Chemistry Reference
In-Depth Information
supersaturated or high-energy form, and to improve the bioavailability of poorly soluble
drugs. Food effects, common to many lipid-soluble drugs, can be overcome by max-
imizing the available drug in solution with the best choice of excipients.
ASDs can be classi
ed into three generations: low molecular weight, highly water-
soluble carriers such as urea, short-chain carboxylic acids (citric/succinic acid), and
sugars (sucrose, mannitol, and trehalose); polymeric carriers such as PVP, PEG, and
cellulose derivatives; and self-emulsifying and surfactant/polymer-based systems [4c].
The small molecule- and/or polymer-based carriers in the
first two types function to
stabilize the drug in an amorphous state, eutectic mixture, or molecular dispersion.
Polymeric carriers are often preferable due to their ability to be processed at lower
temperatures, such as melt blending/extrusion, in addition to spray drying or congealing
to form solid matrices. With the addition of surfactants in the third type, improved
properties such as wetting, dispersion, and solubilization in aqueous media can result and
are important especially for very poorly soluble and hydrophobic drugs. Polyethoxylated
surfactants such as Gelucire
, Tween
, and Labrasol
have shown improved dissolution
and oral bioavailability when incorporated into ASDs [4c]. Other surfactants such as
ionic surfactants (i.e., sodium lauryl sulfate) and nonionic surfactants (i.e., PEO
PPO
block copolymers) have been used to improve dissolution and solubility of the active
ingredient; however, many of these materials tend to be waxy at room temperature
complicating their incorporation into solid dosage forms such as tablets. Alternatives
such as direct
-
filling of melts into hard gelatin capsules have been explored, to ensure
effective containment and physical stability of the matrix. However, higher molecular
weight blends of PEG (MW up to 8000) can be combined with surfactants to enable them
to process into solids that can be tableted and easily disintegrated in aqueous media.
Several examples have been cited by Leuner and Dressman [3b] that show synergies of
amphiphilic or surfactant-like materials with PVP, cellulosic polymer derivatives,
polyacrylates, and other classes as solid dispersion systems. Favorable interactions
have been reported with PEG 4000, 6000, and 20,000 and Tween
80 or sodium lauryl
sulfate with drugs such as naproxen and griseofulvin. Other synergistic interactions to
form solid solutions have been found with alkali dodecyl sulfates, bile salts, and
cholesterol esters. Increased wettability of the dosage forms and improved solubilization
have been attributed to bioavailability enhancement
in vivo
[3b].
The drug, polymer, and surfactant interactions, where homogeneous solid disper-
sions form, may be predicted by constructing a phase diagram. In certain cases, solid
eutectic mixtures may occur at a unique composition, where very
fine particles crystallize
out from each component and comprise a physical mixture. This system does not involve
the molecular dispersion of the drug within a homogeneous polymer
surfactant matrix.
On the other hand, solid solutions, where all components are molecularly dispersed
within a common matrix, can form based on controlling speci
-
c compositional and
temperature ranges for that system [3b,4c]. Figure 2.12 shows a typical example of a
binary phase diagram for predicting regions forming solid solutions.
In a eutectic mixture, the components may be insoluble in the solid state but miscible
in the molten liquid state. Solubilization enhancement and increased dissolution may
occur due to the high surface area to volume ratio of the
fine particles and enhanced
wettability with the presence of surfactant and polymer. In the solid solution, de
ned
