Physicochemical Properties and Drug Delivery Systems

Oral bioavailability depends on several factors, mainly solubility and dissolution rate in the gastric and intestinal fluids, permeability, and metabolic stability. As discussed earlier, the effect of physicochemical properties of drugs on bioavail-ability is mainly on the availability of the drug at the absorption sites. To date, formulation strategies have been far more successful in improving the bioavail-ability of compounds with poor solubility, poor dissolution rate, and poor chemical stability in acidic environments. The effect on permeability is mainly by the molecular properties, and is more effectively addressed by molecular design than by drug delivery systems. Although many studies have been reported to enhance permeability through the use of absorption enhancers such as medium chain fatty acids, bile salts, surfactants, liposacharides, and chitosans, because of the safety concerns associated with the effect of these absorption enhancers on the cell membranes, their applications in drug products are still very limited (Gomez-Orellana, 2005). With many currently ongoing research aiming to better understand the limiting factors to permeability such as active transporters and P-gp-pump, it is expected that more successful and safer permeability enhancers are to be discovered in the future.

Figure 2.5 is a formulation decision tree modified from Rabinow's review (2004). This decision illustrates the impact of physicochemical properties on the formulation strategies. Having a good understanding of the key physicochemical properties of the drug substance should not only help us understand the causes of low oral absorption but also guide us in defining the appropriate formulation strategies to improve bioavailability.

For ionizable compounds, forming a more soluble salt is obviously the first consideration for solubility enhancement. For compounds with high log P,

Increasing Lipophilicity

pH Adjustment & Salt Formation




Amorphous & Solid Dispersions

Lipid Based Systems


k i

L i

k J

k. i

k. i


Stable (chemical and physical) amorphous/solid dispersions?

Soluble and stable in co-solvents?

Stable (chemical and physical) amorphous/solid dispersions?

Soluble and stable in complexes?

Soluble and stable in lipid systems?



High melting point & High dose?



High L

og P?

Soluble salt (s)?



Figure 2.5. A decision tree for selection of formulation approach based on physicochem-ical properties of drug substance lipid-based systems typically work well. However, for compounds whose solubility is low due to high crystallinity indicated by high melting point (MP), destroying crystalline structure by making them as amorphous or metastable forms should be the focus of solubilization. Additional factors to consider include dose level, chemical and physical stability.

For compounds that are not stable in gastric fluids, their hydrolysis may be prevented or reduced by using enteric coating, inclusion of pH modifier in the formulation to modify the environmental pH, a less soluble salt, or pro-drugs. Compared to gastric degradation, compounds with intestinal stability problems are more difficult to formulate. Although there may be formulation options such as pH modifiers or enzyme inhibitors these problems are better avoided by discovering more stable derivatives or pro-drugs.

For compounds with poor aqueous solubility in the intestinal fluids, enhancing solubility by lipid-based systems or maintaining supersaturation by the inclusion of crystallization inhibitors such as polymers have been proven to be successful.

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