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“Dissolution of Pharmaceutical Solid

Dosage Form”

Definition :

“the amount of drug substance that goes into solution per unit time under

standardized conditions of liquid/solid interface, temperature, solvent

composition .”

Importance

1. To show that the release of drug from the tablet is close to 100%.

2. To show that the rate of drug release is uniform batch to batch.

3. And to show that release is equivalent to those batches proven to

be bioavailable and clinically effective.

Applications

1. Important tool during development of dosage form.

2. Quality Assurance.

3. Product Stability.

4. Comparability Assessment.

Mechanism of Dissolution

1. Diffusion layer model

2. Danckwert’s model

3. Interfacial barrier model

1.Diffusion Layer Model(film theory):

Formation of a thin film at the interface, called as stagnant

layer.

2 steps are involved:

A) Interaction of solvent with drug surface to forma

saturated drug layer , called stagnant layer.

B) Diffusion of drug molecules from stagnant layer into

bulk of the system

Noyes-Whitney’s equation:

Where,

D = diffusion coefficient of the drug

A = surface area of the dissolving solid

Kw/o = water/oil partition coefficient of the drug.

V = volume of dissolution medium

h = thickness of the stagnant layer

(Cs – Cb)= concentration gradient for diffusion of drug.

2. Danckwert’s Model (Penetration or Surface Renewal

Theory)

This model suggest that turbulence in dissolution

medium exists at the solid/liquid interface. As a result, agitated fluid consisting

of macroscopic mass of eddies or packets reach the interface in random

fashion due to eddy currents, absorb the solute by diffusion and carry it to

bulk of the solution.

Such solute containing packets are continously replaced with new packets of

fresh solvent due to which drug conc. At S/L interface never reaches Cs and

has lower limiting value of Ci.

m = mass of solid dissolved

γ = rate of surface renewal (or the interfacial tension)

3. Interfacial Barrier Model:

• Drug dissolution is a function of solubility rather than diffusion.

• Intermediate concentration exist at the interface as a result of

solvation.

• Dissolution rate per unit area, G is given by,

G= Ki(Cs-Cb)

where Ki = effective interfacial transport constant.

Dissolution Apparatus:

According to B.P. apparatus used are:

1. Apparatus I – BASKET APPARATUS

2. Apparatus II – PADDLE APPARATUS

3. Apparatus III – FLOW THROUGH CELL APPARATUS

According to USP 30 dissolution apparatus used are

1 . BASKET

2 . PADDLE

3 . RECIPROCATING CYLINDER

5 . PADDLE OVER DISK

6 . CYLINDER – (N/A )

7 . RECIPROCATING HOLDER

Apparatus 1- Basket apparatus:

DESIGN:

Vessel: -Made of borosilicate glass.

-Semi hemispherical bottom

-Capacity 1000ml

Shaft :

-Stainless steel 316

-Rotates smoothly without significance

wobble(100 rpm)

-Speed regulator

Water bath:

-Maintained at 37±0.5ºC.

USE:

Tablets, capsules, delayed release suppositories, floating

dosage forms.

Advantages

-Full pH change during the test

Can be easily automated which is important for routine

investigations.

Disadvantages

-Basket screen is clogged with gummy particles.

-Hydrodynamic „dead zone“ under the basket

-Degassing is particularly important

-Mesh gets corroded by HCl solution.

Apparatus 2- Paddle apparatus:DESIGN:

Vessel:

-Same as basket apparatus

Shaft:

-The blade passes through the shaft

so that the bottom of the blade fuses with

bottom of the shaft.

Stirring elements:

-Stainless steel 316

Water-bath:

-Maintains at 37±0.5°C

Advantages:

• Easy to use

• pH change possible

• Can be easily adapted to apparatus

Disadvantages

• Floating dosage forms require sinker

• Positioning of tablet

Apparatus 3- Reciprocating cylinder:

Advantages:

1. Easy to change the pH-profiles

2. Hydrodynamics can be directly

influenced by varying the dip rate.

Disadvantages:

1. small volume (max. 250 ml)

• a set of cylindrical,

• flat- bottomed glass vessels;

• a set of glass reciprocating cylindrical;

• stainless steel fitting;

• screen;

• a motor and drive.

Standard volume: 200-250 ml/station

DISSOLUTION ACCEPTAN CECRITRIA

Q –Value:

Define as a percentage of drug content dissolved in a given time

period

Level Samples tested Acceptance criteria

S1 6 Each value is not less than Q + 5%

S2 6 Average value of the 12 dosage units (S1 +

S2 ) is equal to or greater than Q and no

unit is less than Q-15%

S3 12 Average value of 24 dosage units (S1 + S2

+ S3 ) is equal to or greater than Q; not

more than 2 units are less than Q - 15%; no

unit is less than Q - 25%.

Enhancement of dissolution rate of

tablet:1. Micronization

2. Nanonization

A. Nanosuspensions

B. Nano crystals

C. Nano emulsion:

1. Micronization

Particle size reduction leads to increase in the effective surface

area resulting in enhancement of solubility and dissolution velocity

of the drug.

