TY - JOUR
T1 - THz-TDS as a PAT tool for monitoring blend homogeneity in pharmaceutical manufacturing of solid oral dosage forms
T2 - A proof-of-concept study
AU - Anuschek, Moritz
AU - Skelbæk-Pedersen, Anne Linnet
AU - Skibsted, Erik
AU - Kvistgaard Vilhelmsen, Thomas
AU - Axel Zeitler, J.
AU - Rantanen, Jukka
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024
Y1 - 2024
N2 - The process analytical technology (PAT) framework is well established and integral to facilitate process understanding, enable a transition from batch to continuous manufacturing, and improve product quality. Near-infrared (NIR) spectroscopy has been established as a standard PAT tool for many process analytical challenges, including monitoring powder blend homogeneity. However, alternative technologies for monitoring powder blending are of interest due to the importance of the blending step in manufacturing solid oral dosage forms. Terahertz time-domain spectroscopy (THz-TDS) is therefore explored in this study as an alternative tool for monitoring blend homogeneity with the potential for endpoint control in a batch blending process. Powder blends of microcrystalline cellulose (MCC) and dibasic calcium phosphate dihydrate and blends of MCC and granulated α-lactose monohydrate were investigated non-invasively at various compositions using THz-TDS in transmission mode for acquiring spectra from samples enclosed in the blending container. It was found that attenuation- and phase-related parameters acquired with THz-TDS could reliably resolve physical changes related to the homogeneity of the blend. Further evaluations revealed that changes in the bulk density of the blend, in addition to the intrinsic optical properties of the materials, played a critical role in the observed trends for both systems. In contrast, the scattering contribution of the powder was mainly crucial for the attenuation-related parameter in blends with materials of high refractive indices. Finally, THz-TDS measurements were acquired throughout a blending process mimicking a continuous acquisition. The method could follow blending dynamics and resulted in reasonable predictive errors of the content of 0.5 – 2.5 %. Relative standard deviations for high content blends (20 %) were acceptable (3 – 7 %) whereas at low contents (5 %) significantly higher values (9 – 35 %) were found. Based on these findings, THz-TDS is a feasible PAT tool for monitoring blend homogeneity and controlling high content blend processes, although precision and accuracy is considered to improve with a more suitable interface.
AB - The process analytical technology (PAT) framework is well established and integral to facilitate process understanding, enable a transition from batch to continuous manufacturing, and improve product quality. Near-infrared (NIR) spectroscopy has been established as a standard PAT tool for many process analytical challenges, including monitoring powder blend homogeneity. However, alternative technologies for monitoring powder blending are of interest due to the importance of the blending step in manufacturing solid oral dosage forms. Terahertz time-domain spectroscopy (THz-TDS) is therefore explored in this study as an alternative tool for monitoring blend homogeneity with the potential for endpoint control in a batch blending process. Powder blends of microcrystalline cellulose (MCC) and dibasic calcium phosphate dihydrate and blends of MCC and granulated α-lactose monohydrate were investigated non-invasively at various compositions using THz-TDS in transmission mode for acquiring spectra from samples enclosed in the blending container. It was found that attenuation- and phase-related parameters acquired with THz-TDS could reliably resolve physical changes related to the homogeneity of the blend. Further evaluations revealed that changes in the bulk density of the blend, in addition to the intrinsic optical properties of the materials, played a critical role in the observed trends for both systems. In contrast, the scattering contribution of the powder was mainly crucial for the attenuation-related parameter in blends with materials of high refractive indices. Finally, THz-TDS measurements were acquired throughout a blending process mimicking a continuous acquisition. The method could follow blending dynamics and resulted in reasonable predictive errors of the content of 0.5 – 2.5 %. Relative standard deviations for high content blends (20 %) were acceptable (3 – 7 %) whereas at low contents (5 %) significantly higher values (9 – 35 %) were found. Based on these findings, THz-TDS is a feasible PAT tool for monitoring blend homogeneity and controlling high content blend processes, although precision and accuracy is considered to improve with a more suitable interface.
U2 - 10.1016/j.ijpharm.2024.124534
DO - 10.1016/j.ijpharm.2024.124534
M3 - Journal article
C2 - 39079591
AN - SCOPUS:85200233490
VL - 662
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
SN - 0378-5173
M1 - 124534
ER -