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Formulation performance and processability window for manufacturing a dual-polymer amorphous solid dispersion via hot-melt extrusion and strand pelletization.
Int J Pharm. 2018 Dec 20; 553(1-2):408-421.IJ

Abstract

This work evaluates several compositions of an amorphous solid dispersion (ASD) comprising nimodipine (NMD) as poorly soluble model API in a dual-polymer carrier system. HPMC E5 and Eudragit E were used for the two polymeric carriers. The formulation was designed for hot-melt extrusion (HME) and subsequent strand pelletization. The aim was to identify a formulation window with desired functional ASD performance, i.e. physical stability and immediate API release, as well as processability in strand pelletization. Samples were prepared using small-scale methods, such as vacuum compression molding (VCM) and benchtop extrusion. Miscibility and phase studies were performed for a wide range of polymer ratios and three levels of API content (10-30% w/w). Ternary ASD formulations were phase-separated, yet physically stable upon exposure to elevated temperature/humidity. A study of phase composition showed that the drug molecules were predominantly solubilized in the Eudragit E fraction of the formulation. The miscibility study and Fourier-transform infrared spectroscopy indicated hydrogen (H)bond interactions between NMD and Eudragit E. In HPMC, the amorphous API was dispersed in polymeric matrix and stabilized due to anti-plasticization and the disruption of intermolecular Hbonding between API molecules. Concerning processability in strand pelletization the formulation is limited at high Eudragit E content. NMD and EE-rich phases exhibit low mixture glass transition, low melt stability and brittle breaking behavior upon strand cutting. The high viscosity and yield point of HPMC contributes to the mechanical robustness of the strand at temperatures relevant for processing. Formulation-intrinsic dissolution rates in VCM ASDs developed as an irregular function of polymer ratio, associated with diverse and competitive dissolution mechanisms in the polymers. With regard to the binary system of NMD with HPMC E5, surface crystallization was observed in VCM ASDs. For extruded pellets this was not the case, and a steady trend of formulation-intrinsic dissolution rate across different polymer ratios was observed. These discrepancies indicated a major influence of shear stress during sample preparation on HPMC-based ASD performance. Finally, a feasible formulation window within a polymer ratio of 1:2-2:3 Eudragit E:HPMC was identified in which Eudragit E acts as a dissolution rate enhancer and ASD stabilizer during dissolution.

Authors+Show Affiliations

Institute for Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13/3, 8010 Graz, Austria.Research Centre for Pharmaceutical Engineering, Inffeldgasse 13/2, 8010 Graz, Austria.Chemical and Pharmaceutical Development, Bayer AG, Müllerstraβe 178, 13353 Berlin, Germany.Maag Automatik GmbH, Ostring 19, 63762 Groβostheim, Germany.Institute for Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13/3, 8010 Graz, Austria; Research Centre for Pharmaceutical Engineering, Inffeldgasse 13/2, 8010 Graz, Austria. Electronic address: khinast@tugraz.at.Institute for Process and Particle Engineering, Graz University of Technology, Inffeldgasse 13/3, 8010 Graz, Austria; Research Centre for Pharmaceutical Engineering, Inffeldgasse 13/2, 8010 Graz, Austria. Electronic address: amrit.paudel@rcpe.at.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30326284

