Biomedical Engineering Reference
In-Depth Information
the cryo-concentration of API and excipients, which may have stability implications due
to local extremes of pH or concentration [40]. Optimization of freezing has been studied
using many analytical techniques. Differential scanning calorimetry (DSC) has been
used routinely to determine glass transition temperature of the product solid state and to
study crystallization states during annealing [42]. The modulated DSC apparatus is
capable of monitoring heat flows showing exothermic and endothermic transitions over
the temperature range from
100 Cto0 C.
The morphology of the solid state of the drug product and ice has been studied using
cryomicroscopy. Examination of the micrographs shows the distribution of icewithin the
drug product and the interface between the ice and the product. Other techniques, such as
X-ray diffractometry and nuclear magnetic resonance spectrometry have been used to
study crystalline states of product and ice, respectively, while electrical resistance
measurements have been used to study cooling rates.
13.5.9 Primary Drying and Secondary Drying
Optimization of primary and secondary drying conditions and times requires appro-
priate shelf temperature and vacuum to obtain the correct sublimation and water
desorption rates. The sublimation end point that marks the end of primary drying has
been controlled in real time using PAT tools that monitor residual water and water vapor
pressure. The completion of the overall drying process (primary and secondary drying)
culminates in constant water content (at the end of the targeted drying value) and a
product temperature equal to the shelf temperature. Water vapor in the drying chamber,
pressure of the chamber, and product temperature can be monitored conventionally in
real time by sensors that provide direct end of drying information while providing
feedback control to maintain constant pressure through nitrogen purging or maintaining
the targeted shelf temperature during drying. Product temperature sensors are typically
thermocouples or resistance temperature detectors that are placed inside the product
vials. These sensors generate some heating themselves and may affect the drying
process of the vials that they are monitoring. The conventional moisture sensor is
typically a Pirani gauge, which detects levels of nitrogen and water vapor and provides
the water vapor profile over the time course of the primary and secondary drying.
The sensor for monitoring pressure in the freeze-drying chamber is typically a
capacitance manometer that provides absolute pressure measurements. More sophisti-
cated analytical instruments have been applied to the determination of moisture levels
during drying. These include mass spectrometry for gas analysis, which samples the gas
stream directly from the freeze-dryer in real time and produces a moisture level profile
for the overall drying process [43]. Online monitoring of the sublimation end point has
been approached using an electronic moisture sensor based on the determination of the
partial pressure of water in the drying chamber [44, 45]. Manometric temperature
measurement (MTM) is a real-time noninvasive PAT method that measures product
temperature at the sublimation interface during primary drying. The MTM method
generates a profile of pressure versus time data that are recorded at timed intervals
during primary drying. At each measuring interval, the valve between the drying
chamber and the condenser is closed for about 25 s, and the rise in chamber pressure
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