Pellet manufacturing by extrusion-spheronization using process analytical technology

Abstract

The aim of this study was to investigate the phase transitions occurring in nitrofurantoin and theophylline formulations during pelletization by extrusion-spheronization. An at-line process analytical technology (PAT) approach was used to increase the understanding of the solid-state behavior of the active pharmaceutical ingredients (APIs) during pelletization. Raman spectroscopy, near-infrared (NIR) spectroscopy, and X-ray powder diffraction (XRPD) were used in the characterization of polymorphic changes during the process. Samples were collected at the end of each processing stage (blending, granulation, extrusion, spheronization, and drying). Batches were dried at 3 temperature levels (60°C, 100°C, and 135°C). Water induced a hydrate formation in both model formulations during processing. NIR spectroscopy gave valuable real-time data about the state of water in the system, but it was not able to detect the hydrate formation in the theophylline and nitrofurantoin formulations during the granulation, extrusion, and spheronization stages because of the saturation of the water signal. Raman and XRPD measurement results confirmed the expected pseudopolymorphic changes of the APIs in the wet process stages. The relatively low level of Raman signal with the theophylline formulation complicated the interpretation. The drying temperature had a significant effect on dehydration. For a channel hydrate (theophylline), dehydration occurred at lower drying temperatures. In the case of isolated site hydrate (nitrofurantoin), dehydration was observed at higher temperatures. To reach an understanding of the process and to find the critical process parameters, the use of complementary analytical techniques are absolutely necessary when signals from APIs and different excipients overlap each other.

Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes

“…Sandler et al (2005) used Raman and NIR spectroscopy at-568 line to increase the understanding of the solid-state behavior of theophylline and nitrofurantoin 569 formulations during pelletization. NIR gave valuable information on the water behavior during 570 processing, but did not allow to detect the hydrate formation in the formulations because of the 571 saturation of the water signal.…”

NIR Spectroscopy Applications in the Development of a Compacted Multiparticulate System for Modified Release

“…Thosar et al (25) prepared tablets of anhydrous theophylline with concentrations ranging from 0 to 120 mg, and they found improved accuracy was obtained using partial least squares (PLS) over multiple linear regression in transmission mode, they did not reduce the concentration range in their calibration dataset. The results showed that prediction errors were larger for the lowest dosages; with errors of 17.6%, 2.3%, 1.4%, 1.1%, and 0.35% for the 3,6,15,30, and 60 mg tablet doses, respectively.…”

“…PAT can provide real-time data to enable improved process understanding and lead to better manufacturing process control, and this information can ultimately reduce end-product testing and its associated costs (1)(2)(3)(4)(5). NIRS has also found utility in the laboratory as well; a recent article discusses PAT applications for the use of NIRS in monitoring polymorphic changes atline during preparation of beads containing either nitrofurantoin or anhydrous theophylline (6). Knowledge of such phase changes is important because the chemical stability, manufacturing processability, and release rate of the drug can be dramatically affected.…”

Miniaturization in Pharmaceutical Extrusion Technology: Feeding as a Challenge of Downscaling

“…In the field of solid dosage forms, twin-screw extrusion has become an efficient and flexible technique because of advantages such as cost reduction, improvement of process efficiency, and flexibility in production capacity (2). Twin-screw extruders are used for various manufacturing processes like pelletization (3,4), bioavailability improvement, or manipulation of solidstate properties of drugs (5,6). Extrusion is also applicable for continuous granulation (7)(8)(9) and the development of novel solid dosage forms for personalized medicine (10).…”