DISSOLUTION

Presented by: Muhammed Fahad

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DISSOLUTIONDefinition:• 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.

• Dissolution is the rate determining step for hydrophobic, poorly aqueous soluble drugs.

E.g. Griseofulvin, spironolactone

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Why dissolution studies?

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.

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Mechanism of Dissolution

1. Diffusion layer model

2. Danckwert’s model

3. Interfacial barrier model

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Dissolution mechanisms

2 steps:

1. Interfacial reaction cause liberation of solid particles into boundary layer (Cs).

2. Migration of solute from boundary layer into bulk of solution (C) by diffusion & convection.

• Overall rate of dissolution depends on the slowest step.

• Usually Step (2) is the RDS.

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Fick’s law:

or

where k = rate constant

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1. Diffusion Layer Model

• Also called ‘film theory’.• Formation of a thin film at the interface, called as

stagnant layer.• 2 steps are involved:

1) Interaction of solvent with drug surface to form a saturated drug layer , called stagnant layer.

2) Diffusion of drug molecules from stagnant layer into bulk of the system.

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Diagram Representing Diffusion through the Stagnant Layer

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Noyes- Whitney’s equation:

dC/dt = dissolution rate of the drug,k = dissolution rate constant,Cs = concentration of drug in the stagnant

layer, andCb = concentration of drug in the bulk of the

solution at time t

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Modified Noyes-Whitney’s equation:

• Where,• D = diffusion coefficient (diffusivity) 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.

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2. Danckwert’s Model • Also called “Penetration or Surface Renewal Theory”.

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• m = mass of solid dissolved, and• γ = rate of surface renewal (or the interfacial

tension)

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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,

where Ki = effective interfacial transport constant.

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Powder Dissolution: The Hixson-Crowell Cube Root Law

• Applicable for drug powders of uniform size.• Rate of dissolution based on cube root of wt. of

particles.

M0 = initial mass of powder

M = mass of powder dissolved in time, tk = cube root dissolution rate constant

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Particulate Dissolution

• Used to study influence of particle size & surface area on dissolution.

• Here, surface area is not made constant.• Weighed powder introduced in dissolution medium

agitated by propeller.• Rate of dissolution increases with decrease in

particle size.• Effective and absolute surface area.

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PROCESS OF DISSOLUTION

States of matter:• Solid, liquid & gaseous states.• Dissolution involves relocation of a solute molecule

from an environment where it is surrounded by other identical molecules, into a cavity in a liquid.

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Energy changes:• For spontaneous reactions, ΔG must be –ve.• ‘G’ is a measure of the energy available to a system

to perform work.

ΔG = ΔH – TΔSWhereΔH = change in enthalpy of the systemΔS = change in entropy of the systemT = temperature

• ΔS is usually positive for spontaneous reactions.

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Intrinsic Dissolution rate

• Rate which is independent of rate of agitation, area

of solute available, etc.

• Intrinsic Dissolution Rate (IDR): rate of mass

transfer per area of dissolving surface.

• It is independent of boundary layer thickness and

volume of slolvent .

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• Thus,

IDR = k1Cs

• IDR measures the intrinsic properties of the drug

only as a function of the dissolution medium, e.g.

its pH, ionic strength, counter ions, etc.)

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Measurement of dissolution ratesApparatus Classification in USP:

1. Apparatus 1 (rotating basket)

2. Apparatus 2 (paddle assembly)

3. Apparatus 3 (reciprocating cylinder)

4. Apparatus 4 (flow-through cell)

5. Apparatus 5 (paddle over disk)

6. Apparatus 6 (cylinder)

7. Apparatus 7 (reciprocating holder)

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Apparatus Classification in European Pharmacopoeia for different dosage forms

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Problems associated with development of dissolution tests:

1. Need to have a manageable volume of dissolution medium.

2. Development of less-soluble drugs.

3. Insufficient analytical sensitivity for low-dose drugs.

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According to USP:

A drug product is considered rapidly dissolving when no less than 85% of the labeled amount of the drug substance dissolves within 30 minutes, using USP Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a volume of 900 ml or less in each of the following media: (1) 0.1 N HCl or Simulated Gastric Fluid USP without enzymes;

(2) a pH 4.5 buffer; and

(3) a pH 6.8 buffer.

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Biopharmaceutical Classification System

• Class I: High solubility—High permeability• Class II: Low solubility—High permeability• Class III: High solubility—Low permeability• Class IV: Low solubility—Low permeability

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Measurement of dissolution rates

Beaker method:• Developed by Levy and Hayes.• Consist of 400 ml beaker with 250 ml dissolution

medium.• Medium is agitated by a 3-bladed polyethylene

stirrer of 50 mm diameter.• Stirrer is immersed to a depth of 27 mm into the

dissolution medium and rotated at 60 rpm.

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Flask-stirrer method:• R.B. flask is used instead of beaker.

Rotating Basket method:• USP Apparatus I• Small wire mesh basket fastened to end of shaft

connected to a motor.• Immersed in a flask maintained at 370C ± 0.50C.• Samples are withdrawn at regular intervals.

