Dissolution

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SEMINAR ON DRUG DISSOLUTION

SUBMITTED BY : GISTIN GEORGE First Year M.Pharm Pharmaceutics.
SUBMITTED TO :
Mr. P . N . KRISHNAN Head Of the Department , Department of Pharmaceutics.

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DISSOLUTION
Definition: o 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. o Dissolution is the rate determining step for hydrophobic, poorly aqueous soluble drugs. E.g. Griseofulvin, spironolactone
Powerpoint Templates Page 3
MECHANISM OF DISSOLUTION 1. Diffusion layer model
2. Danckwerts model
3. Interfacial barrier model
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1. Diffusion layer model:

Diagram Representing Diffusion through the Stagnant Layer
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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 Diffusion of the soluble solute from the stagnant layer to the bulk of the solution .this step is slower and is there for the rate determining step in drug dissolution.
dc/dt =k(cs-cb) where dc/dt = dissolution rate of a drug, K = dissolution rate constant. Cs = concentration of drug in the stagnant layer. Cb =concentration of drug in the bulk of the solution at time t. Burner incorporated Ficks first law of diffusion and modified the Noyes Whitneys equation to
dc/ dt = DAK
(cs - cb) Vh Powerpoint Templates

w/o
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Where D A K V h
w/o
= diffusion coefficient of the drug = surface area of the dissolving solid. = intrinsic dissolution rate constant. = volume of dissolution medium. = thickness of the stagnant layer.
(Cs- cb) = concentration gradient for diffusion

of drug.
2. DANCKWERTS MODEL (penetration or Surface Renewal theory)

Agitated fluid consists of eddies or packets reach solid/liquid interface, absorb the solute by diffusion, carry to bulk of solution Concentration never reaches Cs, since packets are replaced Solvent packets are exposed to new solid surface, known as surface renewal theory V dC/dt = dm/dt = A(Cs-Cb).D, where m =mass of solid dissolved
= rate of surface renewal

3. INTERFACIAL BARRIER MODEL (Limited solvation theory)

1. The rate-determining step of dissolution is mass transport 2. Solid-solution equilibrium achieved at
solid/liquid interface
intermediate concentration can exist at the interface as a result of solvation mechanism
G = Ki (Cs-Cb)
where G = dissolution rate per unit area Ki = effective interfacial transport constant Powerpoint Templates Page 10
Apparatus Classification in the USP

Apparatus 1 - (rotating basket) Apparatus 2 - (paddle assembly) Apparatus 3 - (reciprocating cylinder)
Apparatus 4 - (flow-through cell)

Apparatus 5 - (paddle over disk)
Apparatus 6 - (cylinder)
Apparatus 7 - (reciprocating holder)
Apparatus Classification in the European Pharmacopoeia (2002) for Different Dosage Forms
DOSAGE FORMS APPARATUS Paddle apparatus
For solid dosage forms
Basket apparatus
Flow-through apparatus
Disk assembly method

For transdermal patches Cell method Rotating cylinder method
For special dosage forms

Chewing apparatus
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Flow-Through Cell
(a) Apparatus for the determination of drug release from medicated chewing gums. Powerpoint Templates (b) flow-through cell for semi-solid products. Page 13
Reciprocating Cylinder
(a) The reciprocating cylinder apparatus (Bio-Dis) and (b) reciprocating cell. Powerpoint Templates Page 14
(a) Assembly for testing timed-release preparations. (b) Continuous flow dissolution apparatus.
FACTORS AFFECTING ABSORPTION

A. PHARMACEUTIC FACTORS
B. PATIENT RELATED FACTORS

Powerpoint Templates Page 16 16
A. PHARMACEUTIC FACTORS
Include the factors relating to the; 1. Physicochemical properties of the drug substance 2. Dosage form charecteristics and Pharmaceutic ingredients
PHYSICOCHEMICAL PROPERTIES OF DRUG SUBSTANCES

Drug solubility and dissolution rate Particle size and effective surface area Polymorphism and amorphism Pseudopolymorphism ( hydrates and solvates) Salt form of the drug
Lipophilicity of the drug

pKa of the drug and pH
Drug stability
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DOSAGE FORM CHARECTERISTICS AND PHARMACEUTIC INGREDIENTS

Disintegration time Dissolution time Manufacturing variables Pharmaceutic ingredients Nature and type of dosage form Product age and storage conditions
B. PATIENT RELATED FACTORS

