Chemistry Reference
In-Depth Information
speci
cant increases in dissolution rate,
for example, have been attained by producing particles with diameters on the order of
100
c surface area (area per unit mass). Very signi
300 nm. One also can increase dissolution rates by adding solubilizers to the
formulation, such as surfactants, or complexing agents, such as cyclodextrins, which
help to produce a supersaturated solution when the API encounters an aqueous medium.
Surfactants can also act as wetting agents to improve access of the aqueous medium to
hydrophobic API, thus effectively increasing the available surface area. High levels of
supersaturation, upon contact with water, can also be obtained by dissolving the API in
liquid lipid-based formulations and administering the product in hard or soft capsule
form. Such an approach tends to produce a supersaturated solution upon exposure to
aqueous dissolution media. Alteration of the API chemically by forming more highly
water-soluble crystalline salts or cocrystals, when possible, can be a very ef
-
cient way of
increasing dissolution rates as long as the dissolved form of the API can be maintained in
a supersaturated state relative to that of the crystalline
“
free form
”
of the API itself.
Finally, since the high lattice energy of an API crystal, as often re
ected at high melting
temperatures, can serve as an impediment to attaining adequate thermodynamic solubil-
ity, any approach that can change, reduce, or eliminate the crystal lattice energy should
be able to enhance the apparent solubility. For example, liquid forms of molecules will
generally exhibit greater solubility than their crystalline counterparts (supersaturation),
all other factors being equal. Indeed, it is well known that higher energy
”
polymorphic crystal forms of an API generally exhibit greater solubility than the most
stable form. It has also been shown that disorder in the crystal lattice introduced as crystal
defects can serve to increase dissolution from the defect sites relative to that from the less
defective crystal. Consequently, it is not surprising that complete elimination of long-
range three-dimensional order in the crystal by forming the amorphous form of an API
can greatly enhance apparent solubility and rates of dissolution. Of course, since the
amorphous state represents a high-energy form relative to the crystal, this approach can
be useful only as long as a supersaturated solution of API can be maintained in the
aqueous medium over the time period required for gastrointestinal absorption. Since the
overall theme of this topic deals with amorphous API-polymer solid dispersions
designed to provide enhanced oral bioavailability by creating such supersaturation, it
will be useful in this introductory chapter to review some of the important physico-
chemical characteristics of amorphous solids as single components and as mixtures of
API with other formulation components that might be used to enhance oral bio-
availability in drug products. A brief discussion of API-polymer amorphous dispersions,
in particular, will serve as an introductory overview of various principles that will be
applied in more detail throughout the rest of the topic.
“
less-stable
1.2 FORMATION OF THE AMORPHOUS STATE AND THE GLASS
TRANSITION TEMPERATURE
Let us
first consider a single-component system such as an API in its most stable
crystalline form. From a classical free energy
-
temperature diagram [3], as illustrated in
Figure 1.2, we can observe a signi
cant reduction in the free energy per mole of the
