Biopharmaceutics 4th year

Dissolution and release of drug from gastrointestinal tract (in vivo and in vitro)

Theories of Dissolution Dissolution is a process in which a solid substance solubilizes in a given solvent. i.e mass transfer from a solid surface to liquid phase.

Theories of Dissolution Some of important theories are: Diffusion layer model/ film theory Dankwert’s model/ penetration or surface renewal theory Interfacial barrier model/double barrier or limited solvation theory

Diffusion layer model/ Film theory Is simplest and most common theory of dissolution Is the process of dissolution of solid particles in liquid, in the absence of chemical forces

Diffusion layer model/ Film theory Consist of two consecutive steps: Solution of the solid to form a thin film or layer at the solid/liquid interface called stagnant film or diffusion layer which is saturated with the drug. This step is rapid

Diffusion layer model/ Film theory Consist of two consecutive steps: 2. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution This step is slower

Diffusion layer model/ Film theory

Diffusion layer model/ Film theory D = diffusion coefficient of drug A = surface area of dissolving drug Kw/o = partition coefficient of drug Cs- Cb = concentration gradient V = volume of dissolution medium h = thickness of stagnant layer

Diffusion layer model/ Film theory The equation that explain the rate of dissolution when the process is diffusion controlled is

Influence of some parameters on dissolution rate of drug Diffusion coefficient D Greater value faster dissolution Diffusion decrease as viscosity of the dissolution medium increase

Influence of some parameters on dissolution rate of drug 2) Surface area A Greater surface area faster dissolution Can be increased by micronization of drug particles

Influence of some parameters on dissolution rate of drug 3) Water/oil partition coefficient Kw/o Higher value , more hydrophilicity , faster dissolution .

Influence of some parameters on dissolution rate of drug 4) Concentration gradient Cs- Cb Greater the concentration gradient , faster diffusion and dissolution Can be increased by increasing drug solubility and volume of the dissolution medium

Influence of some parameters on dissolution rate of drug 5) Thickness of the stagnant layer Increase thickness, lesser diffusion and dissolution Can be decreased by agitation

Diffusion layer model/ Film theory The in vivo dissolution is always rapid than in vitro dissolution ?? The moment the drug dissolves, it absorbed into systemic circulations Cb = 0 Under in vivo condition there is no concentration build up in the bulk Cs >> Cb The dissolution will be at maximum sink conditions are maintained

Diffusion layer model/ Film theory In case of in vitro dissolution, after sometime the dissolution slows down due to build up in the concentration of drug in the bulk of the solution So it under non sink condition

Bathing the dissolving solid with fresh solvent from time to time To obtain good in vitro – in vivo dissolution rate correlation, the in vitro dissolution rate must be carried under sink condition: Bathing the dissolving solid with fresh solvent from time to time Increase the volume of dissolution fluid Removing of the dissolved drug Adding water miscible solvent such as alcohol Adding adsorbent to remove dissolved drug

Danckwert’s Model (Penetration or Surface Renewal Theory) Suggest that turbulence in the dissolution medium exists at the solid/liquid interface. The agitated fluid consisting of macroscopic mass of eddies or packets reach the solid/liquid interface at random fashion due to eddy currents Absorb the solute by diffusion and carry it to the bulk of the solution

Danckwert’s Model (Penetration or Surface Renewal Theory) Packets are continuously replaced by new packets from fresh solvent Drug concentration at solid/liquid interface never reaches Cs and has lower limit of Ci

Danckwert’s Model (Penetration or Surface Renewal Theory) Danckwert’s Model is expressed by equation M = mass of solid dissolving Ɣ = rate of surface renewal

Danckwert’s Model (Penetration or Surface Renewal Theory)

Interfacial Barrier Mode According to this model, an intermediate concentration is exist at interface as a result of solvation mechanism This model expressed by G = dissolution rate per unit area Ki = effective interfacial constant

In vitro Dissolution Test In the pharmaceutical industry, in vitro dissolution is one of the most important physicochemical tests of drug products. In general there are many dissolution apparatus. Apparatus I (rotating basket) and Apparatus II (rotating paddle) are the most commonly used for oral dosage forms.

Factors considered in the design of dissolution test” Factors relating to the dissolution apparatus: Size and shape of container, nature and speed of agitation, performance precision of apparatus. 2. Factors relating to the dissolution fluid: Composition (water, 0.1N HCL, buffer,..), volume, temperature (37Cº)

Factors considered in the design of dissolution test” 3. Process parameters: Methods of introduction of dosage form, sampling techniques, changing the dissolution medium

Rotating Basket Apparatus (Apparatus 1) Consist of: beaker having semispherical bottom with 1 L capacity Immersed in a water bath to maintain the temperature 37Cº Basket of 22 mesh located 2 cm distance from bottom rotated through a shaft

Rotating Paddle Apparatus (Apparatus 2) It is the same as Apparatus 1 except the basket is replaced by paddle Dosage form is allowed to sink at the vessel bottom.

In vitro Dissolution Test

In vitro – In Vivo Correlation

In vitro – In Vivo Correlation there has been increased investigation and success in using in vitro tests to evaluate or predict in vivo performance of solid drug product FDA defines IVIVC as “A predictive mathematical model describing the relationship between an in vitro property of a dosage form (usually the rate or extent of drug dissolution or release) and a relevant in vivo response

Objective To ensure batch to batch consistency of a drug product To serve as a tool for development of a new dosage form

In Vitro – In Vivo Correlation Correlation Based on the Plasma Level Data Correlation Based on the Urinary Excretion Data Correlation Based on Pharmacologic Response