Tablet Evaluation Tests/Dissolution
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Dissolution is the process by which a solid solute enters a solution. In the pharmaceutical industry, it may be defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition.
Dissolution is considered one of the most important quality control tests performed on pharmaceutical dosage forms and is now developing into a tool for predicting bioavailability, and in some cases, replacing clinical studies to determine bioequivalence. Dissolution behaviour of drugs has a significant effect on their pharmacological activity. In fact, a direct relationship between in vitro dissolution rate of many drugs and their bioavailability has been demonstrated and is generally referred to as in vitro-in vivo correlation, IVIVC38.
Solid dosage forms may or may not disintegrate when they interact with gastrointestinal fluid following oral administration depending on their design (Figure 1).
Figure 1: Schematic diagram of the dissolution process
Dissolution kinetics is important in determining the bioavailability of a drug39. Levy45 and some other workers46 reported that
the dissolution rate controls the rate of build up of certain drugs in the blood stream. It was thus recognised that in-vitro
dissolution kinetics provides useful information on the availability of drugs and their subsequent therapeutic effects in-vivo45.
This led to the inclusion of dissolution tests in the United States NF XIII (1970) and USP XVIII (1970) monographs for one
capsule and twelve tablet preparations. In 1975, dissolution tests were included in the British Pharmacopoeia (amendment to BP 1973)
for digoxin tablets. The various pharmacopoeias contain specifications on the
dissolution requirements of various drugs. A variety of designs of apparatus for dissolution testing have been proposed and
tested, varying from simple beaker with stirrer to complex systems with lipid phases and lipid barrier where an attempt is made
to mimic the biological milieu. The choice of the apparatus to be used depends largely on the physicochemical properties of the
dosage form 47.
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Theories of dissolution
Some workers 48,49 have reviewed the factors which can affect the dissolution of tablets and these include the stirring speed, temperature, viscosity, pH, composition of the dissolution medium and the presence or absence of wetting agents.
Physical models have been set up to account for the observed dissolution of tablets. According to Higuchi50, there are three models which either alone or in combination, can be used to describe the dissolution mechanisms. These are:
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Introduction |
The Diffusion layer model
This model (Fig 2) assumes that a layer of liquid, H cm thick, adjacent to the solid surface remains stagnant as the bulk liquid passes over the surface with a certain velocity. The reaction at the solid/liquid interface is assumed to be instantaneous forming a saturated solution, Cs, of the solid in the static liquid film. The rate of dissolution is governed entirely by the diffusion of the solid molecules from the static liquid film to the bulk liquid according to Fick’s first law:
J = - Df dc / dx (4)
where J is the amount of substance passing perpendicularly through a unit surface area per time, Df ,is the diffusion coefficient and dc / dx, is the concentration gradient. After a time t, the concentration between the limit of the static liquid layer and the bulk liquid becomes Ct. Once the solid molecules pass into the bulk liquid, it is assumed that there is rapid mixing and the concentration gradient disappears.
The theory predicts that if the concentration gradient is always constant i. e. Cs - Ct is constant because Cs >> Ct (“sink” conditions which usually mean Cs > 10 Ct) then a uniform rate of dissolution is obtained.
Fig. 2. Diffusion Layer Model
The Interfacial Barrier Model
In the interfacial barrier model (Fig 3), it is assumed that the 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. Thereafter the dissolution mechanism is essentially the same as in (i) above, with the concentration at the limit of the static layer of liquid becoming Ct after time t.
The rate of diffusion in the static layer is relatively fast in comparison with the surmounting of the energy barrier, which therefore becomes rate limiting in the dissolution process.
Fig. 3. Diagrammatic representation of the free energy barrier to dissolution
The Danckwert’s Model
The Danckwert’s model (Fig 4) assumes that macroscopic packets of solvent reach the solid/liquid interface by eddy diffusion in some random fashion.
Fig. 4. The Danckwert’s Model.
At the interface, the packet is able to absorb solute according to the laws of diffusion and is then replaced by a new packet of
solvent. This surface renewal process is related to the solute transport rate and hence to the dissolution rate.
The rate laws predicted by the different mechanisms both alone and in combination, have been discussed by Higuchi50.
However, the earliest equation expressing dissolution rate in a quantitative manner was proposed by Noyes and
Whitney51 as:-
dc / dt = k (Cs - Ct) (5)
where dc / dt is the rate of change in concentration with respect to time, and k is the rate constant. The integrated form of the equation is:
In [Cs / (Cs - Ct) ] = kt (6)
The equation in resemblance to the other rate law equations50, predicts a first order dependence on the concentration gradient (i.e. Cs - Ct ) between the static liquid layer next to the solid surface and the bulk liquid. Noyes and Whitney explained their dissolution data using a concept similar to that used for the diffusion model50. This considerations relate to conditions in which there is no change in the shape of the solid during the dissolution process ( i. e. the surface area remains constant). However, for pharmaceutical tablets, disintegration occurs during the dissolution process and the surface area generated therefore varies with time.
Aguiar et al52 proposed a scheme which holds that dissolution occurs only when the drug is in small particles. Wagner53 modified this idea and showed that dissolution occurs from both the intact tablet and the aggregates and/or granules produced after disintegration by using a plot of the percentage of drug dissolved versus time on logarithmic - probability graph papers.
A modification of this approach was proposed by Kitazawa et al54,55. Employing the integrated form of Noyes and Whitney equation (equation 6), they determined the dissolution rate constant of uncoated caffeine tablets. The Kitazawa equations have been used to determine the dissolution rates of some pharmaceutical tablet formulations7,25,41,42.
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