Age Gastric emptying time Intestinal transit time Gastrointestinal pH Disease states Blood flow through the GIT Gastrointestinal contents Presystemic metabolism
DRUG SOLUBILITY AND DISSOLUTION RATE
Absolute solubility maximum amount of

solute dissolve in a given solvent under standard conditions of temperature, pressure and pH Dissolution rate - amount of solid substances
in solution per unit

time,temperature,pH,surface area.
The Rate Determining Step in absorption of oral drugs
1. Rate of dissolution :
eg: griseofulvin,spironolactone Hydrophobic drugs
2. Rate of drug permeation through the membrane:
eg: cromolyn, neomycin

Hydrophilic drugs
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THEORIES OF DRUG DISSOLUTION Dissolution- a solid substance solubilizes in a given solvent
1. DIFFUSION LAYER MODEL/FILM THEORY

Process of dissolution, in absence of chemical forces consists of two steps
1. Solution of solid to form stagnant layer at the interface 2. diffusion of soluble solute from stagnant layer to bulk of solution
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2. DANCKWERTS MODEL (penetration or Surface Renewal theory)

Agitated fluid consists of eddies or packets reach solid/liquid interface, absorb the solute by diffusion, carry to bulk of solution Concentration never reaches Cs, since packets are replaced Solvent packets are exposed to new solid surface, known as surface renewal theory V dC/dt = dm/dt = A(Cs-Cb).D, where m =mass of solid dissolved
= rate of surface renewal

3. INTERFACIAL BARRIER MODEL (Limited solvation theory)

1. The rate-determining step of dissolution is mass transport 2. Solid-solution equilibrium achieved at
solid/liquid interface
intermediate concentration can exist at the interface as a result of solvation mechanism
G = Ki (Cs-Cb)
where G = dissolution rate per unit area Ki = effective interfacial transport constant Powerpoint Templates Page 27
FACTORS INFLUENCING RATE OF DRUG DISSOLUTION

Increase in surface area of drug increases dissolution. Increase in viscosity of GI fluids decrease the dissolution coefficient, hence decrease the dissolution rate. Gastric emptying rate increase dissolution rate. Solubility of drugs increases with increase in temperature. As concentration decreases rate of dissolution increases. Powerpoint Templates Page 28
PARTICLE SIZE AND EFFECTIVE SURFACE AREA

Particle size and surface area of drug are inversely related Smaller the drug particle, greater is the surface area, higher the dissolution rate.
Micronization of poorly aqueous soluble drugs

results in superior dissolution rates Addition of surfactant and hydrophilic diluents,convert absolute S.A to effective S.A of hydrophobic drugs Powerpoint Templates
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POLYMORPHISM AND AMORPHISM

Polymorph - substance existing in more than one form. Enantiotropic - reversibly change to other form by altering temperature. Monotropic unstable at all temperature and
pressure.
Polymorphs differ from each other respect to physical factors
On relative stability, one form will be more stable

than others
Amorphous form having no internal structure Greater aqueous solubility than crystalline form Energy required to transfer a molecule from
crystal lattice is greater than that for amorphous

solid The order for dissolution of different solid forms of drugs amorphous > metastable > stable
HYDRATES/SOLVATES (Pseudopolymorphism)
Solvates solvent molecules are incorporated in crystal lattice of the solid Trapped solvates can exist in different crystalline forms called as pseudopolymorphs. Hydrate In a solvate, solvent associated with the drug is water
SALT FORM OF THE DRUG

Most drugs are either weak acids or weak bases Salt form of drug enhance solubility and
dissolution rate
Salt form is absorbed faster than their acid or base. The size of the counter ion influences the solubility of the salt forms of the drug. Smaller the size of the counter ion, greater the solubility of the salt
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Marked difference have been observed in rate and extent of absorption of a weak acid [H+]d = hydrogen ion concentration of the diffusion layer
[H+]b = hydrogen ion concentration of the bulk of

solution For salts of weak acids, [H+]d > [H+]b For salts of weak bases, [H+]d < [H+]b Aspirin is prone to hydrolysis in salt form, than as the free acid.
DRUG Pka AND GASTROINTESTINAL pH

