Crystallization of Amorphous Pharmaceuticals at Ambient and Elevated …
73
3 Physical Stability Studies of Amorphous APIs
at Conditions Mimicking Their Manufacturing
The amorphous APIs and their molecular dispersions might be produced by either
melting or solvent methods [45]. However, due to both economic and ecological limitations of solvent techniques, currently the most preferred production way of these
systems is Hot Melt Extrusion (HME) [46–48]. A typical HME process includes
heating and softening of a physical mixture of an API and a thermoplastic polymer
inside the extruder, followed by pressurization of the molten mass through a die, to
finally form the granules, cylinders or films [47, 49]. In this technological process
the temperature plays undeniably a crucial role [50]. Therefore, it has to be carefully
chosen to finally obtain an appropriate dosage form. The manufacturing temperature
cannot be too high or too low. At too high temperature the sample might undergoes thermal degradation [51, 52]. If, however, the elevated temperature does not
harm the extruded composition, it can still over-reduce the sample’s viscosity, and
consequently will make it impossible to form the filaments. At the same time, the
manufacturing temperature should not be too low. Firstly, at insufficient temperature
the dissolution of an API into the polymeric matrix or its melting (depending on the
drug concentration) might not be possible. Secondly, at that conditions the material
can be too viscous to be extrudable. Choosing appropriate processing temperature,
one should also keep in mind that at this specific temperature an amorphous sample
might undergoes re-crystallization [53–55]. Therefore, it is important to investigate the effect of elevated temperature on the physical stability of amorphous APIs.
The studies of amorphous drugs re-crystallization performed at elevated temperature
conditions were a subject of the above subsection. Another, very important, factor
on which the drug is exposed to during its manufacturing process is elevated pressure. It can be exerted on a sample at both: (i) supercooled liquid state i.e. during
pressurization of the molten mass through a die to form the filaments as well as (ii)
glassy state i.e. during palletization, grinding and tableting (depending on the final
dosage form: tablet or capsule). Thus, another important question which should be
asked prior the production is: whether the compression triggers the re-crystallization
of the investigated API?
It has been recently shown that the influence of the compression imitating conditions during manufacturing of amorphous APIs on their physical stability might be
investigated by employing BDS equipped with the high-pressure setup. One of the
best examples of pharmaceutical extremely sensitive to compression is PBC. As can
be seen in Fig. 13a, the amorphous form of this API reveals incredibly high physical stability, when store at room temperature. According to long-term isothermal
XRD studies, this material does not reveal any signs of re-crystallization even after
200 days of storage (T room and p = 0.1 MPa). Interestingly, PBC is physically stable
also at elevated temperature conditions (see panel b of Fig. 13). However, despite
high physical stability observed at atmospheric pressure, a very gentle compression
triggers PBC’s re-crystallization (see Fig. 13c).
73
3 Physical Stability Studies of Amorphous APIs
at Conditions Mimicking Their Manufacturing
The amorphous APIs and their molecular dispersions might be produced by either
melting or solvent methods [45]. However, due to both economic and ecological limitations of solvent techniques, currently the most preferred production way of these
systems is Hot Melt Extrusion (HME) [46–48]. A typical HME process includes
heating and softening of a physical mixture of an API and a thermoplastic polymer
inside the extruder, followed by pressurization of the molten mass through a die, to
finally form the granules, cylinders or films [47, 49]. In this technological process
the temperature plays undeniably a crucial role [50]. Therefore, it has to be carefully
chosen to finally obtain an appropriate dosage form. The manufacturing temperature
cannot be too high or too low. At too high temperature the sample might undergoes thermal degradation [51, 52]. If, however, the elevated temperature does not
harm the extruded composition, it can still over-reduce the sample’s viscosity, and
consequently will make it impossible to form the filaments. At the same time, the
manufacturing temperature should not be too low. Firstly, at insufficient temperature
the dissolution of an API into the polymeric matrix or its melting (depending on the
drug concentration) might not be possible. Secondly, at that conditions the material
can be too viscous to be extrudable. Choosing appropriate processing temperature,
one should also keep in mind that at this specific temperature an amorphous sample
might undergoes re-crystallization [53–55]. Therefore, it is important to investigate the effect of elevated temperature on the physical stability of amorphous APIs.
The studies of amorphous drugs re-crystallization performed at elevated temperature
conditions were a subject of the above subsection. Another, very important, factor
on which the drug is exposed to during its manufacturing process is elevated pressure. It can be exerted on a sample at both: (i) supercooled liquid state i.e. during
pressurization of the molten mass through a die to form the filaments as well as (ii)
glassy state i.e. during palletization, grinding and tableting (depending on the final
dosage form: tablet or capsule). Thus, another important question which should be
asked prior the production is: whether the compression triggers the re-crystallization
of the investigated API?
It has been recently shown that the influence of the compression imitating conditions during manufacturing of amorphous APIs on their physical stability might be
investigated by employing BDS equipped with the high-pressure setup. One of the
best examples of pharmaceutical extremely sensitive to compression is PBC. As can
be seen in Fig. 13a, the amorphous form of this API reveals incredibly high physical stability, when store at room temperature. According to long-term isothermal
XRD studies, this material does not reveal any signs of re-crystallization even after
200 days of storage (T room and p = 0.1 MPa). Interestingly, PBC is physically stable
also at elevated temperature conditions (see panel b of Fig. 13). However, despite
high physical stability observed at atmospheric pressure, a very gentle compression
triggers PBC’s re-crystallization (see Fig. 13c).