Micronization technique is used to improve dissolution rates of

drugs into the biological environment, in order to improve the oral

bioavailability

2. Nanonization :

Various nanonization strategies have emerged to increase the

dissolution rates and bioavailability of numerous drugs that are

poorly soluble in water. Nanonization broadly refers to the study

and use of materials and structures at the Nano scale level of

approximately 100 nm or less.

A. Nanosuspensions:

Nanosuspensions are sub-micron colloidal dispersion of

pure particles of drug, which are stabilized by surfactants.

Nanosuspensions technology solved the problem of drugs

which are poorly aqueous soluble and less bioavailability

B. Nano crystals:

The term drug Nano crystals imply a crystalline state of the discrete

particles, but depending on the production method they can also be

partially or completely amorphous. Drug Nano crystals can be produced

by bottom up technologies (precipitation methods) or alternatively by

top down technologies (size reduction methods).

C. Nano emulsion:

Nano emulsions are a nonequilibrium, heterogeneous system

consisting of two immiscible liquids in which one liquid is dispersed as

droplets in another liquid.

Factors that Influence Dissolution Testing:

Factors affecting Drug Dissolution :-

1. Factors related to apparatus and test parameters

2. Factors relating to the physicochemical properties of drug.

3. Factors relating to the dosage forms

1. FACTORS RELATED TO APPARATUS AND TEST

PARAMETERS

1.Temperature

2. Agitation

1. Agitation

-Rate of dissolution depends on type of agitation used, the degree of

laminar and turbulent flow in system, the shape and design of stirrer. -

Speed of agitation should be such that it prevent turbulence and sustain a

reproducible laminar flow, which is essential for obtaining reliable results. -

So, agitation should be maintained at a relatively low rate

2. Temperature

-Should be maintained at 37 ± 0.5 º C 4

2. Factors relating to the physicochemical

properties of drug-

1. Solubility-

• Solubility plays important role in controlling dissolution from dosage form.

• From Noyes-Whitney equation it shows that aqueous solubility of drug

which determines its dissolution rate

ii. Particle size and effective surface area of the drug –

• Particle size and surface area are inversely related to each other.

Two types of surface area –

Absolute surface area which is the total surface area of any particle.

Effective surface area which is the area of solid surface exposed to the

dissolution medium

• Effective surface area is directly related 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.

iii. Polymorphism and amorphism –

• When a substance exists in more than one crystalline form, the different

forms are designated as polymorphs and the phenomenon as

Polymorphism.

• Amorphous form of drug which has no internal crystal structure

represents higher energy state and greater aqueous solubility than

crystalline forms.

IV. Salt form of the drug-

• Dissolution rate of weak acids and weak bases can be enhance by

converting them into their salt form.

• With weakly acidic drugs, a strong base salt is prepared like sodium

and potassium salts of barbiturates and sulfonamides.

• With weakly basic drugs, a strong acid salt is prepared like the

hydrochloride or sulfate salts of alkaloidal drugs

2. Factors relating to the dosage forms –

Pharmaceutical excipients –

1. Binder and granulating agents:

2. Disintegrants

3. Lubricants

4. Coatings

5. Complexing agents

1. Binders and granulating agents:

- In general, the hydrophilic ( aqueous) binders show better

dissolution profile with poorly wettable drugs like phenacetin by

imparting hydrophilic properties to the granule surface.

- Large amounts of such binders increase hardness and decrease

disintegration / dissolution rates of tablets.

2. Disintegrants

- Disintegrating agent added before & after the granulation affects

the dissolution rate.

- Microcrystalline cellulose is a very good disintegrating agent but at

high compression force, it may retard drug dissolution.

- Starch is not only an excellent diluent but also superior disintegrant

due to its hydrophilicity and swelling property.

3. Lubricants:

- The nature, quantity, and quality of lubricants added can

affect the dissolution rate.

- Lubricants are hydrophobic in nature (several metallic

stearate & waxes) which inhibit wettability, penetration of water

into tablet so decrease in disintegration and dissolution

4. Coatings

-In general, the deleterious effect of various coatings on drug dissolution from

a tablet dosage form is in the following order: Enteric coat > Sugar coat >

Non- enteric film coat.

5. Buffers

- Buffers are sometimes useful in creating the right atmosphere for drug

dissolution, e.g. buffered aspirin tablets.

6. Complexing agents

- A complexed drug may have altered stability, solubility, molecular size,

partition coefficient and diffusion coefficient.

- E.g. Enhanced dissolution through formation of a soluble complex of

ergotamine tartarate-caffeine complex and hydroquinone-digoxin complex

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.

3. Factors relating to the dosage forms

B. Compression force

- The compression process influence density, porosity, hardness, disintegration

time & dissolution of tablet.

Conclusion :

By studying various factors influencing the rate of dissolution, we can

optimize the different properties of the formulation. By conducting

dissolution studies we can know the batch to batch reproducibility.

We can estimate the solubility profiles of the drug.

The best available tool today which can at least quantitatively assure

about the biological availability of drug from its formulation is its invitro

dissolution.

“Prevention Is Better

Than Cure”

THANKS