detail about dissolution

1. DISSOLUTION
BY:
Shreeshail Tumbagi
1st year M.Pharm
ABMRCP-1071

2. CONTENTS:-
Definition
BCS Classification
Noyes-Whitney’s dissolutions rate law
Study of various approaches to improve dissolution of poorly soluble drug
 In-vitro dissolution testing models
In-vitro release kinetic models
similarity and dissimilarity factors
In-vitro- In –vivo correlation.
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3. DEFINITION:-
֍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.
֍Rate of dissolution is the amount of drug substance that goes in solution per
unit time under standardized conditions.
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4. BCS Classification:-
• It is a system to differentiate the drugs on the basis of their solubility and
permeability.
• The drug substances are classified as:
• Class I - High permeability, High solubility. Ex:- Metoprolol.
• Class II - High permeability, Low solubility. Ex:- Ezetimibe.
• Class III - Low permeability, High solubility. Ex:- Cimetidine.
• Class IV - Low permeability, Low solubility. Ex:- Hydrochlorothiazide
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5. THEORIES OF DISSOLUTION:-
I) Diffusion Layer Model (Film Theory):-
• It is a simplest model where dissolution of crystal, immersed in liquid takes
place without involving reactive or electrical forces
• It consist of two stages:-
Solution of the solid to form a thin film or layer at the solid / liquid
interface called as stagnant film or diffusion layer which is saturated with
the drug this step is usually rapid (instantaneous).
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 the
drug dissolution. 5

6. Diffusion Layer Model Diagrammatic:-
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7. NOYES AND WHITNEY EQUATION
The rate of change in concentration of dissolved material with time it directly
proportional to the concentration difference between the two sides of diffusion
layer
i.e. = k (Cs- Cb)
Where, dc/dt - Dissolution rate of drug.
k - Rate constant
Cs - Concentration of solution at solid surface
Cь - Bulk of the solution
dc
dt
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8. Modified Noyes-Whitney’s Equation :-
 Brunner incorporated surface area ‘A’ in Noyes & Whitney equation.
dc/dt = kA ( Cs – Cb )
 Afterwards Brunner, incorporated Fick’s law of diffusion & expanded his given
eq to include diffusion coefficient ‘D’, thickness of stagnant diffusion layer ‘h’
& volume of dissolution medium ‘v’.
dc
dt
Where, D = diffusion coefficient of drug.
A = surface area of dissolving solid.
Kw/o = water/oil partition coefficient of drug.
V = volume of dissolution medium.
h = thickness of stagnant layer.
C – C = conc. gradient for diffusion of drug.
DAKw/o (Cs – Cb)
Vh
=
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9. Non sink conditions :-
Modified noyes-whitney’s equation represents the first order dissolution
process, the driving force which the concentration gradient (Cs- Cb), and this
condition is said as non sink condition , done only for in-vitro
Sink conditions :-
The in-vivo dissolution is always rapid than in-vitro dissolution because the
moment the drugs dissolves , it is absorbed in the systemic circulation , as a
result Cb= 0 and the dissolution is at maximum.
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10. Conc.ofdissolveddrug
Time
first order dissolution under
non-sink condition
zero order dissolution
under sink condition
Dissolution rate under non-sink and
sink conditions.
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11. HIXON-CROWELL CUBE ROOT RELATIONSHIP
• Major assumptions in Noyes-Whitney relationship is that the S.A.(A) term
remains constant throughout dissolution process. This is true for some
formulations, such as transdermal patches.
• However, size of drug particles from tablets, capsules and suspensions will
decrease as drug dissolves.
• This decrease in size of particles changes the effective S.A.
• Thus, Hixon & Crowell modified the equation to represent rate of appearance
of solute by weight in solution by multiplying both sides of volume term.
Wo
1/3- W1/3 = kt
Where , W0 = Original mass of drug
W = Mass of drug remaining to dissolve at time t
K = Dissolution rate constant.
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12. II) Danckwert’s model/Penetration or surface renewal Theory :-
• Dankwert 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.
• The Danckwert’s model is expressed by equation
Where, m = mass of solid dissolved
Gamma (γ) = rate of surface renewal
D = diffusion coefficient of drug.
A = surface area of dissolving solid.
dC
dt
=
dm
dt
= A (Cs-Cb). Dγ
V
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13. 13

