JANUARY/FEBRUARY 2016 | PHARMACEUTICAL PROCESSING 27
seconds per sample point). An effective calibration
system, which takes into account the overlapping
spectrum from the various solvents, can allow one
mass spectrometer to monitor several dryers each
with different analytical methods.
The fragmentation of the molecules from each
solvent in the sample yields often complex mass
spectra as observed in the example of ethanol in
figure 1. The selection of the preferred peak(s)
used for calibration and subsequent measurement
of concentrations should take into account the
presence of peaks from other solvents at the same
or adjacent mass numbers. It is observed that the
molecular ion of ethanol (mass 46) is in fact not
the most significant peak and typically mass 31
(the CH2OH+ fragment ion) is selected as the
base peak for ethanol calibration. Other solvents
will have their own unique mass spectra, often
referred to as a “fingerprint” which can enable
measurement with a high degree of selectivity.
Figures 2 and 3 demonstrate the selectivity of the
mass spectrometer where dryer 1 contains ethanol,
methanol, tetrahydrofuran, cyclohexane, and
ethyl acetate, while dryer 2 contains only ethanol.
Note that in Dryer 2 all of the solvent readings
except ethanol remain at zero, indicating no cross
interference as a result of a successful multi-component calibration.
Conventionally, mass spectrometers are calibrated
against certified gas mixtures in cylinders. This
is still a method that can be employed in solvent
drying applications, but where calibration mixtures
are unavailable or cost-prohibitive (particularly
when many different solvents are to be calibrated).
The implementation of liquid calibration standards
can be very advantageous since the pure solvents
are readily available at the pharmaceutical
manufacturing facility. A simple method of
introducing a vial of solvent in liquid phase, where
the solvent vaporizes into the low pressure region
upstream of the mass spectrometer ion source,
enables calibration at the high concentrations
typically encountered at the start of the drying
process. This provides an inexpensive calibration
method for the user.
Dryer End Point Determination
The successful implementation of a PAT initiative
may result in a more predictable process operation,
reduced material costs, time savings, or more
consistent product quality. The use of mass
spectrometry for online solvent dryer monitoring
is designed to fulfill all of these objectives. The
ability to observe in near real-time the rate at which
solvents are being removed from the API provides
the basis for online control of the dryer endpoint.
A method for controlling this function reliably is to
use the slope average or rate of change of slope in
the reducing concentrations of solvents measured;
the mass spectrometer software is equipped with
derived values which interpret the raw data to
provide these parameters.
Benefits of Magnetic Sector Technology
Magnetic sector MS has many inherent
characteristics of benefit to the user, including
resistance to contamination, long intervals between
calibrations, and a high degree of precision and
accuracy. Depending on the complexity of the gas
mixture being analyzed, magnetic sector MS offers
analytical precision between two and 10 times
better than that of quadrupole analyzers, which
have also been used for this measurement.
Beyond the inherent value of the technology,
several design improvements can increase the
performance of a magnetic sector MS system even
further. Systems with laminated magnets, for
example, can scan at speeds equal to those
of quadrupole analyzers, offering both rapid
analysis and low maintenance. Enclosed ion
sources can also improve magnetic sector MS
performance by increasing sensitivity, minimizing
background interference, and maximizing
Figure 2: Dryer 1 containing five solvents.
Figure 3: Dryer 2 containing only ethanol (note that all other
solvent readings remain at zero).