ABSTRACT
Regardless the administration route, key factor for the success and reliability
of a whatever formulation is drug bioavailability, defined as the rate and
extent to which the active drug is absorbed from a pharmaceutical form and
becomes available at the site of drug action [1]. Although metabolism and physio-
logical factors highly affect drug absorption by living tissues, bioavailability
strongly depends on drug permeability through cell membranes and drug
solubilization in physiological fluids. Indeed, especially for what concerns
oral formulations, if solubilization is the first absorption step, permeation is
the second one (see also Chapter 2) as drug must dissolve in the physiological
fluids and then it must cross cellular membranes. Although solubilization
implies the drug dissolution process, permeation implies drug partitioning
between a polar aqueous phase and an apolar phase (cellular membranes)
unless active mechanisms rule drug permeation as discussed in Chapter 2.
Indeed, for example, partitioning is the basis for the interpretation of passive
absorption according to the two-step distribution model [2-4] interpreting
permeability as the sum of two polar-apolar partitioning steps on both cell
membrane sides (internal and external) as discussed later on. On the other hand,
dissolution assumes relevant importance for poorly water-soluble drugs that,
interestingly, represent more than 40% of the drugs recorded in the US Pharmacopoeia [5,6]. Indeed, most of them are optimized solely on the basis
of pharmacological activity and not for what concerns bioavailability. In
addition, this percentage is expected to increase with the advent of new
biotechnology-based products (peptides and proteins) and the ever-increasing
number of new compounds emerging from the discovery process that inte-
grates combinatorial chemistry and high-throughput screening techniques [7].
Examples of commonly marketed drugs that are poorly soluble in water (less
than 100 mg=cm3) include analgesics, cardiovasculars, hormones, antivirals, immune suppressants, and antibiotics. Drugs with improved water solubility
can be administered in a lower concentrated dose, with a reduction of local
and systemic side-effects; this is crucial for drugs with important side-effect;
profiles, such as antibiotics, antifungals, or antivirals. Moreover, improved
