Dissolution

DISSOLUTION
Subject Name: Advanced Biopharmaceutics & Pharmacokinetics.
Subject Code:MPH202T.
Prepared By: Patel Snehal.
M Pharmacy
Sem II
Department of Pharmaceutics.
1

CONTENTS:
• Dissolution.
• Dissolution rate.
• Noyes-Whitney Equation.
• Factors affecting the dissolution rate.
• References.
2

 DISSOLUTION:
Dissolution is defined as the process in which a solid substance solubilizes in a
given solvent i.e. mass transfer from the solid surface to the liquid phase.
DISSOLUTION RATE:
Dissolution rate is the transfer rate of individual drug molecules from the solid
particles into solution as individual free drug molecules.
Rate of dissolution is the amount of drug substance that goes into solution
per unit time under standardized conditions of liquid/solid interface,
temperature& solvent composition.
3

Theories of Dissolution:
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).
1. Diffusion Layer Model/Film Theory.
This is the simplest and the most common theory for dissolution. Here, the
process of dissolution of solid particles in a liquid, in the absence of reactive
or chemical forces, consists of two consecutive steps:
i. Solution of the solid to form a thin film or layer at the solid/ liquid interface
called as the stagnant film or diffusion layer which is saturated with the
drug. This step is usually rapid.
ii. Diffusion of the soluble solute from the stagnant layer to the bulk of the
solution. This step is slower and is therefore the rate-determining step in
drug dissolution. 4

 NOYES-WHITNEY EQUATION
The rate of change in concentration of dissolved material with time it is
directly proportional to the concentration difference between the two sides of
diffusion layer.
dc = K(Cs-Cb)
dt
Where, dcdt= Dissolution rate of drug
K=Rate constant
Cs= Concentration of solution at solid surface
Cb= Concentration of bulk of the solution
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 MODIFIED NOYES-WHITNEY EQUATION
 Brunner incorporated surface area ‘A’ in Noyes & Whitney equation
dc =KA(Cs-Cb)
dt
 Afterwards Brunner, incorporated fick’s law of diffusion & expanded his given equation
to include diffusion coefficient ‘D’, thickness of stagnant diffusion layer ‘h’ & volume of
dissolution medium ‘V’.
dc = DAKwo(Cs-Cb)
dt Vh
Where, D= Diffusion coefficient of drug.
A= Surface area of dissolving solid.
K wo=wateroil partition coefficient of drug.
V= Volume of dissolution medium.
h= thickness of stagnant layer.
Cs-Cb= conc. Gradient for diffusion of drug.
7

 FACTORS AFFECTING DISSOLUTION RATE
1.Factors related to physicochemical properties of drug.
2.Factors related to Drug Product Formulation.
3.Processing factors.
4.Factors relating Dissolution Apparatus.
5.Factors relating Dissolution Test Parameters.
8

1.PHYSICOCHEMICAL PROPERTIES OF DRUG
A. Particle size and effective surface area of the drug
Larger the surface area, higher the dissolution rate. Since the surface area
increases with decreasing particle size, a decrease in particle size which can be
accomplished by micronisation will result in higher dissolution rate.
It is important to note that it is not the absolute surface area but the effective
surface area that is proportional 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.
E.g. Micronisation of poorly aqueous soluble drugs like griseofulvin,
chloramphenicol & several salts of tetracycline leads to increase in dissolution rate.
E.g. In case of hydrophobic drugs like aspirin, phenacetin & phenobarbital
micronisation results in decrease in effective surface area and fall in dissolution rate.
9

B. DRUG SOLUBILITY
Minimum aqueous solubility of 1% required to avoid potential solubility limited
absorption problems.
Studies on several compound of different chemical classes and a wide range of
solubility revealed that initial dissolution rate of these substances is directly
proportional to their respective solubility.
E.g. Poorly soluble drug: griseofulvin, spironolactone
hydrophilic drug: neomycin.
C. Solid State characteristics
Anhydrous forms dissolve faster than hydrated form because they are
thermodynamically more active than hydrates.
eg Ampicillin anhydrate faster dissolution rate than trihydrate.
10

