DISSOLUTION

Presented by: Muhammed Fahad

 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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Mechanism of Dissolution

1. Diffusion layer model

2. Danckwert’s model

3. Interfacial barrier model

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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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Fick’s law:

or

where k = rate constant

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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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Diagram Representing Diffusion through the Stagnant Layer

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Noyes- Whitney’s equation:

dC/dt = dissolution rate of the drug,

k = dissolution rate constant,
Cs = concentration of drug in the stagnant
layer, and
Cb = concentration of drug in the bulk of the
solution at time t

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Modified Noyes-Whitney’s equation:

• Where,
• D = diffusion coefficient (diffusivity) of the drug
• A = surface area of the dissolving solid
• Kw/o = water/oil partition coefficient of the drug.
• V = volume of dissolution medium
• h = thickness of the stagnant layer
• (Cs – Cb)= concentration gradient for diffusion of drug.

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 2. Danckwert’s Model
• Also called “Penetration or Surface Renewal Theory”.

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• m = mass of solid dissolved, and
• γ = rate of surface renewal (or the interfacial
tension)

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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 – TΔS
Where
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
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Cylinder 35
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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Recent developments in dissolution testing

• Use of more biorelevant media—FaSSIF & FeSSIF

media.
• FaSSIF—Fasted State Simulated Intestinal Fluid
• FeSSIF—Fed State Simulated Intestinal Fluid
Advantages:
• Provide physicochemical properties similar to human
GIT.

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 REFERENCE
1. Fonner. D. E, Banker. G. S., Granulation & Tablet Characteristics,
In Pharmaceutical Dosage Forms: Tablets. Vol. 2. Edited by H.
Lieberman & L. Lachman, Dekker, New York, 1982, p. 202
2. Leon Lachman, Herbert. A. Lieberman, The Theory and Practice
of Industrial Pharmacy, 3rd edition, Varghese Publishing House,
Bombay, 1991, pp. 301-303
3. Brahmankar. D. M., Sunil Jaiswal. B, Biopharmaceutics and
Pharmacokinetics—A Treatise, 1st edition, Vallabh Prakashan,
New Delhi, 2006, pp. 19-25
4. Alfred Martin, James Swarbrick, Physical Pharmacy, 3rd edition,
Varghese Publishing House, Bombay, 1991, pp. 408-412
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