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Theories of dissolution Release rates and constants Mechanisms of conventional release Mechanisms of controlled release Dissolution data treatment Factors affecting dissolution Types of dissolution equipments IVIVC

REFERENCES

Encyclopedia of Pharmaceutical Technology - JSwarbrick Advanced Pharmaceutical Solids - JT Carstensen Pharmaceutical Dissolution Testing UV Banakar USP CDER guidelines

Rate limiting step Rate and extent of absorption Tools for predicting in vivo performance Monitoring product quality The enantiomer of ibuprofen has higher aqueous solubility, higher density, and better flowability, but a lower IDR when compared to its racemate

Dissolution is generally defined as a process by which a solid substance is solubilized into the solvent to yield a solution Process by which a solid substance dissolves

Two steps govern rate & extent of dissolution SOLVATION Drug + solvent solvated drug Breaking existing intermolecular forces Solid-solid and liquid-liquid interaction Takes place at the solidliquid interface. Solubility controlled

Thermodynamically Net entropy +ve favors dissolution Net enthalpy zero, the reaction will continue until all available solid is dissolved Net enthalpy change is +ve, the reaction will progress until equilibrium is reached ( G=0) and a saturated solution is obtained In liquid water hydrogen bonds are constantly being broken and reformed, because thermal energy is sufficient to cause cleavage of these interactions. At RT, the rate of solvation is generally so fast that equilibrium is almost instantaneous

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MASS TRANSPORT

Transport of solvated molecules from the solidliquid interface to the bulk solution. Involves molecules moving a large distance compared to molecular dimensions Usually much slower Rate limiting step Controls the dissolution process Diffusion controlled Agitation

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Single particulate systems Multiparticulate systems Multicomponent polyphase systems Planar surface dissolution systems

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Ficks laws Noyes and Whitney 1897 Nernst and Brunner 1904

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In dissolution testing, diffusion + convection processes generate dissolved drug in solution Diffusion is the process by which atoms, molecules or small particles are transported from a region of higher concentration to a region of lower concentration, due to random motion. Brownian motion/diffusion is a primary transport mechanism For small particles (<0.1 m) Transport distance is small (<few mm). Over larger distances, diffusion is slow Convection - important to obtain significant transport of material in a reasonable time period

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Rate of transfer (dQ/dt ) of a diffusing substance through unit area (A) in one dimension (x) is proportional to the concentration gradient, C/x

J is the flux (rate of diffusion) D is the diffusion coefficient Applicable only at steady state conditions Equation for rate of mass transfer

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For non steady state - concentration with time Equation for acceleration/deceleration of mass transfer

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Dissolution by pure diffusion is rare Convection - accompanies diffusion in transporting dissolved molecules NOYES AND WHITNEY THEORY Basic transport controlled model for solid dissolution When surface area is constant, the dissolution rate(dQ/dt) is proportional to the difference between solubility (CS) and the bulk solution concentration (Cb) where k is a constant (mass transfer coefficient)

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Nernst 1904 The film theory Explains basic principles of dissolution of single particulate system Less complicated than other theories There is a stagnant diffusion layer surrounding the solid particles NernstBrunner thickness layer The dissolution rate of the solid particles is controlled by diffusion of solute through the stagnant layer

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C ! t

(C C ) Vh

dm DA(Cs C ) ! dt h

dm ! kA(Cs C ) dt

kACs C! t V

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Cube root model Monosize large spherical particles Under sink conditions, isotropic dissolution Assumption

DR is proportional to the surface area For large particles, the diffusion layer on the

particle surface can be approximated as planar when the thickness of the layer is substantially smaller than the particle diameter of spherical particles

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W = particle weight at time t; Wo = initial particle weight K1/3 are composite rate constants = density of particle; N = number of particles D = diffusion coefficient CS = solubility, h = diffusion layer thickness

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Two-thirds-root law Very small spherical, monosized particles Under sink conditions Assumption

Thickness of the diffusion layer is substantially

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Time taken for complete dissolution (hrs) Higuchi Hixson 0.01 1.6 0.8 16.2 3.2 32.4 13 64.8 81 162 8101.9 1620.4 202546.3 8101.9

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Stagnant diffusion layer adhering to the solid surface is hydrodynamically unrealistic Mass transport in the direction parallel to solid surface is disregarded Nernsts layer is considered to have constant thickness everywhere Surface area is assumed to remain constant

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Transport controlled dissolution in a stirring liquid involves two fundamental process Molecular diffusion due to conc gradient Forced convection due to moving solvent Dissolution is usually a combination of these two mechanisms, which is called convective diffusion Extension of Ficks second law of diffusion, with the addition of convection terms More hydrodynamically realistic

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In the convective diffusion model, solvent stream movement depends on its distance from the solid surface. At distances far from the solid surface, convection dominates over diffusion for transport of solute molecules. At distances very close to the solid surface the solvent stream movement is slow, while the concentration gradient is large. In such regions, the contribution of diffusion to the solute molecule movement is comparable to or larger than convection. This region is also called the diffusion layer, but it is different from Nernsts concept.

