58
J. Knapik-Kowalczuk et al.
the further investigations, it has been realized that solving the problem associated
with physical instability of amorphous pharmaceuticals is impossible only on the
basis of the thermodynamic factors [25]. It turns out that the investigated macroscopic thermodynamic quantities do not fully reflect the molecular mechanisms that
govern the devitrification. Thus, the most relevant factor that is currently recommended to be studied to predict the tendency of amorphous pharmaceuticals toward
re-crystallization is molecular mobility [1, 14, 26–29]. It has to be highlighted that
the search for the proper correlation between physical stability of amorphous APIs
and their molecular mobility is also not an easy task. It is mainly because pharmaceuticals usually exhibit complex molecular structures of different configurational
topologies and a variety of intra- or intermolecular interactions such as hydrogen
bonds of various strength and electrostatic forces. Consequently, amorphous pharmaceuticals usually reveal complex molecular mobility that is reflected in the multitude
relaxation processes. Taking this fact into account, it is crucial to assess which molecular motion is responsible for the re-crystallization of the specific amorphous API.
Does the primary (global) relaxation, associated with the glass transition, control
the devitrification process? Or maybe the secondary (local) relaxation plays here a
crucial role?
There is a number of experimental methods which can be employed to study
molecular dynamics of amorphous pharmaceuticals. The following list includes
some of them: mechanical spectroscopy, Broadband Dielectric Spectroscopy (BDS),
Nuclear Magnetic Resonance (NMR), Temperature-Modulated Differential Scanning Calorimetry (TMDSC), Quasielastic Neutron Scattering (QENS), Photon Correlation Spectroscopy (PCS), Terahertz spectroscopy (THz) or Positron Annihilation
Lifetime Spectroscopy (PALS) [12, 25, 30]. Taking into account that BDS, in comparison with the other techniques, allows to perform measurements in the widest range
of frequency (i.e., 18 decades—from μHz to THz), temperatures (from 123 to 523 K)
and even pressures (from 0.1 MPa to 1.8 GPa) it is considered the most powerful
tool to study the molecular dynamics of disordered APIs (see Fig. 1). By employing
this experimental method, it is possible to examine the molecular mobility of pharmaceuticals in both supercooled liquid and glassy states that enable to distinguish
both global and local molecular motions.
In addition, it has been recently demonstrated that the BDS technique can be
used to investigate the physical stability of amorphous APIs at conditions imitating
drugs manufacturing, for example, short-term compression. Because in some cases
it was established that such conditions might entirely modify the tendency of amorphous APIs toward devitrification, the imitating drug manufacturing dielectric studies
become more and more important [16, 19, 31, 32]. Based on dielectric data, it is also
possible to determine the solubility limit of the amorphous drug in stabilizer, e.g.
polymeric matrix, what finally allows to create a saturated solution [33]. This is
crucial considering the fact that supersaturated solution (e.g. of the API–polymer
composition) is by definition thermodynamically unstable.
In this chapter, it will be described how to investigate the tendency of amorphous
pharmaceuticals toward re-crystallization based only on the dielectric data. It will
be shown how quickly, i.e., based on non-isothermal studies, determine which API
J. Knapik-Kowalczuk et al.
the further investigations, it has been realized that solving the problem associated
with physical instability of amorphous pharmaceuticals is impossible only on the
basis of the thermodynamic factors [25]. It turns out that the investigated macroscopic thermodynamic quantities do not fully reflect the molecular mechanisms that
govern the devitrification. Thus, the most relevant factor that is currently recommended to be studied to predict the tendency of amorphous pharmaceuticals toward
re-crystallization is molecular mobility [1, 14, 26–29]. It has to be highlighted that
the search for the proper correlation between physical stability of amorphous APIs
and their molecular mobility is also not an easy task. It is mainly because pharmaceuticals usually exhibit complex molecular structures of different configurational
topologies and a variety of intra- or intermolecular interactions such as hydrogen
bonds of various strength and electrostatic forces. Consequently, amorphous pharmaceuticals usually reveal complex molecular mobility that is reflected in the multitude
relaxation processes. Taking this fact into account, it is crucial to assess which molecular motion is responsible for the re-crystallization of the specific amorphous API.
Does the primary (global) relaxation, associated with the glass transition, control
the devitrification process? Or maybe the secondary (local) relaxation plays here a
crucial role?
There is a number of experimental methods which can be employed to study
molecular dynamics of amorphous pharmaceuticals. The following list includes
some of them: mechanical spectroscopy, Broadband Dielectric Spectroscopy (BDS),
Nuclear Magnetic Resonance (NMR), Temperature-Modulated Differential Scanning Calorimetry (TMDSC), Quasielastic Neutron Scattering (QENS), Photon Correlation Spectroscopy (PCS), Terahertz spectroscopy (THz) or Positron Annihilation
Lifetime Spectroscopy (PALS) [12, 25, 30]. Taking into account that BDS, in comparison with the other techniques, allows to perform measurements in the widest range
of frequency (i.e., 18 decades—from μHz to THz), temperatures (from 123 to 523 K)
and even pressures (from 0.1 MPa to 1.8 GPa) it is considered the most powerful
tool to study the molecular dynamics of disordered APIs (see Fig. 1). By employing
this experimental method, it is possible to examine the molecular mobility of pharmaceuticals in both supercooled liquid and glassy states that enable to distinguish
both global and local molecular motions.
In addition, it has been recently demonstrated that the BDS technique can be
used to investigate the physical stability of amorphous APIs at conditions imitating
drugs manufacturing, for example, short-term compression. Because in some cases
it was established that such conditions might entirely modify the tendency of amorphous APIs toward devitrification, the imitating drug manufacturing dielectric studies
become more and more important [16, 19, 31, 32]. Based on dielectric data, it is also
possible to determine the solubility limit of the amorphous drug in stabilizer, e.g.
polymeric matrix, what finally allows to create a saturated solution [33]. This is
crucial considering the fact that supersaturated solution (e.g. of the API–polymer
composition) is by definition thermodynamically unstable.
In this chapter, it will be described how to investigate the tendency of amorphous
pharmaceuticals toward re-crystallization based only on the dielectric data. It will
be shown how quickly, i.e., based on non-isothermal studies, determine which API