Nonionized form- function of both dissociation constant of drug and pH of the solution The pH hypothesis was based on assumption that The GIT is simple lipoidal barrier to transport of drug Larger the fraction of un-ionized drug faster the absorption Greater the lipophilicity of un-ionized drug better the absorption.
The lower the pKa of an acidic drug, stronger the

acid. The higher the pKa of a basic drug, stronger the base amount of ionized and non-ionized drug in solution pH and percent of drug ionized at this pH can be determined by Henderson-Hasselbach equations
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For weak acids:

Very weak acids (pKa > 8) unionized at all pH values absorption is rapid, independentant of pH.e.g phenytoin
Acids (2.5 to 7.5) are greatly affected by

changes in pH, absorption is pH dependent e.g. aspirin Stronger acids pKa < 2.5 are ionized in the entire pH range, poorly absorbed. e.g cromolyn
sodium
For basic drugs

Very weak bases (Pka < 5) such as caffeine, unionized at all pH, absorption is rapid, pH independent.
Bases (5 to 11) are greatly affected by changes

in pH, absorption is pH dependent, e.g. chloroquine Stronger (pKa>11) like guanethidine are ionized in the entire pH range of GIT, poorly
absorbed
LIPOPHILICITY AND DRUG ABSORPTION

pKa of a drug determines the degree of ionization at a particular pH Oil/water partition coefficient (Ko/w) value
determines lipid solubility

measure of degree of distribution of drug between organic, water immiscible, lipophilic solvents Lipid soluble drugs of favorable partition
coefficients are usually absorbed after oral

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administration
LIMITATIONS OF pH-PARTITION THEORY

1. Presence of virtual membrane pH Virtual pH exists at membrane surface, different from luminal pH
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2. Absorption of ionized drugs
Theory states that only unionized form of the drug
is absorbed and permeation of the ionized drug is negligible pH absorption curve shift suggested that ionized forms also get absorbed, If such drugs have a large
lipophilic group
The absorption of ionized drug cause the pH absorption curve, shift to right for weak acid ,left for weak base Extent of shift depends on the relative permeability
of the ionized drug.
3. Influence of GI surface area and residence time pH-partition theory states- acidic drugs are best absorbed from stomach and basic drugs from intestine, more ionized Acidic drug reaches intestine, the remaining
fraction will be poorly absorbed

But, both acidic and basic drugs are rapidly absorbed from intestine, its large surface area
Powerpoint Templates and long residence time Page 43
4. Presence of aqueous unstirred diffusion
layer pH shift of acidic and basic drugs shows, bulk luminal fluid is in contact with aqueous unstirred diffusion layer Increased absorption rate due to reducing thickness of layer Drug must diffuse first through aqueous barrier and then through lipoidal barrier Drugs of large partition coefficient can rapidly penetrate lipid membrane, but through diffusion layer is the rate limiting step
CHEMICAL STABILTY OR DRUG STABILITY

Chemical stability is an important physicochemical property impacting
bioavailability
Needs to be stable before it is absorbed in the GI fluid
Compound needs to be stable for the shelf-life

of product For ionizable drugs, stability as a function of pH, to understand stability on absorption.
Dosage Form Factors Affecting Drug Absorption

1. Disintegration Time: Directly relates to the, - amount of binder present - the compression force Increased by, -disintegrants
2. Manufacturing Variables
Method of granulation -wet granulation -direct compression
-agglomerative phase of communition

Compression force
-influence density, porosity, hardness,

disintegration time,dissolution
Intensity of packing of capsule contents packing density; either inhibit or promot dissolution
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PHARMACEUTIC INGREDIENTS
Vehicles Diluents(Fillers) Binders and granulating agent Disintegrants Lubricants Coatings Colorants Powerpoint Templates
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NATURE AND TYPE OF DOSAGE FORM

Solutions Emulsions Suspensions Capsules Tablets Sustained release products
PRODUCT AGE AND STORAGE CONDITION
Changes in the physiochemical properties of the drug
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PATIENT RELATED FACTORS

AGE GASTRIC EMPTYING
# first order process
# parameters
# influencing factors
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1. VOLUME OF MEAL
2.
COMPOSITION OF MEAL
3. VISCOSITY OF MEAL
4. TEMPERATURE OF MEAL
5. GI pH
6. ELECTROLYTES AND OSMOTIC PRESSURE
7. BODY POSTURE
8. EMOTIONAL STATE 9. EXERCISE 10. DISEASE STATE 11. DRUG
INTESTINAL TRANSIT
GASTROINTESTINAL PH DISINTEGRATION DISSOLUTION ABSORPTION STABILITY
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DISEASE STATES
GASTROINTESTINAL DISEASES ALTERED GI MOTILITY
GASTROINTESTINAL DISEASES AND INFECTIONS
GASTROINTESTINAL SURGERY
CARDIO VASCULAR DISEASE
HEPATIC DISEASES
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BLOOD FLOW TO THE GIT

