Denise Z L Ng1,2,3, Arif Z Nelson2,3, Gareth Ward4, David Lai5,6, Patrick S Doyle7,8, Saif A Khan9,10. 1. Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117576, Singapore. 2. Critical Analytics for Manufacturing Personalized-Medicine, Singapore-MIT Alliance for Research and Technology, Singapore, 138602, Singapore. 3. Campus for Research Excellence and Technological Enterprise, Singapore, 138602, Singapore. 4. GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG12NY, UK. 5. GlaxoSmithKline LLC, Product and Process Engineering, 709 Swedeland Road, King of Prussia, Pennsylvania, 19406, USA. 6. GlaxoSmithKline LLC, Advanced Manufacturing Technologies, 830 Winter Street, Waltham, Massachusetts, 02451, USA. 7. Critical Analytics for Manufacturing Personalized-Medicine, Singapore-MIT Alliance for Research and Technology, Singapore, 138602, Singapore. pdoyle@mit.edu. 8. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA. pdoyle@mit.edu. 9. Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117576, Singapore. saifkhan@nus.edu.sg. 10. Campus for Research Excellence and Technological Enterprise, Singapore, 138602, Singapore. saifkhan@nus.edu.sg.
Abstract
PURPOSE: Industrial implementation of continuous oral solid dosage form manufacturing has been impeded by the poor powder flow properties of many active pharmaceutical ingredients (APIs). Microfluidic droplet-based particle synthesis is an emerging particle engineering technique that enables the production of neat or composite microparticles with precise control over key attributes that affect powder flowability, such as particle size distribution, particle morphology, composition, and the API's polymorphic form. However, the powder properties of these microparticles have not been well-studied due to the limited mass throughputs of available platforms. In this work, we produce spherical API and API-composite microparticles at high mass throughputs, enabling characterization and comparison of the bulk powder flow properties of these materials and greater understanding of how particle-scale attributes correlate with powder rheology. METHODS: A multi-channel emulsification device and an extractive droplet-based method are harnessed to synthesize spherical API and API-excipient particles of artemether. As-received API and API crystallized in the absence of droplet confinement are used as control cases. Particle attributes are characterized for each material and correlated with a comprehensive series of powder rheology tests. RESULTS: The droplet-based processed artemether particles are observed to be more flowable, less cohesive, and less compressible than conventionally synthesized artemether powder. Co-processing the API with polycaprolactone to produce composite microparticles reduces the friction of the powder on stainless steel, a common equipment material. CONCLUSIONS: Droplet-based extractive solidification is an attractive particle engineering technique for improving powder processing and may aid in the implementation of continuous solid dosage form manufacturing.
PURPOSE: Industrial implementation of continuous oral solid dosage form manufacturing has been impeded by the poor powder flow properties of many active pharmaceutical ingredients (APIs). Microfluidic droplet-based particle synthesis is an emerging particle engineering technique that enables the production of neat or composite microparticles with precise control over key attributes that affect powder flowability, such as particle size distribution, particle morphology, composition, and the API's polymorphic form. However, the powder properties of these microparticles have not been well-studied due to the limited mass throughputs of available platforms. In this work, we produce spherical API and API-composite microparticles at high mass throughputs, enabling characterization and comparison of the bulk powder flow properties of these materials and greater understanding of how particle-scale attributes correlate with powder rheology. METHODS: A multi-channel emulsification device and an extractive droplet-based method are harnessed to synthesize spherical API and API-excipient particles of artemether. As-received API and API crystallized in the absence of droplet confinement are used as control cases. Particle attributes are characterized for each material and correlated with a comprehensive series of powder rheology tests. RESULTS: The droplet-based processed artemether particles are observed to be more flowable, less cohesive, and less compressible than conventionally synthesized artemether powder. Co-processing the API with polycaprolactone to produce composite microparticles reduces the friction of the powder on stainless steel, a common equipment material. CONCLUSIONS: Droplet-based extractive solidification is an attractive particle engineering technique for improving powder processing and may aid in the implementation of continuous solid dosage form manufacturing.
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