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Q = amount dissolved at time t CS = solubility D = diffusion coefficient v = bulk solvent velocity a = particle radius

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Penetration theory Danckwerts model 1951 Transport of solute is achieved by the macroscopic packets that reach the solid surface Turbulence or eddy currents deliver solvent packets Solvent pockets absorb solutes at the surface, and deliver them to the bulk solution Molecules must first solvate/dissolve

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m is the mass of dissolved substances and K is the interfacial tension also defined rate of surface renewal

dm ! A( D)1 / 2 (Cs C ) dt

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Stagnant layer usually not observed No boundary layer as turbulence extends to surface Surface is replaced continuously with fresh solvent Diffusion of solvent from bulk through layer of thickness to the surface is rate limiting step

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According to Toor Marchello 1958 Film theory and penetration theory are not separate unrelated concepts. Is this statement justified????????

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Limited Solvation rate theory Film and surface renewal theories assume

Solid solution equilibrium exist at solid liquid

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Dissolution is described by two rate processes Rate of interfacial or solid-solvent reaction Rate associated with diffusional or transport process An intermediate concentration less than saturation may occur at interface

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Reaction at the solid/liquid interface is not instantaneous due to a high activation free energy barrier which has to be surmounted before the solid can dissolve assumes that the reaction at the solid surface is significantly slower than the diffusion across the interface equilibrium exists at the surface, and the liberation of solutes at the solidliquid interface controls the overall rate of the transport process

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G is the dissolution rate per unit area ki is the interfacial transport coefficient

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Planar surface dissolution is easier to model than particulate dissolution The mathematics is simpler. The simplest expression-NoyesWhitney equation. The diffusion layer model More accurately described with convective diffusion models based on different hydrodynamic conditions.

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DR is dependent on many factors Advantageous to measure DR which is independent of many factors Intrinsic dissolution rate (IDR) The rate of mass transfer per area of dissolving surface. Amount of substance dissolved per unit time and unit surface area mg cm-2 min-1

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Dissolution medium properties pH, ionic strength, counter ions

Independent of

boundary layer thickness volume of solvent (if sink conditions are

IDR vs DR

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When dissolution is controlled solely by diffusion the rate of diffusion is directly proportional to the saturated solubility, The rate constant K1 is defined by

K1 ! 0.62 D 2 / 3R 1/ 6[ 1/ 2

v = kinematic viscosity; [ = angular velocity By maintaining the dissolution fluid viscosity and rotational speed of the sample constant, the dissolution rate(dcldf) from a constant surface area (A) will be constant and related solely to solubility. Under sink conditions (Cs >C) gives

dc ! K 1Cs d V

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The amount of drug release is monitored usually by UV with time. The slope of the line divided by the exposed surface area gives the IDR 0.1mg/(cm2*min)

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IDR

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da 2 DCs ! dt l da 2 DCs ! dt ka

Non disintegrating Rapidly disintegrating Slowly disintegrating

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Model

Zero order First order Higuchi Peppas

Equation

Mt = M0 + K0 t Mt = M (1-e-K1t) Mt /Mw = KH t1/2 Mt /Mw = K.tn

Plot of graph

Mt /M0 vs t log Mt vs t Mt /Mw vs t1/2 log (Mt/Mw) vs log t

Parameters

Ko- zero order rate constant K1- first order rate constant KH=DCS(2A-CS) KH- Higuchi constant K- kinetic constant n-exponent characterizing diffusional mechanism KHC Hixon-Crowell constant. a, b constants. b = shape factor (define the diffusional process) a = (1/td)b (location factor)

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HixonCrowell Weibull

1/3-

Mt1/3 = KHC t

1/3-

Mt1/3 vs t

Mt /Mw = 1-e-atb

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Model

Equation

Plot

Bt vs t give slope of B D = Bdp2/ 4 2.

Boyd & Bt = -2.303 log10(1-F) - 0.498 Reichenberg at F>0.85 Bt = 6.283 - 3.290F - 6.283(11.047F)1/2 at F<0.85 Bhaskar -ln (1-F) = Kt0.65 K= 1.59(6/dp)1.3 D0.65 t0.65

-ln(1-F) vs t0.65

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The lower value of b reflects the slowing down of the diffusion process in the disordered medium. B = 0.690.75 Fickian diffusion 0.75<B<1 anomalous transport b=1 First order Fickian b<=1 no disintegration occurs, and DR will decrease steadily b>1 Sigmoid curve complex mechanism, the drug release rate is slow initially followed by an increase in release rate

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