Instrumentation & Measurement Magazine 24-5 - 36

Application of a Fiber Optic
Refractometric Sensor to Measure
the Concentration of Paracetamol
in Crystallization Experiments
Liliana Soares, Patrícia Cruz, Susana Novais, António Ferreira,
Orlando Frazão, and Susana Silva
A
refractometric sensor was applied to measure in realtime
the concentration of Active Pharmaceutical
Ingredients (APIs) in crystallization experiments.
Paracetamol was used as a model system due to the extensive
literature available for this API. The refractometric sensor was
fabricated by a simple and inexpensive method that consisted
in splicing a short section of a multimode fiber to a single mode
fiber. The compact geometry of this sensor, with an external diameter
of just 125 μm, allowed it to measure the concentration
of paracetamol, both in a stirred tank crystallizer operating in
batch and in an oscillatory flow crystallizer operating continuously.
The proposed technique shows the potential to monitor
the concentration of APIs in crystallizers of different sizes and
geometries as an alternative to more expensive and complex
analysis equipment.
Introduction to Process Analytical
Technology in Crystallization
Crystallization, with its ability to control the yield, polymorphic
form, purity, particle size and shape of the final product,
is one of the most important operations involved in the manufacturing
of Active Pharmaceutical Ingredients (APIs).
Nevertheless, it is still a relatively poorly understood and
poorly controlled process and so can benefit greatly from the
use of Process Analytical Technology (PAT) [1].
The term PAT covers a variety of tools that can be used to
design, analyze, and control the manufacturing processes
with the aim of ensuring the quality of the final product.
In the early stages of development, the use of PAT contributes
to the mechanistic understanding of the process. In the
transition to pilot scale, PAT can be used for process monitoring
and verification, to ensure that the process runs as
expected, to monitor batch-to-batch variability, and also
to facilitate the process transfer between different vessels
or sites. Finally, in the commercial manufacturing stage,
PAT can be used for process control and troubleshooting,
to enable continuous improvement and detect robustness
issues [2].
The implementation of PAT requires sensors that measure
the variables of interest. Depending on the location of the sensor,
it can be classified as off-line (when the measurement is
performed on a sample extracted from the process stream),
on-line (when the measurement is performed in real-time on
a diverted sample stream, which may be returned to the process
after measurement), in-line (when the measurement is
performed in real-time on the process stream, but the process
stream might be disturbed) and non-invasive (when the measurement
is performed in real-time on the process stream and
the process stream is not disturbed). Real-time measurements
are more appealing than off-line measurements because they
avoid sample preparation and time delays. They are also preferred
when the sample is difficult to access, when the off-line
sample may not be representative, when the process of sampling
changes the material, or even when frequent sampling
is required [3]. Nevertheless, sometimes real-time measurements
are not feasible, particularly when the vessel is very
small, and the probes cannot be immersed in the process
stream. An example is monitoring the concentration of an API
in an Oscillatory Flow Crystallizer (OFC). The OFC consists of
a tubular crystallizer that contains evenly spaced orifice baffles
which are transversely assembled to a periodically oscillating
flow. These crystallizers can be operated batchwise or continuously
in horizontal tubes/channels or vertical columns. The
development and application of OFCs has received significant
attention in the past few decades due to the rise of continuous
manufacturing in the pharmaceutical industry [4].
However, the use of PAT in these crystallizers is still limited
by the diameters of the probes which typically exceed the
diameter of the tubes/channels. In the literature it is possible
to find studies in which the concentration of paracetamol was
measured in real-time by a dielectric constant sensor [5], a densitometer
[6], attenuated total reflectance Fourier transform
This work was financially supported by: Base Funding [UIDB/50014/2020] of INESC TEC, Base Funding [UIDB/00511/2020]
and Programmatic Funding [UIDP/00511/2020] of LEPABE - funded by national funds through the FCT/MCTES (PIDDAC).
36
IEEE Instrumentation & Measurement Magazine
1094-6969/21/$25.00©2021IEEE
August 2021
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