Chemistry Reference
In-Depth Information
Figure 2.13.
Spring and parachute
mechanism. (Adapted from
Ref. 46a.)
the spring and parachute concept. The mechanism of precipitation inhibition involves
additives that attempt to reduce the collision between monomeric drug molecules in
solution and prevent nucleation and crystallization. This is not merely by increasing the
local viscosity of the solution, but possibly by adsorbing to newly formed drug nuclei and
disrupting lattice formation [4c,46a].
For additives that control the rate of crystallization, the rate of nucleation (
I
) can be
de
ned by the differential between the activation free energy for molecular diffusion
from the nucleus to the crystal lattice (
Δ
G
a
) and free energy associated with formation of
G
∗
):
a spherical nucleus of a critical size (
Δ
I
A
exp
Δ
G
a
Δ
G
*
:
(2.2)
kT
The free energy for nucleus formation also depends on the balance of free energy
between the amorphous and crystalline phases (
Δ
G
v
) and the energy to form a new solid
surface (
G
v
, dependent upon volume, as formation of
the crystalline phase is more energetically favorable. However,
Δ
G
s
). Nucleation is favored by
Δ
G
s
is dependent upon
surface area and interfacial tension, counteracts nucleation as formation of a new
surface requires energy, and this value is generally more positive than
Δ
Δ
G
v
[4c]. The
magnitude of change between the two free energies as a function of nucleus diameter
can determine the critical nucleus size to induce crystallization. Polymers can inhibit the
diffusion rate of nuclei, reduce drug diffusivity, and adsorb to interfaces preventing
crystallization. In addition, polymers and surfactants that can lower the interfacial
tension can stabilize smaller nuclei and prevent growth to a
“
critical size
”
for crystal
lattice formation.
Surfactants in formulations can be limited in their use for certain poorly soluble
drugs as solubilization capacity has been reported to be less than 20mg of drug in
micelles per gram of surfactant used [46b]. Although large doses of surfactants may be
less than practical for commercial use, smaller quantities can improve the wettability of
