Instrumentation & Measurement Magazine 24-5 - 37

infrared (ATR-FTIR) spectroscopy [7], ATR ultraviolet/visible
(ATR-UV/Vis) spectroscopy [8], ATR mid-infrared (ATR-Mir)
spectroscopy [9], and near-infrared (NIR) spectroscopy [10].
However, all these works were performed in Stirred Tank
Crystallizers (STC), whereas the use of PAT in OFC-like crystallizers
remained forgotten.
In view of the need to monitor the concentration of APIs in
real-time and in crystallizers such as OFC, in this work, a refractometric
sensor was applied to measure the concentration
of paracetamol in crystallization experiments. The refractometric
sensor works as follows: the light propagates inside the
fiber by total internal reflection; when the light reaches the fiber/liquid
interface, it is partly transmitted into the liquid and
partly reflected into the fiber. The sensor measures the spectrum
and the optical power of the reflected wave light [11].
The concentration of paracetamol was monitored in realtime
in two different crystallizers: in a STC operating in batch
and in an OFC operating continuously. Monitoring in the
STC was carried out to compare the results obtained in this
crystallizer with the results obtained during the monitoring
in the OFC and thus, to validate the developed technique.
Paracetamol was used as a model system due to the extensive
literature available for this API.
Materials and Methods
Portable Interrogation System
A short section of a multimode fiber (MMF GIF 625 μm, supplied
by Thorlabs, Newton, NU, USA) spliced to a single mode
fiber (SMF 28e, supplied by Thorlabs, Newton, NJ, USA) was
used as a refractometric sensor to measure the concentration of
paracetamol in crystallization experiments. These fibers have a
germanium doped silica core with a pure silica cladding and a
mechanically strippable acrylate coating. The SMF has a core diameter
of 8.2 μm and the MMF has a core diameter of 62.5 μm.
Both fibers have a cladding diameter of 125 μm and a coating diameter
of 242 μm. The refractometric sensor was fabricated by
splicing a section of MMF with a length of 10 cm to a SMF by
means of a splicing fusion machine (TYPE-72C), thus forming a
Calibration Curve
Ten standard solutions of paracetamol (CAS number 103-9002,
min. 99% purity, supplied by Sigma-Aldrich) in a mixture
of 40% (v/v) ethanol/water were prepared at room temperature
(~20 °C). The concentration of the solutions ranged from
53 to 261 g/kg (g of paracetamol per kg of solvent), corresponding
to an index range of 1.3634 RIU to 1.3947 RIU. The
refractive index of each solution was measured by an Abbe refractometer
(ATAGO, DR-A1).
The sensing head was vertically immersed in each standard
solution and its optical power response was monitored.
Through this optical power response, the calibration curve
relating the concentration and optical power was plotted.
Posteriorly, this calibration allowed the concentration of
paracetamol in the crystallizers to be monitored during the
crystallization process.
In situ Monitoring
The concentration of paracetamol was monitored in real-time,
under the same experimental conditions, in a STC operating
in batch and in an OFC operating continuously. The purpose
was to compare the results obtained in the two monitoring situations
to prove the potential of the developed technology to
monitor API concentrations in crystallizers, regardless of their
geometry. The experimental setups for the STC and the OFC
are presented in Fig. 2.
MMF fiber tip. The MMF length was chosen to ensure that its entire
core was excited. The refractometric sensor was connected
to an optical interrogator (BraggMETER FS22), and the response
was recorded by a data acquisition software (BraggMONITOR
SI) at 1550 nm. The portable interrogation system, and the refractometric
sensor operating in reflection, is presented in Fig. 1.
Fig. 1. Portable interrogation system and the detail of the refractometric
sensor working in reflection.
August 2021
Fig. 2. Experimental setups. (a) STC; (b) OFC.
IEEE Instrumentation & Measurement Magazine
37
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