DISSOLUTION

BY:

Shreeshail Tumbagi

1st year M.Pharm

ABMRCP-1071

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.2

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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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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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

Diffusion Layer Model Diagrammatic:-

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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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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.

Cs – Cb = conc. gradient for diffusion of drug.

DAKw/o (Cs – Cb)

Vh=

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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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Conc. of dis

solv

ed d

rug

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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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 someformulations, such as transdermal patches.

• However, size of drug particles from tablets, capsules and suspensions willdecrease as drug dissolves.

• This decrease in size of particles changes the effective S.A.

• Thus, Hixon & Crowell modified the equation to represent rate of appearanceof solute by weight in solution by multiplying both sides of volume term.

Wo1/3- W1/3 = kt

Where , W0 = Original mass of drug

W = Mass of drug remaining to dissolve at time t

K = Dissolution rate constant.11

II) Danckwert’s model/Penetration or surface renewal Theory :-

• Dankwert takes into account the eddies or packets that are present in theagitated fluid which reach the solid-liquid interface, absorb the solute bydiffusion and carry it into the bulk of solution.

• These packets get continuously replaced by new ones and expose to newsolid 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). DγV

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STUDY OF VARIOUS APPROACHES TO IMPROVE DISSOLUTION OF POORLY SOLUBLE DRUG

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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 method15

ROTATINGBASKETMETHOD :(APPARATUS-1)

It is basically a closed compartment, beaker type apparatus comprising of acylindrical 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 timereplace same volume of dissolution medium after withdrawal.

Sample should be withdraw from the top end of the basket and basket shouldremain 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 ondosage form and to avoid clogging.

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PADDLE METHOD: (APPARATUS-2)

• It was originally developed by Poole 1969 and was refined by scientists atUSFDA.

• The specification of Apparatus-2 are identical with those of apparatus -1except that paddle is substituted for the rotating basket.

• The paddle which acts as a stirrer and the dosage form allow to sink to thebottom of the vessel.

• The area of paddle blade creates considerable flow, and wobble has theeffect of increasing the angular velocity at the paddle tips in the manner thatcouples with the fluid much more significantly than would comparablewobble in basket.

• The counter of the paddle blade must not included any sharp edges at thetips, for instance that could produce turbulent instead of laminar flow.

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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 glassbeads to trap the large particles, filter to trap the un dissolved drug fromdosage form.

• A reservoir: to collect the sample.

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• 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.19

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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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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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].22

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. 408-1223

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