Chemistry Reference
In-Depth Information
compatibility between a drug entity and an excipient has been described by Serajuddin
et al. [91]. In this method, physical mixtures of the drug and excipient are placed at elevated
temperatures with added moisture and evaluated for chemical transformations. As this is a
generalized method, it can be used to screen all components of a drug formulation of
chemical incompatibility and applicable to selecting a polymer or surfactant carrier for the
formation of an ASD. The chemical stability of an ASD can be detected through common
chromatographic and vibrational spectroscopy methods.
The chemical stability of ASDs can be in
uenced by an array of parameters. As an
example, derivatives of cyclodextrin can have profound impact on the stability. Inclusion
complexes of CD derivatives with ziprasidone suggest that when the CD contains
electron-donating side chains it will catalyze the oxidative drug degradation in solu-
tion [92]. In addition, the inclusion of any side chains on the CD increased molecular
mobility in the solid state creating a physically unstable ASD. Another example of
chemical instability is the formation of reactive intermediates that in turn can cause drug
degradation. In one instance, the formation of formaldehyde from oxidation of PEG 400
in solution resulted in the degradation of
O
6
-benzylguanine and was the predominant
form of
O
6
-benzylguanine degradation [93]. Similarly, polyoxyethylene surfactants
readily form formaldehydes and peroxides via air oxidation [94], which in turn has
resulted in cross-linking in gelatin capsules that affects the dissolution pro
le of the drug
formulation [94b,c,e].
An additional cause of chemical instability in ASDs is water that is in the dispersion
as residual from processing or from the environment. Drug molecules that are molecu-
larly dispersed in the matrix are more susceptible to chemical reactions such as
hydrolysis than their crystalline form. This phenomenon has recently been investi-
gated in the literature where relationships between water content and stability were
reviewed [83].
2.4.4.1 Physical Stability
The most challenging aspect of formulating an ASD
is stabilizing the high-energy amorphous state and preventing crystallization of the drug
in the solid state. Failure to stabilize the amorphous drug can result in crystallization of
the drug, slower dissolution kinetics, and lower bioavailability. Despite the vast wealth of
information on the physical properties of drug compounds, polymers, and the method-
ology for making ASDs, the stability of ASDs remains unpredictable. In fact, the use of
accelerated conditions to extrapolate the long-term stability of a drug formulation (ICH
Q1E guidelines) cannot be applied to ASDs [95]. Typically, long-term stability studies
must be performed requiring longer development time and increased resources.
Recently, there have been several reported methods to predict and describe the stability
of ASDs [95,96].
As a method to predict whether an ASD will be stable under long-term conditions, a
general suggestion of the storage temperature being less than
T
g
50
C has been
°
provided [97]. This
T
g
50
stems from a body of work in which
indomethacin was allowed to crystallize in its native state and in dispersions of PVP. It
was found that the amorphous indomethacin, with a
T
g
20
C
“
rule of thumb
”
°
C above storage temperature,
recrystallized in less than 6 weeks, whereas ASDs of indomethacin in PVP, with a
T
g
approximately 50
°
C above storage temperature, inhibited crystallization. This general
°
