane:

1. Facilitated transport
2. Passive transport
3. Active transport

• Active transport requires that the cell use energy that it has obtained from food to move
the molecules (or larger particles) through the cell membrane.

• Facilitated and Passive transport does not require such an energy expenditure, and occur
spontaneously.

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Membrane Transport Mechanisms
I. Passive Transport
 Diffusion- simple movement from regions of high concentration to low
concentration

 Osmosis- diffusion of water across a semi-permeable membrane

 Facilitated diffusion- protein transporters which assist in diffusion

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+
Membrane Transport Mechanisms
II. Active Transport
 Active transport- proteins which transport against concentration
gradient.

 Requires energy input

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+

Elementary Drug Release

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+ Osmosis

The diffusion of water across a selectively permeable membrane.

Water moves from a high concentration of water (less salt or sugar dissolved in it) to
a low concentration of water (more salt or sugar dissolved in it).
This means that water would cross a selectively permeable membrane from a dilute
solution (less dissolved in it) to a concentrated solution (more dissolved in it).

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Ultrafiltration and Dialysis

 Ultrafiltration is used to separate colloidal

particles and macromolecules by the use of a
membrane.

 Hydraulic pressure is used to force the solvent

through the membrane, whereas the
microporous membrane prevents the passage
of large solute molecules

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+ Dialysis
Separation process based on unequal rates of passage of solute and
solvent through microporous membrane, carried out in batch or
continuous mode.

Hemodialysis
Used in treating kidney malfunction to rid the blood of metabolic waste
products (small molecules) while preserving the high molecular weight
components of the blood

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+
Haemodialyzer

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 Fick’s laws of diffusion
 Flux: is the rate of flow of molecules across a given surface.
 Flux is in the direction of decreasing concentration.
 Flux is always a positive quantity
 Flux equal zero (diffusion stop) when the concentration gradient
equal zero.

Diffusion coefficient also called diffusivity. It is affected by:

 Chemical nature of the diffusant drug.
 Solvent properties.
 Temperature
 Pressure
 Concentration
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 Diffusion
Diffusional release system: Reservoir system

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02/03/2023 20
 + Membrane permeability

 The membrane can have a partition

coefficient that affects the concentration of
the diffusant inside it.

 Therefore the concentration inside

membrane is a function of at the
concentratio the boundary the
n
partition coefficient of
andthe membrane.
the

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+
Diffusion
Zero-order process

M  PSCd t
- Amount of drug transported is constant
over time
- Only if Cd does not change
- Diffusion of drug from transdermal patch
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 Diffusio
n

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+
Example : To study the oral absorption of paclitaxel(PCT) from an oil-water emulsion
formulation, an inverted closed-loop intestinal model was used.
- surface area for diffusion = 28.4 cm2

- concentration of PCT in intestine = 1.50 mg/ml.

- the permeability coefficient was 4.25 x 10-6 cm/s

Calculate the amount of PCT that will permeate the intestine in 6 h of study (zero-order transport under sink
conditions)

Using the equation M= PSCdt ,

M = (4.25 x 10-6)(28.4)(1.50)(21,600)
= 3.91 mg

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Burst effect

 In many of the controlled release formulations, immediately upon

placement in the release medium, an initial large bolus of drug is
released before the release rate reaches a stable profile. This
phenomenon is typically referred to as ‘burst release.’

 Initial release of drug into receptor side is at a higher rate than the
steady-state release rate

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+

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 Lag time, Burst effects

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+ Multilayer Diffusion
 Diffusion across biologic barriers

 The passage of gaseous or liquid solutes through the walls

of containers and plastic packaging materials

 The passage of a topically applied drug from its vehicle through the
lipoidal and lower hydrous layers of the skin.

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+ Procedures and Apparatus For Assessing Drug Diffusion

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 DISSOLUTION
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.
• Dissolution is the rate determining step for
hydrophobic, poorly aqueous soluble drugs.
E.g. Griseofulvin, spironolactone

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 Why dissolution studies?

1. To show that the release of drug from the tablet is

close to 100%.
2. To show that the rate of drug release is uniform
batch to batch.
3. And to show that release is equivalent to those
batches proven to be bioavailable and
clinically effective.

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 Dissolution mechanisms

2 steps:
1. Interfacial reaction  cause liberation of solid
particles into boundary layer (Cs).
2. Migration of solute from boundary layer into bulk of
solution (C) by diffusion & convection.
• Overall rate of dissolution depends on the slowest
step.
• Usually Step (2) is the RDS.