Amorphous forms of drug tend to dissolve faster than crystalline materials e.g.
Novobiocin, Griseofulvin.
Where in the dissolution rate of amorphous erythromycin estolate is markedly
lower than the crystalline form of erythromycin estolate.
Metastable polymorphic form have better dissolution than stable form eg Methyl
prednisone.
D. 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 & potassium salts of penicillin G, phenytoin, barbiturates, tolbutamide etc.
While in case of phenobarbital dissolution of sodium salt was slower than that of weak acid.
Due to decreased disintegration of sodium salt.
Hydrochlorides and sulphates of weak bases are commonly used due to high solubility eg
epinephrine, tetracycline. 11

2.FACTORS RELATED TO DRUG PRODUCT
FORMULATION
A. Binders
The hydrophilic binders show better dissolution profile with poorly wettable
drugs like phenacetin by imparting hydrophilic properties to the granule surface.
Large amounts of binders increases hardness and decrease dissolution rate of
tablets.
Non aqueous binders such as ethyl cellulose retard the drug dissolution.
Phenobarbital tablet granulated with gelatin solution provide a faster
dissolution rate in human gastric juice than those prepared using Na-
carboxymethyl cellulose or polyethylene glycol 6000 as binder.
12

B. DISINTEGRANTS
Disintegrating agent added before and after the granulation affects the
dissolution rate.
Studies of various disintegrating agents on phenobarbital tablet showed that
when copagel added before granulation decreased dissolution rate but if added
after did not had any effect on dissolution rate.
Microcrystalline cellulose is a very good disintegrating agent but at high
compression force, it may retard drug dissolution.
C. Effect of Lubricants
Lubricants are hydrophobic in nature(metallic stearates) and prolong the
tablet disintegration time by forming water repellent coat around individual
granules. This retarding the rate of dissolution of solid dosage forms.
13

Both amount and method of addition affect the property. It should be added in
small amount and should be tumbled or mixed gently for only very short time.
Prolonged mixing affect the dissolution time.
The best alternative is use of soluble lubricants like SLS and carbowaxes
which promote drug dissolution.
D. Surfactants
They enhance the dissolution rate of poorly soluble drug. This is due to
lowering of interfacial tension, increasing effective surface area which in turn
results in faster dissolution rate.
Eg Non ionic surfactant polysorbate 80 increase dissolution rate of phenacetin
granules.
The increase was more pronounced when the surfactant was sprayed on
granules than when it was dissolved in granulating agent. 14

E. COATING POLYMERS
Tablets with MC coating were found to exhibit lower dissolution profiles than
those coated with HPMC at 37°c. The differences are attributed to thermal
gelation of MC at temp near 37°, which create a barrier to dissolution process &
essentially changes the dissolution medium.
In general the deleterious effect of various coatings on drug dissolution from a
tablet dosage forms is in the following order
Enteric coat>Sugar coat>Non enteric film coat.
The dissolution profile of certain coating materials change on aging eg shellac
coated tablets, on prolonged storage dissolve more slowly in the intestine.
15

F. COMPLEXING AGENTS
A complexed drug may have altered stability, solubility, molecular size,
partition coefficient and diffusion coefficient.
Eg enhanced dissolution through formation of a soluble complex of ergotamine
tartarate-caffeine complex and hydroquinone-digoxin complex.
16

3.PROCESSING FACTORS
A. Method of granulation
Wet granulation has been shown to improve the dissolution rate of poorly
soluble drugs by imparting hydrophilic properties to the surface of granules.
A newer technology called as APOC “Agglomerative Phase of Comminution”
was found to produce mechanically stronger tablets with higher dissolution rates
than those made by wet granulation. A possible mechanism is increased internal
surface area of granules produced by APOC method.
17

B. COMPRESSION FORCE
The compression process influence density, porosity, hardness, disintegration
time & dissolution of tablet.
The curve obtained by plotting compression force versus rate of dissolution
can take one of the 4 possible shapes.
18

