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Control of Drug-Excipient Particle Attributes with Droplet Microfluidic-based Extractive Solidification Enables Improved Powder Rheology

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A Correction to this article was published on 22 April 2022

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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.

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Acknowledgments

The authors thank Ms. Ariel Chua from the National University of Singapore (Department of chemical engineering) for assistance with the characterization of particle size distributions of equant shaped artemether Raw and artemether Recrystallized samples and Dr. Rajeev Dattani from Freeman Technology for technical assistance on the aeration tests. The authors thank Longfei Chen and Dr. Swati Shikha for assistance on the characterisation of residual solvents levels of artemether PCL, artemether SA via 1H-NMR, and neat polycaprolactone particles via PXRD. The authors report no conflicts of interest.

Funding

This research was supported by the National Research Foundation, Prime Minister's Office, Singapore under its Campus for Research Excellence and Technological Enterprise program and GSK-EDB fund (R279-000–507-592). Financial support was also provided by the Pharmaceutical Innovation Programme Singapore (grant number A19B3a0012).

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Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore, 117576, Singapore

    Denise Z. L. Ng & Saif A. Khan

  2. Critical Analytics for Manufacturing Personalized-Medicine, Singapore-MIT Alliance for Research and Technology, Singapore, 138602, Singapore

    Denise Z. L. Ng, Arif Z. Nelson & Patrick S. Doyle

  3. Campus for Research Excellence and Technological Enterprise, Singapore, 138602, Singapore

    Denise Z. L. Ng, Arif Z. Nelson & Saif A. Khan

  4. GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG12NY, UK

    Gareth Ward

  5. GlaxoSmithKline LLC, Product and Process Engineering, 709 Swedeland Road, King of Prussia, Pennsylvania, 19406, USA

    David Lai

  6. GlaxoSmithKline LLC, Advanced Manufacturing Technologies, 830 Winter Street, Waltham, Massachusetts, 02451, USA

    David Lai

  7. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA

    Patrick S. Doyle

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  1. Denise Z. L. Ng
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Contributions

All authors contributed to the study conception and design. Material preparation, and data collection were performed by D.Z.L.N. Data analysis was performed by D.Z.L.N and A.Z.N. The first draft of the manuscript was written by D.Z.L.N and A.Z.N. All authors commented on previous versions of the manuscript, read, and approved the final manuscript.

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Correspondence to Patrick S. Doyle or Saif A. Khan.

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Both Patrick S. Doyle and Saif A. Khan are recipients of grant number [A19B3a0012].

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Ng, D.Z.L., Nelson, A.Z., Ward, G. et al. Control of Drug-Excipient Particle Attributes with Droplet Microfluidic-based Extractive Solidification Enables Improved Powder Rheology. Pharm Res 39, 411–421 (2022). https://doi.org/10.1007/s11095-021-03155-0

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