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 1. Diffusion Layer Model
• 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 to form
a saturated drug layer , called stagnant layer.
2) Diffusion of drug molecules from stagnant layer
into bulk of the system.

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 3. Interfacial Barrier Model
• Drug dissolution is a function of solubility rather than
diffusion.
• Intermediate concentration exist at the interface as a
result of solvation.
• Dissolution rate per unit area, G is given by,

where Ki = effective interfacial transport constant.

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 Powder Dissolution:
The Hixson-Crowell Cube Root Law

• Applicable for drug powders of uniform size.

• Rate of dissolution based on cube root of wt. of
particles.

M0 = initial mass of powder

M = mass of powder dissolved in time, t
k = cube root dissolution rate constant

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 Particulate Dissolution
• Used to study influence of particle size & surface
area on dissolution.
• Here, surface area is not made constant.
• Weighed powder introduced in dissolution
medium
 agitated by propeller.
• Rate of dissolution increases with decrease in
particle size.
• Effective and absolute surface area.
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 PROCESS OF DISSOLUTION
States of matter:
• Solid, liquid & gaseous states.
• Dissolution involves relocation of a solute molecule
from an environment where it is surrounded by
other identical molecules, into a cavity in a liquid.

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 Energy changes:
• For spontaneous reactions, ΔG must be –ve.
• ‘G’ is a measure of the energy available to a
system to perform work.

ΔG = ΔH –
Where TΔS
ΔH = change in enthalpy of the
system ΔS = change in entropy of the
system T = temperature
• ΔS is usually positive for
spontaneous reactions.
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 Intrinsic Dissolution rate

• Rate which is independent of rate of agitation, area

of solute available, etc.
• Intrinsic Dissolution Rate (IDR): rate of
mass transfer per area of dissolving surface.
• It is independent of boundary layer thickness and
volume of slolvent .

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 • Thus,

IDR = k1Cs
• IDR measures the intrinsic properties of the drug
only as a function of the dissolution medium, e.g.
its pH, ionic strength, counter ions, etc.)

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 Measurement of dissolution rates
Apparatus Classification in USP:
1. Apparatus 1 (rotating basket)
2. Apparatus 2 (paddle assembly)
3. Apparatus 3 (reciprocating cylinder)
4. Apparatus 4 (flow-through cell)
5. Apparatus 5 (paddle over disk)
6. Apparatus 6 (cylinder)
7. Apparatus 7 (reciprocating holder)

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 Apparatus Classification in European
Pharmacopoeia for different dosage forms

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 Problems associated with development of
dissolution tests:

1. Need to have a manageable volume of dissolution

medium.
2. Development of less-soluble drugs.
3. Insufficient analytical sensitivity for low-dose
drugs.

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 According to USP:
A drug product is considered rapidly dissolving when no
less than 85% of the labeled amount of the drug
substance dissolves within 30 minutes, using USP
Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a
volume of 900 ml or less in each of the following media:
(1)0.1 N HCl or Simulated Gastric Fluid USP
without enzymes;
(2) a pH 4.5 buffer; and
(3) a pH 6.8 buffer.

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 Biopharmaceutical Classification System

• Class I: High solubility—High permeability

• Class II: Low solubility—High permeability
• Class III: High solubility—Low permeability
• Class IV: Low solubility—Low permeability

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 Measurement of dissolution rates

Beaker method:
• Developed by Levy and Hayes.
• Consist of 400 ml beaker with 250 ml dissolution
medium.
• Medium is agitated by a 3-bladed polyethylene
stirrer of 50 mm diameter.
• Stirrer is immersed to a depth of 27 mm into the
dissolution medium and rotated at 60 rpm.

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 Flask-stirrer
method:
• R.B. flask is used instead of beaker.

Rotating Basket method:

• USP Apparatus I
• Small wire mesh basket fastened to end of shaft
connected to a motor.
• Immersed in a flask maintained at 370C ± 0.50C.
• Samples are withdrawn at regular intervals.

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 Paddle Assembly
method
• USP Apparatus II
• Basket in above method is replaced by paddle.
• Paddle is continuous with the shaft.
• Tablet is placed at the bottom of the medium.
Disadvantages:
• Since dissolution volume is limited, use of poorly
soluble drugs is limited.

