Dissolution

The rate of solution of solid in a solvent. It is the transfer of solute molecules from the surface of solid into the bulk of solvent. Dissolution is the process by which a solid solute with relatively low solubility enters into a solution in the presence of solvent The rate of dissolution, is the Amount of active ingredient in a solid dosage form dissolved in unit time under standardized conditions of liquid/solid interface, temperature, and media composition

‡ Mechanisms of dissolution ‡ Three dissolution models :1. Diffusion Layer Model or Film Theory 2. Interfacial Barrier Model or Limited Solution Theory 3. Danckwerts Model or Surface renewal theory. These models can be used either alone or in combination to describe the dissolution rate.

Suspension Tablet or Capsule Fine particles Granules Dissolution Solution Drug in Solution Absorption .

Gradient is destroyed. Diffusion Layer Model or Film Theory  Simplest Model  A static liquid film adjacent to the solid surface. then the model is expressed the Noyes-Whitney Equation .  Rapid reaction occurs between solid and liquid film interface.1. ‡ The rate at which the dissolution takes place from a particle into its fluid.  Rapid mixing occurs and conc.

diffusion coefficient  A-effective surface area  h-the thickness of the diffusion layer  Cs-saturation solution solubility of the drug in diffusion layer  Cg ±conc. Of the drug in solution in the bulk of GI Fluids .rate of the dissolution of the particles  D.Noyes-Whitney Equation:‡ The rate of dissolution (dm/dt)can be dm/dt=DA(Cs-Cg)/h Where : dm/dt.

the particle size and surface area are also changed. W0 1/3-Wt 1/3 = k t where :  W0 = original mass of the drug  Wt = mass of the drug remained at time t  k= dissolution rate constant. ‡ These changes during dissolution is known as Hixson and crowells cube root law of dissolution«.‡ The dissolution of drug takes place. ..

. ‡ So the rate of solubility of solid in the liquid film becomes rate limiting rather than diffusion of dissolved molecules.Interfacial Barrier Model or Limited Salvation Theory  The reaction at the solid surface is not rapid .2. ‡ The equation for describing the dissolution rate of solid is md/dt=Ki(Cs-Cg) ‡ Where :‡ Ki ± the effective interfacial transport rate constant. due to high free energy of activation required for solubility of a solid.

 The turbulence present in the dissolution medium at the solid and liquid interfacial responsible for the rapid movement of solvent. never reaches Cs because rapid movement of solvents.3. .  The drug conc.Danckwerts Model or surface renewal Theory  Used for the existence of a saturated diffusion layer and proposed that transport of a solute away from the solid surface adsorb the solute by normal diffusion.

 Micronisation of drugs can also increase the rate and extent of adsorption by reducing the particle size. digoxin and benoxaprofen. greater the SA.particle size and effective surface area.  Reduce the particle size.  The addition of surface active agent can leads the increase the dissolution of drugs.Factors affecting the rate of dissolution 1.  Smaller the drug particle. . can increase the bioavailability of certain drugs like griseofulvin.

‡ Prevention of aggregation and agglomeration of the drug particles. ‡ An increase in aqueous solubility of the drug due to the presence of drug particles in small size. others factors also contribute to the improvement of the rate of dissolution by solid dispersion.‡ In Addition to size reduction. ‡ Excellent wettabillity ‡ Possible formation of metastable polymeric forms. . ‡ Improvement solubility of the drug in diffusion layer.

‡ It can be modified by increasing and decreasing its saturation solubility. . MW and Melting point of drugs.satuartion solubility of the drug. ‡ It also depend on physical and chemical properties of drug like partion coefficient.2. Cs ‡ It affect both patient and pharmaceutical parameters.

Cs = total solubility of drug in the fluid [HA]=the intrinsic solubility of unionized drug [A-] = the conc.‡ The pH effect ‡ The solubility of weak acidic drugs is ‡ Cs= [HA] + [A-] ‡ Where. of its anion Total solubility of weak acidic drugs Cs =Co+CoKa/[H+] = Co(1+Ka)/[H+] For weak basis drug Cs= Co+Co[H+]/Ka = Co(1+[H+])/Ka .

