Biopharmaceutics. Группа авторов

use of lipid or oil‐based formulations is a strategy used for lipophilic drug compounds; these formulation can also improve permeability and lymphatic transport. In these formulations, the drug is blended with lipidic excipients including long‐chain triglyceride (such as sesame or other vegetable oils), long‐chain monoglycerides and diglycerides (such as Peceol®) or medium‐chain triglyceride (eg, Miglyol® 812), medium‐chain monoglycerides & diglycerides (eg, Capmul® MCM), phospholipids (eg, Phosal® 53 MCT). The most commonly cited example is Neoral, a lipidic formulation of cyclosporin A.

Surfactant formulations are another strategy to improve solubility of drugs. In oral liquid formulations, surfactants can be added to the formulation to improve solubility, typically by the formation of micelles within the liquid that can contain the drug to solubilise it. Examples of surfactants used include the following: Polysorbate 80 (Tween 80), Polyoxyl‐35 castor oil (Cremophor® EL/Kolliphor® EL), caprylocaproyl polyoxyl‐8 glycerides (Labrasol) and sodium lauryl sulphate (SLS) [19].

      Cyclodextrin formulations can be also used to improve drug solubility. These are also known as inclusion complex formulations. Cyclodextrins have an exterior that is water soluble yet they contain an internal hydrophobic cavity; drugs can sit within this cavity forming an inclusion complex. There are several marketed cyclodextrin‐containing formulations [20].

4.10 Risk of Precipitation

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).

4.11 Solubility and Link to Lipophilicity

      The lipophilicity of a compound is described in terms of a partition coefficient, log P, which is defined as the ratio of the concentration of the unionised compound, at equilibrium, between organic and aqueous phases. Since it is virtually impossible to determine log P in a realistic biological medium, octanol has been widely adopted as a model of the lipid phase. Generally, drug compounds with log P values between 1 and 3 show good bioavailability.

4.12 Conclusions

      Drug solubility depends on the fluid composition, pH and temperature. Poor solubility within the intestinal environment can limit drug absorption; thus understanding solubility is key to prediction of pharmacokinetics for orally administered drugs. Various solubilisation techniques can be employed to improve drug solubility and these will be discussed in Chapters 8 and 9.

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