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 Variables in USP Apparatus I & II
• Type of dissolution medium & its volume.
• Type of apparatus to be used.
• Speed (rpm) of rotation.
• Total time of the test.
• Further assay procedures.

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 USP Testing methods:
• 6 tablets  monograph tolerance limit, Q + 5%
• If fail, 6 more tablets are used  avg. of 12 tabs ≥
Q, and none is < Q-15%.
• If failed, 12 more tablets used  avg. of 24 tabs ≥
Q, and no 2 tab is < Q-15% & none is < Q-25%.
• Usual tolerance in USP / NF is “not less than
75% dissolved in 45 min”.

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 Reciprocating
Cylinder
• Proposed by Beckett & incorporated in USP in 1991.
• Mainly used for dissolution testing of extended-
release products.
• Also used for poorly soluble drugs.
• Capable of agitation and media composition changes
during a run & full automation.
• Dips per minute (dpm) is used.
• Inner reciprocating tubes & outer tubes.

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 Reciprocating Cylinder
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 Use:
• Especially useful in the case of chewable tablets.
• Studies show that 5 dpm in Apparatus 3 is
equivalent to 50 rpm in Apparatus 2.
• So higher dpm can achieve rigorous movts. similar
to chewing—not possible by Apparatus 2.
• Used for solutions requiring pH/buffer changes like
enteric-coated/extended-release drugs.

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 Flow-Through
Cell
• Introduced by Langenbucher.
• Open system—offer unlimited medium supply—
especially useful for poorly soluble drugs.
• Also used for dissolution test of sugar-coated tabs,
suppositories, soft gelatin capsules, semi-solids,
granules, implants, etc.
• Small volume cell is subjected to continuous stream
of dissolution media  flow from bottom to top.

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 • Agitation is achieved by pulsating movement of
piston.
• Results obtained as fraction dissolved per unit
time
(due to continuous media flow).
• Data is transformed to the usual cumulative amt.
dissolved vs. time.
Advantages:
• Maintenance of sink conditions.
• Minimizing downtime between tests.

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 Flow-Through Cell

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 Qualification & Validation of the
Apparatus
• To maintain “quality by design”.
• Physical & chemical calibrations—geometrical &
dimensional accuracy & precision.
• Vibration or undesired agitation to be avoided.
• Temperature, rotation speed/flow rate, volume, sampling
probe, procedures, etc. need to be monitored periodically.
• Use of USP calibrator tablets for App. 1 & 2 (to be
performed not less than twice a year)

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 Factors Affecting Dissolution

Surface area & undissolved solid

• Surface area α dissolution.
• Coherent masses may reduce total surface area
available  overcome by using wetting agent.
• Presence of pores.
 E.g. dissolution of phenacetin (hydrophobic) is
enhanced by adding diluent gelatin (hydrophilic)
during granulation.

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  Addition of Tween 80 to dissolution medium
(0.1 N HCl) for phenacetin increased the
dissolution rate by increasing effective
surface area.

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 Solubility of solid in dissolution medium

 Temp. of dissolution medium

 pH of the medium

 Solubility of the drug in dissolution medium

 Presence of cosolvents

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 Concentration of solute in solution

• Should simulate sink conditions present in GI tract.

• Larger volume of dissolution medium helps to
maintain ‘C’ negligible compared to ‘Cs’.
• Removal of dissolved solute from dissolution
medium enhances rate of dissolution.
 Eg. Adsorption onto another substance
 Partition to another immiscible liquid
 Removal of solute by dialysis
 Cont. replacement of dissolution
medium
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 Dissolution rate constant
Depend upon
 Thickness of boundary layer
 Degree of agitation
 Speed of stirring
 Shape, size & position of stirrer
 Vol. of dissolution medium
 Shape & size of container
 Viscosity of dissolution medium

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 Disintegration & Deaggregation
• Disintegration and subsequent deaggregation may
also be RDS for dissolution.
o E.g. coated dosage forms
• After disintegration, larger aggregates need to
deaggregate to yield fine particles.

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 Effect of manufacturing processes
 Addition of lubricants
E.g.: 325-mg salicylic acid dissolved rapidly in 0.1 N
HCl when SLS was added to it.
Dissolution rate decreases with addition of
hydrophobic lubricants like Mg. stearate.
• Most effective lubricants are hydrophobic  act by
particle coating  hence mfg. process is imp.

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  Addition of disintegrating agents like starch  swell
& enhance dissolution.
 Compression force
• Increase in compression force may decrease or
increase dissolution rate.

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