Citation

Hörmann, T R., et al. "Formulation Performance and Processability Window for Manufacturing a Dual-polymer Amorphous Solid Dispersion Via Hot-melt Extrusion and Strand Pelletization." International Journal of Pharmaceutics, vol. 553, no. 1-2, 2018, pp. 408-421.
Hörmann TR, Jäger N, Funke A, et al. Formulation performance and processability window for manufacturing a dual-polymer amorphous solid dispersion via hot-melt extrusion and strand pelletization. Int J Pharm. 2018;553(1-2):408-421.
Hörmann, T. R., Jäger, N., Funke, A., Mürb, R. K., Khinast, J. G., & Paudel, A. (2018). Formulation performance and processability window for manufacturing a dual-polymer amorphous solid dispersion via hot-melt extrusion and strand pelletization. International Journal of Pharmaceutics, 553(1-2), 408-421. https://doi.org/10.1016/j.ijpharm.2018.10.035
Hörmann TR, et al. Formulation Performance and Processability Window for Manufacturing a Dual-polymer Amorphous Solid Dispersion Via Hot-melt Extrusion and Strand Pelletization. Int J Pharm. 2018 Dec 20;553(1-2):408-421. PubMed PMID: 30326284.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Formulation performance and processability window for manufacturing a dual-polymer amorphous solid dispersion via hot-melt extrusion and strand pelletization. AU - Hörmann,T R, AU - Jäger,N, AU - Funke,A, AU - Mürb,R-K, AU - Khinast,J G, AU - Paudel,A, Y1 - 2018/10/14/ PY - 2018/08/11/received PY - 2018/10/12/revised PY - 2018/10/13/accepted PY - 2018/10/17/pubmed PY - 2019/3/9/medline PY - 2018/10/17/entrez KW - Amorphous solid dispersion KW - Dual-polymeric carrier formulation KW - Hot-melt extrusion KW - Molecular interactions KW - Nimodipine KW - Strand pelletization SP - 408 EP - 421 JF - International journal of pharmaceutics JO - Int J Pharm VL - 553 IS - 1-2 N2 - This work evaluates several compositions of an amorphous solid dispersion (ASD) comprising nimodipine (NMD) as poorly soluble model API in a dual-polymer carrier system. HPMC E5 and Eudragit E were used for the two polymeric carriers. The formulation was designed for hot-melt extrusion (HME) and subsequent strand pelletization. The aim was to identify a formulation window with desired functional ASD performance, i.e. physical stability and immediate API release, as well as processability in strand pelletization. Samples were prepared using small-scale methods, such as vacuum compression molding (VCM) and benchtop extrusion. Miscibility and phase studies were performed for a wide range of polymer ratios and three levels of API content (10-30% w/w). Ternary ASD formulations were phase-separated, yet physically stable upon exposure to elevated temperature/humidity. A study of phase composition showed that the drug molecules were predominantly solubilized in the Eudragit E fraction of the formulation. The miscibility study and Fourier-transform infrared spectroscopy indicated hydrogen (H)bond interactions between NMD and Eudragit E. In HPMC, the amorphous API was dispersed in polymeric matrix and stabilized due to anti-plasticization and the disruption of intermolecular Hbonding between API molecules. Concerning processability in strand pelletization the formulation is limited at high Eudragit E content. NMD and EE-rich phases exhibit low mixture glass transition, low melt stability and brittle breaking behavior upon strand cutting. The high viscosity and yield point of HPMC contributes to the mechanical robustness of the strand at temperatures relevant for processing. Formulation-intrinsic dissolution rates in VCM ASDs developed as an irregular function of polymer ratio, associated with diverse and competitive dissolution mechanisms in the polymers. With regard to the binary system of NMD with HPMC E5, surface crystallization was observed in VCM ASDs. For extruded pellets this was not the case, and a steady trend of formulation-intrinsic dissolution rate across different polymer ratios was observed. These discrepancies indicated a major influence of shear stress during sample preparation on HPMC-based ASD performance. Finally, a feasible formulation window within a polymer ratio of 1:2-2:3 Eudragit E:HPMC was identified in which Eudragit E acts as a dissolution rate enhancer and ASD stabilizer during dissolution. SN - 1873-3476 UR - https://www.unboundmedicine.com/medline/citation/30326284/Formulation_performance_and_processability_window_for_manufacturing_a_dual_polymer_amorphous_solid_dispersion_via_hot_melt_extrusion_and_strand_pelletization_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(18)30770-1 DB - PRIME DP - Unbound Medicine ER -