Instrumentation & Measurement Magazine 24-5 - 39

of paracetamol had to be measured offline in an HPLC system
coupled to an UV detector. Therefore, this is the first time that
the concentration of paracetamol was measured in real-time
in an OFC.
Conclusions
Fig. 5. Paracetamol concentration during crystallization in the OFC. (Inset:
Evolution of the optical power during crystallization).
to the increase of optical density. Then, the concentration of
paracetamol decreases due to crystal growth and secondary
nucleation, which reduces the optical density and the refractive
index of the solution. When the concentration approaches
the solubility of paracetamol at 25 °C, the system reaches
the thermodynamic equilibrium, and the concentration of
paracetamol stabilizes at 100-120 g/kg, respectively.
Oscillatory Flow Crystallizer
The optical power was monitored in the OFC by two refractometric
sensors, one at the input and another one at the output.
The concentration of paracetamol in the mother liquor was
then calculated from the calibration curve (Fig. 4). As expected,
the signal of optical power measured by the sensor at the input
is lower than that measured by the sensor at the output. The
signal is virtually constant at both locations, which suggests
that crystallization occurs at steady state.
At the input, the concentration of paracetamol fluctuates
between 200 and 220 g/kg, when paracetamol is fully
dissolved. Then, the solution cools inside the OFC and becomes
supersaturated. The supersaturation is then gradually
consumed as paracetamol crystallizes. At the output, the concentration
fluctuates between 100-120 g/kg, which suggests
that the solution reaches solubility before leaving the OFC.
The results obtained in the OFC are in agreement with
those obtained in the STC as the concentration at the input of
the OFC is comparable to the concentration at the beginning
in the STC (200-220 g/kg), and the concentration at the output
of the OFC is comparable to the concentration at the end in
the STC (100-120 g/kg). These results prove the viability of the
portable interrogation system to monitor the concentration of
paracetamol in STC-like systems operating in batch or in OFClike
systems operating continuously.
Most previous studies on the crystallization of paracetamol
in OFCs have not reported the use of any PAT to monitor the
concentration of the mother liquor [13]. The study of Jiang and
Ni [14] is the exception, but even in this case, the concentration
August 2021
In this work, a portable interrogation system was used to monitor
the concentration of paracetamol in an OFC system in real-time.
To measure the concentration, a refractometric sensor was used,
based on a small section of an MMF capable of measuring the
optical power as a function of the concentration. It was found
that the optical power varies linearly with the concentration of
paracetamol in the concentration range of 53- 261 g/kg. Therefore,
the concentration of paracetamol can be obtained directly
as a function of the optical power without diluting the solution.
The refractometric sensor was also used in an STC to calibrate the
paracetamol crystallization process. This solution allows it to be
applied in OFC systems due to the reduced dimensions, because
it does not disturb the process inside of the crystallizer. The results
obtained in this work show the potential of this sensor in
monitoring in real-time the concentration of APIs in crystallizers
of different sizes and geometries, such as the OFC. This technique
can respond to the needs pointed out in this sense, being an alternative
to more expensive and complex analysis equipment.
Acknowledgment
L. Soares acknowledges doctoral scholarship 2020.05297.BD,
and P. Cruz acknowledges doctoral scholarship [SFRH/
BD/119391/2016], both supported by the Foundation for Science
and Technology (FCT).
References
[1] D. Zhang, S. Xu, S. Du, J. Wang and J. Gong, " Progress of
pharmaceutical continuous crystallization, " Engineering, vol. 3,
no. 3, pp. 354-364, 2017.
[2] L. L. Simon, H. Pataki, G. Marosi et al., " Assessment of recent
process analytical technology (PAT) trends: a multiauthor
review, " Org. Process Res. Dev., vol. 19, no. 1, pp. 3-62, 2015.
[3] L. Yu, R. Lionberger, A. Raw, R. D'Costa, H. Wu and A. Hussain,
" Applications of process analytical technology to crystallization
processes, " Adv. Drug Deliv. Rev., vol. 56, no. 3, pp. 349-369, 2004.
[4] T. McGlone, N. E. B. Briggs, C. A. Clark, C. J. Brown, J. Sefcik and
A. J. Florence, " Oscillatory flow reactors (OFRs) for continuous
manufacturing and crystallization, " Org. Process Res. Dev., vol. 19,
no. 9, pp. 1186-1202, 2015.
[5] M. W. Hermanto, G. He, M. Tjahjono, P. S. Chow, R. B. H. Tan and
M. Garland, " Calibration of dielectric constant measurements
to improve the detection of cloud and clear points in solution
crystallization, " Chem. Eng. Res. Des., vol. 89, no. 12, pp. 26132619,
2011.
[6] J. Worlitschek and M. Mazzotti, " Model-based optimization
of particle size distribution in batch-cooling crystallization of
paracetamol, " Cryst. Growth Des., vol. 4, no. 5, pp. 891-903, 2004.
[7] D. J. Griffin, Y. Kawajiri, R. W. Rousseau and M. A. Grover, " Using
MC plots for control of paracetamol crystallization, " Chem. Eng.
Sci., vol. 164, pp. 344-360, 2017.
IEEE Instrumentation & Measurement Magazine
39

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