Sink condition
Concentration gradient for continued drug absorption
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GASTROINTESTINAL CONTENTS
Food-drug interactions
Fluid volume
Interaction of drug with normal GI constituents Drug-drug interactions
PRE SYSTEMIC METABOLISM
LUMENAL ENZYMES
GUTWALL ENZYMES BACTERIAL ENZYMES HEPATIC ENZYMES
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REFERENCES
JENNIFER DRESSMAN , PHARMACEUTICAL DISSOLUTION TESTING p.g.no.15 - 23
MILO GIBALDI, BIOPHARMACEUTICS AND CLINICAL PHARMACOKINETICS p.g.no 40-58 P.L. MADAN, BIOPHARMACEUTICS AND PHARMACOKINETICS , p.g.no 77 79 D.M. BRAHMANKAR,SUNIL B.JAISWAL, BIOPHARMACEUTICS AND PHARMACOKINETICS Powerpoint Templates Page 61 p.g.no 19-39
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Dissolution

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Powerpoint Templates

SEMINAR ON DRUG DISSOLUTION

Mr. P . N . KRISHNAN Head Of the Department , Department of Pharmaceutics.

MECHANISM OF DISSOLUTION 1. Diffusion layer model

1. Diffusion layer model:

(cs - cb) Vh Powerpoint Templates

(Cs- cb) = concentration gradient for diffusion

2. DANCKWERTS MODEL (penetration or Surface Renewal theory)

= rate of surface renewal

3. INTERFACIAL BARRIER MODEL (Limited solvation theory)

Apparatus Classification in the USP

Apparatus 4 - (flow-through cell)

Disk assembly method

For special dosage forms

FACTORS AFFECTING ABSORPTION

B. PATIENT RELATED FACTORS

PHYSICOCHEMICAL PROPERTIES OF DRUG SUBSTANCES

Lipophilicity of the drug

DOSAGE FORM CHARECTERISTICS AND PHARMACEUTIC INGREDIENTS

B. PATIENT RELATED FACTORS

DRUG SOLUBILITY AND DISSOLUTION RATE

Absolute solubility maximum amount of

in solution per unit

The Rate Determining Step in absorption of oral drugs

2. Rate of drug permeation through the membrane:

eg: cromolyn, neomycin

THEORIES OF DRUG DISSOLUTION Dissolution- a solid substance solubilizes in a given solvent

1. DIFFUSION LAYER MODEL/FILM THEORY

2. DANCKWERTS MODEL (penetration or Surface Renewal theory)

= rate of surface renewal

3. INTERFACIAL BARRIER MODEL (Limited solvation theory)

FACTORS INFLUENCING RATE OF DRUG DISSOLUTION

PARTICLE SIZE AND EFFECTIVE SURFACE AREA

Micronization of poorly aqueous soluble drugs

POLYMORPHISM AND AMORPHISM

On relative stability, one form will be more stable

crystal lattice is greater than that for amorphous

SALT FORM OF THE DRUG

[H+]b = hydrogen ion concentration of the bulk of

DRUG Pka AND GASTROINTESTINAL pH

The lower the pKa of an acidic drug, stronger the

For weak acids:

Acids (2.5 to 7.5) are greatly affected by

For basic drugs

Bases (5 to 11) are greatly affected by changes

LIPOPHILICITY AND DRUG ABSORPTION

determines lipid solubility

coefficients are usually absorbed after oral

LIMITATIONS OF pH-PARTITION THEORY

2. Absorption of ionized drugs

Theory states that only unionized form of the drug

of the ionized drug.

fraction will be poorly absorbed

4. Presence of aqueous unstirred diffusion

CHEMICAL STABILTY OR DRUG STABILITY

Compound needs to be stable for the shelf-life

Dosage Form Factors Affecting Drug Absorption

-agglomerative phase of communition

-influence density, porosity, hardness,

NATURE AND TYPE OF DOSAGE FORM

PRODUCT AGE AND STORAGE CONDITION

Changes in the physiochemical properties of the drug

PATIENT RELATED FACTORS