Oral absorption efficiency can be influenced by several factors, acting independently or in concert. These include the physicochemical properties of the administered agent, human physiology, pathology (including disease state), the way the drug is presented (formulated) and possibly the amount that is administered (dose). Other influences include time of administration, whether the patient is resting or active and body position, for example, recumbent or standing. Optimizing absorption requires knowledge of how these variables affect the drug or formulation. However, it may take many years before such comprehensive knowledge can be gleaned on compound-specific behaviours.

In the absence of such detailed insight it may necessary, particularly with novel therapeutic agents being dosed to humans for the first time, to design a formulation based on generic considerations of factors affecting absorption, the physicochemical properties of the agent being administered and in vivo or ex vivo findings in animals or animal tissue. Such a strategy can help identify the optimum form of the drug and clarify possibilities and limitations for manipulating its properties to optimize delivery.

Hence, good understanding of the physicochemical properties of the drug, and of the anatomy and physiology of the gastrointestinal (GI) tract provides valuable insight on the possibilities and constraints for optimizing oral absorption.

Table I Aqueous solubilities of tetracycline and erythromycin derivatives.

Solubility enhancement Some materials are absorbed by active transport across the intestinal barrier, but absorption by passive diffusion is probably far more prevalent.¹ Regardless of the mode of transport, however, it is reasonable to conclude that, in the vast majority of cases the drug must be in the solvated state to diffuse into and across the enterocytes lining the intestinal lumen. Thus, solubility and rate of dissolution of the drug are of major importance and many approaches to absorption enhancement concern the optimization of these properties.

Poorly soluble drugs present a major challenge in dosage form development. In simple terms, a material must be in solution if it is to pass from the intestine to the systemic system. At the same time, lipophilicity is frequently associated with higher activity, or receptor specificity and is invariably incorporated in molecular structures by the medicinal chemist. Low aqueous solubility (which is usually associated with high lipophilicity) and poor bioavailability are often a consequence of such molecular design. Improving absorption in such cases may mean using a form of the drug with optimum solubility, or employing a vehicle in which the compound is soluble. Optimizing solubility may entail using a more soluble salt or polymorph (if one exists), or even the amorphous form of a compound. Each approach has advantages and complications, and such options may not always be available, depending on the molecular composition and physical behaviours of the material under consideration.

Salt forms. Agharkar found that the solubility of the free base form of the antimalarial, α-(2-piperidyl)-β-3, 6-bis(trifluoromethyl)-9-phenanthrenemethanol was 7 μg/mL.² The hydrochloride salt in contrast had solubility of approximately 30 μg/mL whereas a value of 1800 μg/mL was attained for the dl-lactate salt. Tetracycline and erythromycin salts also exhibit differing solubilities (Table I). Bastin et al. also found that some salts of the cardiovascular compound RPR127963 afforded significantly improved solubilites compared with the free base (Table II).³