Scale-Up and In-line Monitoring During Continuous Melt Extrusion of an Amorphous Solid Dispersion
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Chemical degradation of drug substances remains a major drawback of extrusion. Larger-scale extrusion equipment has advantages over smaller equipment due to deeper flight elements and added flexibility in terms of screw design, unit operations, and residence time. In a previous study, we extruded a meloxicam-copovidone amorphous solid dispersion (ASD) on a Nano-16 extruder and achieved 96.7% purity. The purpose of this study is to introduce a strategy for scaling the process to an extruder with dissimilar geometry and to investigate the impact on the purity of the ASD. The formulation previously optimized on the Nano-16, 10:90 meloxicam and copovidone, was used for scale-up. Our approach to scale-up to the ZSE-18, utilized specific mechanical energy input and degree of fill from the Nano-16. Vacuum was added to prevent hydrolysis of meloxicam. Downstream feeding and micronization of meloxicam were introduced to reduce the residence time. In-line monitoring of the solubilization of meloxicam was monitored with a UV probe positioned at the die. We were able to achieve the same purity of meloxicam with the Micro-18 as we achieved with Nano-16. When process conditions alone were not sufficient, meglumine was added to further stabilize meloxicam. In addition to the chemical stability advantage that meglumine provided, we also observed solubility enhancement which allowed for an increase in drug loading to 20% while maintaining 100% purity.
KEY WORDSmelt extrusion amorphous solid dispersion meloxicam chemical stability scale-up
Some of this work was presented at the 2017 AAPS Annual Meeting and Exhibition, San Diego, CA. The authors would like to acknowledge Nada Kittikunakoin for her help in completing this work.
- 3.Brown C, DiNunzio J, Eglesia M, Forster S, Lamm M, Lowinger M, Marsac P, McKelvey C, Meyer R, Schenck L, Terife G. Hot-melt extrusion for solid dispersions: composition and design considerations. In: Amorphous solid dispersions. New York: Springer; 2014. p. 197–230.Google Scholar
- 4.Brown C, DiNunzio J, Eglesia M, Forster S, Lamm M, Lowinger M, Marsac P, McKelvey C, Meyer R, Schenck L, Terife G. HME for solid dispersions: scale-up and late-stage development. In: Amorphous solid dispersions. New York: Springer; 2014. p. 231–260.Google Scholar
- 7.Tadmor Z, Gogos CG. Principles of polymer processing. 2nd ed. UK: John Wiley & Sons; 2013.Google Scholar
- 12.Todd DB. Plastics compounding: equipment and processing. Munich: Carl Hanser Verlag GmbH & Co; 1998.Google Scholar
- 14.Martin C. Twin screw extrusion for pharmaceutical processes. In: Melt extrusion. New York: Springer; 2013. p. 47–79.Google Scholar
- 17.Martin AN, Swarbrick J, Cammarata A. Physical pharmacy: physical chemical principles in the pharmaceutical sciences. 3rd ed. Philadelphia: Lea & Febiger; 1993.Google Scholar
- 30.Kolter K, Karl M, Gryczke A. Hot-melt extrusion with BASF pharma polymers. Ludwigshafen: BASF SE, Pharma Ingredients & Services; 2012.Google Scholar