On the one hand higher compression force increases the density and
hardness of tablet, decreases porosity and hence penetrability of the solvent
into the tablet, retards wettability by forming a firmer and more effective
sealing layer by the lubricant and promotes tighter bonding between the
particles all of which results in slowing of the dissolution rate of tablets.
On the other hand higher compression forces cause deformation, crushing or
fracture of drug particles into smaller ones or convert a spherical granule into a
disc shaped particle with a large increase in the effective surface area. This
results in increase in the dissolution rate of the tablet.
C. Drug excipient interaction.
These interactions occur during any unit operation such as mixing, milling,
blending, drying and granulating result change in dissolution.
Increase in mixing time of formulation containing 97 to 99% microcrystalline
cellulose result in enhance dissolution rate of prednisolone.
19

Polysorbate 80 used as excipient in capsules causes formation of
formaldehyde by autoxidation which causes film formation by denaturing the
inner surface of capsule. This causes decrease in dissolution rate of capsules.
D. Storage conditions
Dissolution rate of hydrochlorthiazide tablets granulated with acacia exhibited
decrease in dissolution rate during 1yr of aging at R.T. A similar decrease was
observed in tablets stored for 14days at 50-80°c or for 4 weeks at 37°c.
Tablets with starch gave no change in dissolution rate either at R.T. or at
elevated temperature.
20

4.FACTORS RELATED TO DISSOLUTION
APPARATUS
A. Agitation
Speed of agitation generates a flow that continuously changes the liq/solid
interface between solvent and drug. Inorder to prevent turbulence and sustain a
reproducible laminar flow, which is essential for obtaining reliable results,
agitation should be maintained at a relatively low rate.
Thus in general relatively low agitation should be applied.
1.Basket method-100rpm
2.Paddle method-50-75rpm
21

B. SAMPLING PROBE POSITION
Sampling probe can affect the hydrodynamic of the system.
USP states that sample should be removed at approximately half the distance
from the upper surface of basket or paddle and surface of dissolution medium
and not closer than 1cm to the side of the flask.
C. Stirring element alignment
The USP states that the axis of the stirring element must not deviate more
than 0.2mm from the axis of the dissolution vessel.
Studies indicate that significant increase in dissolution rate up to 13% occurs
if shaft is offset 2-6mm from the centre axis of the flask.
Tilt in excess of 1.5°c may increase dissolution rate from 2 to 25%.
22

5.FACTORS RELATING DISSOLUTION TEST
PARAMETERS
A. Temperature
Drug solubility is temperature dependent, therefore careful temperature
control during dissolution process is extremely important.
Generally a temperature of 37°±0.5 is maintained during dissolution
determination of oral dosage forms and suppositories. However for topical
preparations temperature as low as 30° and 25° have been used.
B. Vibration
The excessive vibration of dissolution apparatus increases dissolution rates.
23

C. VESSEL DESIGN AND CONSTRUCTION
Plastic vessels provide more perfect hemisphere than glass vessels.
D. pH of dissolution medium
Weak acids, dissolution rate increases with increase in pH where as
for weak bases, increase with decrease in pH.
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 REFERENCES:
1. Biopharmaceutics and Pharmacokinetics A Treatise by D. M. Brahmankar, Sunil
B. Jaiswal, 3rd edition, Vallabh Prakashan.
2. Biopharmaceutics and Clinical Pharmacokinetics by Milo Gibaldi, 4th edition,
Philadelphia, LeaandFebiger, 1991.
3. Applied Biopharmaceutics and Pharmacokinetics by Shargel. LandYuABC, 2nd
edition, ConnecticutAppleton Century Crofts, 1985.
4. Pharmacokinetics by Milo Gibaldi and D. Perrier, 2nd edition, Marcel
DekkerInc.,New York, 1982.
5. Pharmaceutics The Science of Dosage Form Design edited by M.E. Aulton
Second edition.
25

Questions:
1. Discuss the diffusion layer theory using Noyes-Whitney’s equation and the
variables that influence drug dissolution?
2. Explain Noyes-Whitney equation and its importance in drug dissolution?
26

Dissolution

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