60
J. Knapik-Kowalczuk et al.
dipoles per unit of volume, which are characterized by the permanent dipole moment
μ (e.g. ε α ∼Nμ
2 in the Onsager model). Thus, by employing the BDS, it is possible
to investigate both the non-isothermal and isothermal crystallization of amorphous
pharmaceuticals by analysing the changes in ε α as a function of temperature or
time.
In the following subsections, it will be presented how to quickly assess the
tendency of amorphous APIs toward re-crystallization based on non-isothermal
dielectric experiments. Additionally, it will be shown what information about the
drug’s physical stability can be obtained from the isothermal dielectric measurement
and the appropriate way to analyse such data. Since pharmaceuticals for most of
the time are stored at standard storage conditions, i.e. room temperature and atmospheric pressure, we will describe the methods that are usually employed to predict
the physical stability of disordered pharmaceuticals stored at glassy state, based on
the dielectric data registered at T > T g .
2.1 Non-isothermal Crystallization Studies
To investigate the molecular mobility of amorphous APIs, and consequently to determine the temperature evolution of the measured relaxation processes, one needs to
perform a non-isothermal BDS experiment. During this measurement, the dielectric spectra might be collected within a broad range of temperatures and frequencies.
Therefore, it is possible to observe the relaxation processes occurring both below and
above the glass transition temperature. In the supercooled liquid region i.e. above T g
(defined as the temperature at which the τ α reaches 100 s), the dominant process is
structural (α; global) relaxation, which originates from cooperative motion of many
molecules. On the other hand, at T < T g , the α-process becomes too slow to be experimentally observed, and only a secondary relaxation processes, which reflect fast local
motions having an inter- or intramolecular origin, can be detected. The representative
imaginary (ε
) and real (ε
) parts of complex dielectric permittivity, of four different
pharmaceuticals, which were investigated at T > T g are presented in Fig. 2. Panels
a and b of this figure show the spectra of flutamide (FLU)—a non-steroidal antiandrogen, which is mainly used to treat prostate cancer. Dielectric dispersion spectra
of nimesulid (NIM) are depicted respectively in panels c and d. This pharmaceutical
is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic
properties [35]. Third pharmaceutical, which spectra have been presented in Fig. 2
(panel e and f) is ezetimibe (EZB). This API is mainly used to lower plasma cholesterol levels. EZB is collected in the small intestinal brush border membrane, where
it selectively inhibits the absorption of cholesterol by binding it to Niemann-Pick
C1-Like1 (NPC1L1) proteins. Probucol (PBC), i.e. the last pharmaceutical of which
dielectric spectra are presented in Fig. 2, has very similar to EZB pharmacological
properties—it lowers cholesterol levels. This API, however, has completely different
mechanism of action than EZB. Mainly, it eliminates cholesterol from the body by
increasing the fractional rate of low-density lipoprotein (LDL) catabolism in the
J. Knapik-Kowalczuk et al.
dipoles per unit of volume, which are characterized by the permanent dipole moment
μ (e.g. ε α ∼Nμ
2 in the Onsager model). Thus, by employing the BDS, it is possible
to investigate both the non-isothermal and isothermal crystallization of amorphous
pharmaceuticals by analysing the changes in ε α as a function of temperature or
time.
In the following subsections, it will be presented how to quickly assess the
tendency of amorphous APIs toward re-crystallization based on non-isothermal
dielectric experiments. Additionally, it will be shown what information about the
drug’s physical stability can be obtained from the isothermal dielectric measurement
and the appropriate way to analyse such data. Since pharmaceuticals for most of
the time are stored at standard storage conditions, i.e. room temperature and atmospheric pressure, we will describe the methods that are usually employed to predict
the physical stability of disordered pharmaceuticals stored at glassy state, based on
the dielectric data registered at T > T g .
2.1 Non-isothermal Crystallization Studies
To investigate the molecular mobility of amorphous APIs, and consequently to determine the temperature evolution of the measured relaxation processes, one needs to
perform a non-isothermal BDS experiment. During this measurement, the dielectric spectra might be collected within a broad range of temperatures and frequencies.
Therefore, it is possible to observe the relaxation processes occurring both below and
above the glass transition temperature. In the supercooled liquid region i.e. above T g
(defined as the temperature at which the τ α reaches 100 s), the dominant process is
structural (α; global) relaxation, which originates from cooperative motion of many
molecules. On the other hand, at T < T g , the α-process becomes too slow to be experimentally observed, and only a secondary relaxation processes, which reflect fast local
motions having an inter- or intramolecular origin, can be detected. The representative
imaginary (ε
) and real (ε
) parts of complex dielectric permittivity, of four different
pharmaceuticals, which were investigated at T > T g are presented in Fig. 2. Panels
a and b of this figure show the spectra of flutamide (FLU)—a non-steroidal antiandrogen, which is mainly used to treat prostate cancer. Dielectric dispersion spectra
of nimesulid (NIM) are depicted respectively in panels c and d. This pharmaceutical
is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic
properties [35]. Third pharmaceutical, which spectra have been presented in Fig. 2
(panel e and f) is ezetimibe (EZB). This API is mainly used to lower plasma cholesterol levels. EZB is collected in the small intestinal brush border membrane, where
it selectively inhibits the absorption of cholesterol by binding it to Niemann-Pick
C1-Like1 (NPC1L1) proteins. Probucol (PBC), i.e. the last pharmaceutical of which
dielectric spectra are presented in Fig. 2, has very similar to EZB pharmacological
properties—it lowers cholesterol levels. This API, however, has completely different
mechanism of action than EZB. Mainly, it eliminates cholesterol from the body by
increasing the fractional rate of low-density lipoprotein (LDL) catabolism in the