Chemistry Reference
In-Depth Information
exceeds the equilibrium solubility of the crystalline material, and thus crystallization is
favorable from a thermodynamic perspective. While it might be thought that it is better to
achieve solubilization rather than supersaturation due to the risk for crystallization and
thus the loss of the solubility advantage in supersaturated solutions,
ux across a
membrane is enhanced for supersaturated solutions, but not for solubilized solu-
tions [133,134]. Therefore, there is a great deal of interest in creating and maintaining
supersaturated solutions. Polymers can act as crystallization inhibitors, even when
present at low concentrations, sustaining supersaturation without altering the driving
force for crystallization. While polymers are often used to ful
ll this role, there is little
mechanistic understanding of the properties of a polymer that make it a good inhibitor of
crystallization for a given compound. It should also be noted that many studies evaluate
the ability of a given additive to inhibit precipitation rather than crystallization.
Precipitation is the appearance of a new phase, and most of the methods used to
evaluate precipitation, for example, turbidity, do not provide information about the
structure of the new phase, for example, if it is crystalline or amorphous. This
consideration is important because if the new phase that evolves in the supersaturated
solution is an amorphous phase, then supersaturation can be maintained [135,136]. In
contrast, if the new phase is crystalline, supersaturation will be depleted.
There have been a number
of studies that have screened the impact of various additives on the precipitation behavior
of compounds of interest. The methodology used for such studies has an impact on
whether such studies should be considered as quantitative evaluations of the impact of
additives on supersaturation duration or qualitative investigations. For quantitative
investigations, it is necessary to
5.6.2.1 In
uence of Additives on Precipitation.
first determine the equilibrium crystalline solubility
in the exact test medium in which supersaturation duration is to be evaluated; this will
provide information about the solubility-enhancing potential of the excipients and will
allow the actual degree of supersaturation to be determined. Second, the initial degree of
supersaturation (rather than concentration of drug added) should be constant for the
different additives if the additive effectiveness is to be compared. Following precipita-
tion, the precipitated material needs to be immediately separated from the solution and
assayed using a quantitative method. Ideally, the separated phase would also be analyzed
to better understand the desupersaturation process. Unfortunately, such quantitative
studies are often challenging to perform experimentally. For example, separating the
precipitated material from the solution phase by filtration can be difficult since material
can adsorb to the
filtration process can induce
crystallization, and very small precipitated species can pass through the
filter, the sample handling needed for the
filter. Challenges
also exist with methods such as centrifugation. This has led to the development of more
qualitative high-throughput screening methods, where the precipitate is evaluated
in situ
using a nonspeci
c method such as turbidity measurements. Turbidity measurements
enable the time when a new phase evolves to be evaluated without sample handling.
Turbidity measurements were used in one study to evaluate the precipitation behavior of
danazol in the presence and absence of many different types of polymers, added at
concentrations of 0.1
0.001% [137]. It was observed that certain cellulose derivatives
appeared to be effective precipitation inhibitors; however, the turbidity pro
-
les as a
