Monitoring Continuous Crystallization of Paracetamol in the Presence of an Additive Using an Integrated PAT Array and Multivariate Methods

Abstract

In this study, an automated intelligent decision support (IDS) framework was applied to monitor the continuous crystallization of form I paracetamol (PCM) and determine steady-state operation. A modified single-stage mixed suspension mixed product removal (MSMPR) crystallizer was used to investigate methods to minimize early onset of fouling and encrustation by carrying out crystallizations in the presence and absence of hydroxyl propyl methyl cellulose (HPMC) additive. The effectiveness of HPMC toward controlling the crystallization process and alleviating fouling and encrustation for prolonged operation of the MSMPR was investigated over a range of concentrations. HPMC was found to suppress nucleation and growth, thereby controlling the crystallization and alleviating fouling and encrustation over extended operating periods. HPMC also affected the product crystal morphology, leading to predominantly tabular shaped crystals. Steady state in the MSMPR was characterized using the IDS, which consisted of an integrated and ancillary array of process analytical technologies (PAT), including the application of Raman spectroscopy with multivariate calibration for solution phase concentration measurement.

Continuous manufacturing – the Green Chemistry promise?

“…Essential for real-time process monitoring and control, a suite of PAT has the potential to be applied to continuous crystallizers for monitoring of concentration, particle size distribution (PSD), and crystal morphology. [156][157][158] Looking towards the future, despite the advances in continuous crystallization platforms, underlying fundamentals of crystallization (nucleation, growth, polymorphism, and crystal structure-property relationships) are still relatively poorly understood. As such, there is a disparate gap between the advances made and new capabilities of flow chemistry com-pared with continuous crystallizations.…”

In situ non-invasive Raman spectroscopic characterisation of succinic acid polymorphism during segmented flow crystallisation

“…PAT can enable an understanding of what is happening during a process, it also allows direct feedback control to either account for potential process variability, inconsistencies in feedstock or facilitate high throughput design of experiments (DOE) optimisation. Traditional invasive PAT, where a probe is inserted into a crystalliser, 5 can cause complications in both the fluid dynamics and crystallisation profile in continuous or flow crystallisation environmentse.g. the size of an immersion probe induces unwanted influence on the flow profile of the crystalliser and is prone to causing nucleation and growth on the probe.…”

“…Due to the complications of integrating Raman into crystallisation environments, previously published examples of exploring crystallisation processes through Raman spectroscopy have either used microscopy in static environments [14][15][16] or immersion probes in batch, 6,[17][18][19] mixed suspension mixed product removal (MSMPR) 5 and hot melt extrusion (HME) 20 environments.…”

Continuous manufacturing: Is the process mean stationary?

“…PAT has become a "must have" tool during the design and operation of pharmaceutical and fine chemical processes. 40 SS is a fundamental property of continuously operated processes. Since then the process monitoring concepts have evolved into intelligent decision platforms, which use Fourier transform-Raman, ultraviolet-visible spectroscopy measurements, and process informatics software.…”

“…Since then the process monitoring concepts have evolved into intelligent decision platforms, which use Fourier transform-Raman, ultraviolet-visible spectroscopy measurements, and process informatics software. 40 SS is a fundamental property of continuously operated processes. The automated and on-line SS detection is motivated by process modeling, monitoring, and control applications.…”