In-Line UV-Vis Spectroscopy as a Fast-Working Process Analytical Technology (PAT) during Early Phase Product Development Using Hot Melt Extrusion (HME)

Abstract

This paper displays the potential of an in-line PAT system for early phase product development during pharmaceutical continuous manufacturing following a Quality by Design (QbD) framework. Hot melt extrusion (HME) is used as continuous manufacturing process and UV–Vis spectroscopy as an in-line monitoring system. A sequential design of experiments (DoE) (screening, optimisation and verification) was used to gain process understanding for the manufacture of piroxicam (PRX)/Kollidon® VA64 amorphous solid dispersions. The influence of die temperature, screw speed, solid feed rate and PRX concentration on the critical quality attributes (CQAs) absorbance and lightness of color (L*) of the extrudates was investigated using multivariate tools. Statistical analysis results show interaction effects between concentration and temperature on absorbance and L* values. Solid feed rate has a significant effect on absorbance only and screw speed showed least impact on both responses for the screening design. The optimum HME process conditions were confirmed by 4 independent studies to be 20% w/w of PRX, temperature 140 °C, screw speed 200 rpm and feed rate 6 g/min. The in-line UV-Vis system was used to assess the solubility of PRX in Kollidon® VA64 by measuring absorbance and L* values from 230 to 700 nm. Oversaturation was observed for PRX concentrations higher than 20% w/w. Oversaturation can be readily identified as it causes scattering in the visible range. This is observed by a shift of the baseline in the visible part of the spectrum. Extrudate samples were analyzed for degradation using off-line High-Performance Liquid Chromatography (HPLC) standard methods. Results from off-line experiments using differential scanning calorimetry (DSC), and X-ray diffraction (XRD) are also presented.

Continuous-flow synthesis and application of polymer-supported BODIPY Photosensitisers for the generation of singlet oxygen; process optimised by in-line NMR spectroscopy

“…To overcome mass transport limitations and inefficient light penetration, we have turned to continuous flow chemistry for both material synthesis and photosensitisation reactions. Flow processes permit in-line spectroscopy such as UV-Vis, IR, mass spectrometry and NMR, which simplifies process optimisation and reaction monitoring with better reproducibility [24][25][26][27][28].…”

Development and Validation of an in-line API Quantification Method Using AQbD Principles Based on UV-Vis Spectroscopy to Monitor and Optimise Continuous Hot Melt Extrusion Process

“…Off-line UV-Vis calibration curve was performed to check content uniformity and 10 min was considered the optimal time for blending. The rationale for using piroxicam and Kollidon ® VA64 is described in [15].…”

“…The colours green to red are described by the axis a*, while blue to yellow are represented by axis b* [14]. Applications of in-line UV-Vis spectroscopy during HME have been reported in the literature for early phase product development [15], feasibility of API quantification [16], residence time distribution determination [17] and monitoring of thermal degradation processes [18]. This technique tends to be both fast to set up and to provide data that is simple to interpret.…”

“…Previous work published by our group reported the benefits of using in-line UV-Vis spectroscopy as a rapid analytical technology with applications in the early phase product development of HME processes [15]. Following this work, optimisation of the manufacturing process of piroxicam (PRX) in Kollidon ® VA 64 (KOL) was carried out for the intended QTPP of immediate release tablets containing 20 mg of API.…”

Novel Cleaning-in-Place Strategies for Pharmaceutical Hot Melt Extrusion

“…For the in-line API analysis of EVA/E2_1% and EVA/E3_5%, the UV-Vis spectrophotometer InspectroX equipped with two transmission polymer melt probes (both ColVisTec AG, Berlin, Germany) was attached to the extruder die in axial alignment, as reported elsewhere [26,29]. The measurements were performed in transmission between 250 and 400 nm with a sampling rate of 0.167 Hz.…”