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Paddle Assembly method

• USP Apparatus II• Basket in above method is replaced by paddle.• Paddle is continuous with the shaft.• Tablet is placed at the bottom of the medium.

Disadvantages:• Since dissolution volume is limited, use of poorly

soluble drugs is limited.

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Variables in USP Apparatus I & II

• Type of dissolution medium & its volume.• Type of apparatus to be used.• Speed (rpm) of rotation.• Total time of the test.• Further assay procedures.

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USP Testing methods:

• 6 tablets monograph tolerance limit, Q + 5%• If fail, 6 more tablets are used avg. of 12 tabs ≥ Q,

and none is < Q-15%.• If failed, 12 more tablets used avg. of 24 tabs ≥ Q,

and no 2 tab is < Q-15% & none is < Q-25%.• Usual tolerance in USP / NF is “not less than 75%

dissolved in 45 min”.

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Reciprocating Cylinder

• Proposed by Beckett & incorporated in USP in 1991.• Mainly used for dissolution testing of extended-

release products.• Also used for poorly soluble drugs.• Capable of agitation and media composition changes

during a run & full automation.• Dips per minute (dpm) is used.• Inner reciprocating tubes & outer tubes.

DISSOLUTION 35Reciprocating Cylinder

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Use:• Especially useful in the case of chewable tablets.• Studies show that 5 dpm in Apparatus 3 is

equivalent to 50 rpm in Apparatus 2.• So higher dpm can achieve rigorous movts. similar

to chewing—not possible by Apparatus 2.• Used for solutions requiring pH/buffer changes like

enteric-coated/extended-release drugs.

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Flow-Through Cell

• Introduced by Langenbucher.• Open system—offer unlimited medium supply—

especially useful for poorly soluble drugs.• Also used for dissolution test of sugar-coated tabs,

suppositories, soft gelatin capsules, semi-solids, granules, implants, etc.

• Small volume cell is subjected to continuous stream of dissolution media flow from bottom to top.

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• Agitation is achieved by pulsating movement of piston.

• Results obtained as fraction dissolved per unit time (due to continuous media flow).

• Data is transformed to the usual cumulative amt. dissolved vs. time.

Advantages:• Maintenance of sink conditions.• Minimizing downtime between tests.

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Flow-Through Cell

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Qualification & Validation of the Apparatus

• To maintain “quality by design”.• Physical & chemical calibrations—geometrical &

dimensional accuracy & precision.• Vibration or undesired agitation to be avoided.• Temperature, rotation speed/flow rate, volume,

sampling probe, procedures, etc. need to be monitored periodically.

• Use of USP calibrator tablets for App. 1 & 2 (to be performed not less than twice a year)

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Factors Affecting Dissolution

Surface area & undissolved solid• Surface area α dissolution.• Coherent masses may reduce total surface area

available overcome by using wetting agent.• Presence of pores.

E.g. dissolution of phenacetin (hydrophobic) is enhanced by adding diluent gelatin (hydrophilic) during granulation.

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Addition of Tween 80 to dissolution medium (0.1 N HCl) for phenacetin increased the dissolution rate by increasing effective surface area.

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Solubility of solid in dissolution medium

Temp. of dissolution medium

pH of the medium

Solubility of the drug in dissolution medium

Presence of cosolvents

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Concentration of solute in solution • Should simulate sink conditions present in GI tract.• Larger volume of dissolution medium helps to

maintain ‘C’ negligible compared to ‘Cs’.

• Removal of dissolved solute from dissolution medium enhances rate of dissolution.

Eg. Adsorption onto another substance Partition to another immiscible liquid Removal of solute by dialysis Cont. replacement of dissolution medium

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Dissolution rate constant

Depend upon Thickness of boundary layer Degree of agitation Speed of stirring Shape, size & position of stirrer Vol. of dissolution medium Shape & size of container Viscosity of dissolution medium

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Disintegration & Deaggregation

• Disintegration and subsequent deaggregation may also be RDS for dissolution.o E.g. coated dosage forms

• After disintegration, larger aggregates need to deaggregate to yield fine particles.

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Effect of manufacturing processes

Addition of lubricants

E.g.: 325-mg salicylic acid dissolved rapidly in 0.1 N HCl when SLS was added to it.

Dissolution rate decreases with addition of hydrophobic lubricants like Mg. stearate.

• Most effective lubricants are hydrophobic act by particle coating hence mfg. process is imp.

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Addition of disintegrating agents like starch swell & enhance dissolution.

Compression force• Increase in compression force may decrease or

increase dissolution rate.

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Recent developments in dissolution testing

• Use of more biorelevant media—FaSSIF & FeSSIF media.

• FaSSIF—Fasted State Simulated Intestinal Fluid• FeSSIF—Fed State Simulated Intestinal Fluid

Advantages:• Provide physicochemical properties similar to human

GIT.

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REFERENCE1. 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. 408-412

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