(W0930-12-78) Process Induced Degradation of Carbamazepine during Hot Melt Extrusion

Purpose: The aim of this study was to evaluate hot melt extrudates of carbamazepine (CBZ) for presence of process induced degradation product iminostilbene (IMB) and quantifying using high performance liquid chromatography (HPLC).<

Methods: CBZ, a Biopharmaceutics Classification System (BCS) class II active pharmaceutical ingredient (API) with multiple polymorphs was used as model drug. Hot-melt extrusion (HME) was performed to prepare solid dispersions (Alshetaili et al., 2020) (Djuris et al., 2013). Different grades of Hydroxypropyl-Methylcellulose-Acetate-Succinate (HPMCAS), Poly (vinyl alcohol) (PVA) and Polyethylene glycol (PEG) were used. PEG was used as plasticizer to lower processing temperature. The extrudates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared (FTIR) studies. HPLC was performed to quantify percentage amount of CBZ and IMB (Džodić et al., 2010).

Results: Drug loading, processing temperature and screw rotations per minute (RPM) showed significant effect on degradation of CBZ in all tested ratios of HPMCAS and PVA. PEG was used as plasticizer to lower processing temperature. CBZ was completely miscible in the polymeric blends to 20% drug loading. The extrudates were characterized DSC, XRD and FTIR studies. DSC and XRD data confirmed formation of amorphous solid dispersions of CBZ in the polymeric blends of HPMCAS, PVA and PEG. HPLC was performed to quantify percentage amount of CBZ and IMB. The United State Pharmacopoeia (USP) recommends: ‘0.2% w/w of iminostilbene as a maximum allowable limit in Carbamazepine or its formulations (USP 30-NF 25)’. Hence formulations containing less than 0.2% w/w of iminostilbene were deemed suitable for further study.

Conclusion: Process induced degradation was significantly low in PVA compared to HPMCAS, further lower with 20% (w/w) PEG. In addition, processing temperature and RPM had direct effect on percentage of IMB formation.

References: Alshetaili, A. et al. (2020) ‘Hot Melt Extrusion Processing Parameters Optimization’, Processes. doi: 10.3390/pr8111516.
Djuris, J. et al. (2013) ‘Preparation of carbamazepine-Soluplus solid dispersions by hot-melt extrusion, and prediction of drug-polymer miscibility by thermodynamic model fitting’, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 84(1), pp. 228–237. doi: 10.1016/j.ejpb.2012.12.018.
Džodić, P. L. et al. (2010) ‘Determination of carbamazepine and its impurities iminostilbene and iminodibenzyl in solid dosage form by column high-performance liquid chromatography’, Journal of AOAC International, 93(4), pp. 1059–1068. doi: 10.1093/jaoac/93.4.1059.

Acknowledgements: I am thankful to University of Bradford, Faculty of Life Sciences, Centre for Pharmaceutical Engineering Science, School of Pharmacy and Faculty of Engineering and Informatics for providing me the platform to carry out the research and for providing adequate support.

Carbamazepine degradation to Iminostilbene and Chromatogram

Graphical representation of results