14. 14
STUDY OF VARIOUS APPROACHES TO IMPROVE
DISSOLUTION OF POORLY SOLUBLE DRUG
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15. IN-VITRO DISSOLUTION TESTING MODELS
ACCORDING TO BP OFFICIAL METHODS:-
Apparatus are used according to standards specified. The BP includes seven
apparatus design for drug release and dissolution testing of immediate release
and for oral dosage form, for extended release, enteric coated, transdermal
drug delivery system.
Methods are listed below :-
Rotating basket method
Paddle method
Flow-through method
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16. ROTATINGBASKETMETHOD :(APPARATUS-1)
It is basically a closed compartment, beaker type apparatus comprising of a
cylindrical glass vessel with hemispherical bottom of one liter.
capacity immersed in a water bath to maintain constant temperature at 37+2c.
Basket of 40 mesh rotated at constant speed between 25 and 150 rpm.
Basket is to hold the dosage form and it is located centrally in vessel.
Basket should be placed at 20mm above from the bottom.
Sample should withdraw periodically at regular interval of time, each time
replace same volume of dissolution medium after withdrawal.
Sample should be withdraw from the top end of the basket and basket should
remain in motion during drawing samples.
All the metal part should be of 316 grade stainless steel.
Basket of mesh size 10,20,30 and 40 mesh screen can be used depending on
dosage form and to avoid clogging.
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17. PADDLE METHOD: (APPARATUS-2)
• It was originally developed by Poole 1969 and was refined by scientists at
USFDA.
• The specification of Apparatus-2 are identical with those of apparatus -1
except that paddle is substituted for the rotating basket.
• The paddle which acts as a stirrer and the dosage form allow to sink to the
bottom of the vessel.
• The area of paddle blade creates considerable flow, and wobble has the
effect of increasing the angular velocity at the paddle tips in the manner that
couples with the fluid much more significantly than would comparable
wobble in basket.
• The counter of the paddle blade must not included any sharp edges at the
tips, for instance that could produce turbulent instead of laminar flow.
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18. FLOW-THROUGH CELL :(APPARAYUS-3)
It consists of following parts,
• A dissolution chamber: which acts as a reservoir of dissolution media.
• A pump: to pump the medium.
• Dissolution chamber: to hold the dosage form and also it consists of glass
beads to trap the large particles, filter to trap the un dissolved drug from
dosage form.
• A reservoir: to collect the sample.
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19. • In this method, a tablet or capsule is placed in dissolution chamber and
dissolution medium is pumped through the dissolution chamber.
• The flow rate is usually maintained between 10 and 100 ml/min. this
dissolution fluid is collected and assayed for drug content.
• It has been extensively used by the Europe before introducing in USP method.
• The flow rate should be held constant, and it is difficult to get laminar flow wit
out turbulence.
• This can be minimize by using pulse free pumps. And also difficult to obtain
desire filter pore size, and dosage composition.
• The main dis advantage of this is filter get clogged, flow rate decreases pump
pressure increases to the point that it damages equipment.
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20. ADVANTAGES :-
 Infinite sink condition can be achieved hence low soluble drugs studies can
be done.
It is easy to change pH of media during test, avoiding hot spots as seen in
basket method.
Minimum dwell time, avoiding problems of degradation of drug during
process.
Ease of sampling and automation of data reduction.
Adaptability to current USP calibrators.
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21. DIS-ADVANTAGES:
› Large volume of media is required.
› Control of constant flow rate is difficulty.
› Clogging results in damage to equipment.
› Pump should produce pulse free flow.
› Pressure may build up due to clogging hence pressure transducer should
used to regulate pressure and to maintain constant flow rate.
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22. In Vitro–In Vivo Correlation
• Level A IVIVC, the model should predict the entire in vivo time course from
the in vitro data. In this context, the model refers to the relationship between
in vitro dissolution of an extended release (ER) dosage form and an in vivo
response such as plasma drug concentration or amount of drug absorbed.’’
• Level B IVIVC uses the principles of statistical moment analysis. The mean in
vitro dissolution time is compared either to the mean residence time or to the
mean in vivo dissolution time. Level B correlation, like a Level A, uses all of
the in vitro and in vivo data, but is not considered to be a point-to-point
correlation.
• Level C IVIVC establishes a single-point relationship between a dissolution
parameter, for example, T 50% dissolved in four hours and a pharmacokinetic
parameter [e.g., 50% area under the curve (AUC), Cmax, Tmax].
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23. 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. 408-12 23

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