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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
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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.
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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.
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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


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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)
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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


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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.
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FACTORS AFFECTING ABSORPTION


A. PHARMACEUTIC FACTORS

B. PATIENT RELATED FACTORS


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A. PHARMACEUTIC FACTORS
Include the factors relating to the; 1. Physicochemical properties of the drug substance 2. Dosage form charecteristics and Pharmaceutic ingredients
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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
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B. PATIENT RELATED FACTORS


Age Gastric emptying time Intestinal transit time Gastrointestinal pH Disease states Blood flow through the GIT Gastrointestinal contents Presystemic metabolism
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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.
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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


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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
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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
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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
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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.
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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.
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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
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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
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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
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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
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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
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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.
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Dosage Form Factors Affecting Drug Absorption


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

-agglomerative phase of communition


Compression force

-influence density, porosity, hardness,


disintegration time,dissolution
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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
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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
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6. ELECTROLYTES AND OSMOTIC PRESSURE

7. BODY POSTURE
8. EMOTIONAL STATE 9. EXERCISE 10. DISEASE STATE 11. DRUG
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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
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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
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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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