ABSTRACT
Recent advances in the latest generation of MEMS (micro-electro-mechanical system) Fabry-Pérot interferometers (FPI) for near infrared (NIR) wavelengths has led to the development of ultra-fast and low cost NIR sensors with potential to be used by the process industry. One of these miniaturised sensors operating from 1350 to 1650 nm, was integrated into a software platform to monitor a multiphase solid-gas-liquid process, for the production of saturated polyester resins. Twelve batches were run in a 2 L reactor mimicking industrial conditions (24 h process, with temperatures ranging from 220 to 240 °C), using an immersion NIR transmission probe. Because of the multiphase nature of the reaction, strong interference produced by process disturbances such as temperature variations and the presence of solid particles and bubbles in the online spectra required robust pre-processing algorithms and a good long-term stability of the probe. These allowed partial least squares (PLS) regression models to be built for the key analytical parameters acid number and viscosity. In parallel, spectra were also used to build an end-point detection model based on principal component analysis (PCA) for multivariate statistical process control (MSPC). The novel MEMS-FPI sensor combined with robust chemometric analysis proved to be a suitable and affordable alternative for online process monitoring, contributing to sustainability in the process industry.
ABSTRACT
PURPOSE: The current trend for continuous drug product manufacturing requires new, affordable process analytical techniques (PAT) to ensure control of processing. This work evaluates whether property models based on spectral data from recent Fabry-Pérot Interferometer based NIR sensors can generate a high-resolution moisture signal suitable for process control. METHODS: Spectral data and offline moisture content were recorded for 14 fluid bed dryer batches of pharmaceutical granules. A PLS moisture model was constructed resulting in a high resolution moisture signal, used to demonstrate (i) endpoint determination and (ii) evaluation of mass transfer performance. RESULTS: The sensors appear robust with respect to vibration and ambient temperature changes, and the accuracy of water content predictions (±13 % ) is similar to those reported for high specification NIR sensors. Fusion of temperature and moisture content signal allowed monitoring of water transport rates in the fluidised bed and highlighted the importance water transport within the solid phase at low moisture levels. The NIR data was also successfully used with PCA-based MSPC models for endpoint detection. CONCLUSIONS: The spectral quality of the small form factor NIR sensor and its robustness is clearly sufficient for the construction and application of PLS models as well as PCA-based MSPC moisture models. The resulting high resolution moisture content signal was successfully used for endpoint detection and monitoring the mass transfer rate.
Subject(s)
Spectroscopy, Near-Infrared/economics , Spectroscopy, Near-Infrared/instrumentation , Technology, Pharmaceutical/methods , Drug Compounding , Micro-Electrical-Mechanical Systems , Powders/chemistry , Pressure , Temperature , WaterABSTRACT
Today, the generation of kinetic models is still seen as a resource intensive and specialised activity. We report an efficient method of generating reaction profiles from transient flows using a state-of-the-art continuous-flow platform. Experimental data for multistep aromatic nucleophilic substitution reactions are collected from an automated linear gradient flow ramp with online HPLC at the reactor outlet. Using this approach, we generated 16 profiles, at 3 different inlet concentrations and 4 temperatures, in less than 3 hours run time. The kinetic parameters, 4 rate constants and 4 activation energies were fitted with less than 4% uncertainty. We derived an expression for the error in the observed rate constants due to dispersion and showed that such error is 5% or lower. The large range of operational conditions prevented the need to isolate individual reaction steps. Our approach enables early identification of the sensitivity of product quality to parameter changes and early use of unit operation models to identify optimal process-equipment combinations in silico, greatly reducing scale up risks.