‡ Therefore for weak acidic drugs is more than in the stomach.‡ The rate of weak acidic drugs increases with increasing pH (i. ‡ The dissolution rate of basic drugs decreasing with an increasing pH. decreasing [H+]).e. . whereas weak basic drugs show a greater dissolution rate in the intestine.

‡ The dissolution of strong alkali salts of weak acids drugs have been considered to the salt form of drug shows a rapid dissolution rate than that of its parent drug.‡ Salt Forms ‡ The salt form of weak acidic drug has relatively high solubility at the elevated pH in the diffusion layer. dissolution of the drug particles will take place at a faster rate. penicillin V and its potassium and calcium salts results peak plasma levels of the drug are best correlated with their dissolution rates. .g. ‡ E.

. therefore if the drug can be given as a salt the solubility can be increased and we should have improved dissolution.If we look at the dissolution profile of various salts. Dissolved Drug Concentration versus Time Salts of weak acids and weak bases generally have much higher aqueous solubility than the free acid or base.

High Permeability (Slow solubility ) Class 3: High Solubility .Low Permeability (Slow permeability) Class 4: Low Solubility .According to the BCS.permeability problems) Class 2: Low Solubility .Low Permeability (Slow permeability) .High Permeability (Well absorbed orally and no solubility . drug substances are classified as follows: Class 1: High Solubility .

Spray freezing into liquid 5.Nanonisation 3.Solid Dispersion .Supercritical Fluid Recrystallisation 4.To improve dissolution of poorly soluble drug 1.Use of salt forms 7. use of surfactant 6.Micronisation 2.

4. 5. 6. 2.In ±vitro dissolution testing models 1. 7. Rotating Basket Apparatus (App 1) Rotating Paddle Apparatus (App 2) Reciprocating cylinder Apparatus (App 3) Flow-through Cell Apparatus (App 4) Paddle Over Disc Apparatus (App 5) Cylinder Apparatus (App 6) Reciprocating Disc Apparatus (App 7) . 3.

Dissolution Menology For Immediate Release product based on BCS Dissolution Methodology Single point NLT 85 % Q in 15 min. Multiple Point NLT Q<85% in 15 Min Multiple Point Same as Class I Same as Class II BCS I II III IV .

of Dosage Units Tested 6 6 Acceptance Criteria S1 S2 No. Dosage unit is Less Than 5% Average of the twelve Dosage units(S1+S2) and No dosage unit is less than Q=15% Average of the twenty four Dosage (S1+S2+S3) and not more than two dosage unit are less than Q=15% and Q=25 % S3 12 .‡ Dissolution Acceptance Criteria Stage No.

.In Vitro ±In Vivo Correlation (IVIVC) As the predictive mathematical model that describes the relationship between an in vitro property (such as the rate and extent of dissolution) of a dosage form and an in vivo response (such as plasma drug profile ).

‡ In vitro-in vivo correlation (IVIVC) ± the correlation between in vitro drug dissolution and in vivo drug absorption .

 The optimization of formulations may require changes in the composition. equipment. .  The correlation between in vitro drug dissolution and in vivo drug absorption  The development of new pharmaceuticals to reduce the number of human studies during the formulation development.CORRELATION LEVELS  The concept of correlation level is based upon the ability of the correlation to reflect the complete plasma drug level-time profile which will result from administration of the given dosage form. and batch sizes. manufacturing process.

equipment. ‡ The main purpose of an IVIVC model ± to utilize in vitro dissolution profiles as a surrogate for in vivo bioequivalence and to support biowaivers ± Data analysis of IVIVC attracts attention from the pharmaceutical industry . manufacturing process.Purpose of IVIVC ‡ The optimization of formulations ± may require changes in the composition. and batch sizes. a considerable amount of efforts is required to study bioequivalence (BE)/bioavailability(BA). ± In order to prove the validity of a new formulation. which is bioequivalent with a target formulation.