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4.10 Risk of Precipitation

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Solubility occurs under dynamic equilibrium, which means that solubility results from the simultaneous and opposing processes of dissolution and phase joining (e.g., precipitation of solids). Equilibrium solubility is defined as the maximum amount of solid that can be dissolved in a solvent when the system reaches equilibrium. In some cases, it can take some time for the system to reach equilibrium thus it is important that the time course is reported. In some cases where solubility enhancing excipients are used there is a transient increase in the measured concentration that generates a solubility value higher than the equilibrium solubility. In these cases, a supersaturated solution has been formed and there is a risk of precipitation. Within the gastrointestinal tract, there is removal of the dissolved drug by absorption. If the rate of absorption is high then the risk of precipitation is low. Figure 4.4 shows some examples schematically.

As shown in Figure 4.4 there are three distinct solubility profiles. In terms of biopharmaceutics, it is important that the greatest solubility value is reached whilst the drug is at the major site of absorption, the small intestine. Thus for the solid line, it would be best if the time at equilibrium (highest solubility) was reached within the small intestine. For the dotted line, it would be useful to include solubility enhancing excipients to improve the rate of solubilisation to maximise concentrations within the GI fluids. For the dashed line if the peak concentration obtained coincides with the small intestine for absorption then this would improve bioavailability. However, the risks around using a supersaturated formulation are high as it is not always possible to control the rate of precipitation for an orally administered formulation. Furthermore, it may be that the form that precipitates is of a different polymorph to that administered, which can further complicate the solubility and dissolution profile. The risks of precipitation are further described in Chapter 6.


Figure 4.4 Examples of solubility vs time plots for a rapidly dissolving solute reaching equilibrium (solid line); a slowly dissolving solute where equilibrium was not reached during the time course measured (dotted line) and a supersaturated solution where precipitation occurred and equilibrium was reached (dashed line).

Biopharmaceutics

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