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Engineering of an Inhalable DDA/TDB Liposomal Adjuvant: A Quality-by-Design Approach Towards Optimization of the Spray Drying Process

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Abstract

Purpose

The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6′-dibehenate (TDB).

Methods

A quality by design (QbD) approach was applied to identify and link critical process parameters (CPPs) of the spray drying process to critical quality attributes (CQAs) using risk assessment and design of experiments (DoE), followed by identification of an optimal operating space (OOS). A central composite face-centered design was carried out followed by multiple linear regression analysis.

Results

Four CQAs were identified; the mass median aerodynamic diameter (MMAD), the liposome stability (size) during processing, the moisture content and the yield. Five CPPs (drying airflow, feed flow rate, feedstock concentration, atomizing airflow and outlet temperature) were identified and tested in a systematic way. The MMAD and the yield were successfully modeled. For the liposome size stability, the ratio between the size after and before spray drying was modeled successfully. The model for the residual moisture content was poor, although, the moisture content was below 3% in the entire design space. Finally, the OOS was drafted from the constructed models for the spray drying of trehalose stabilized DDA/TDB liposomes.

Conclusions

The QbD approach for the spray drying process should include a careful consideration of the quality target product profile. This approach implementing risk assessment and DoE was successfully applied to optimize the spray drying of an inhalable DDA/TDB liposomal adjuvant designed for pulmonary vaccination.

Diagram of an optimal operating space highlighting the process design space where the critical criteria are met: White: No criteria met. Dark blue: One criterion met. Light blue: Two criteria met. Green: All criteria met.

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Abbreviations

CPP:

critical process parameter

CQA:

critical quality attribute

DDA:

dimethyldioctadecylammonium

DoE:

Design of Experiments

FPF:

fine particle fraction

MMAD:

mass median aerodynamic diameter

OOS:

optimal operating space

PDI:

polydispersity index

QbD:

Quality by Design

QTPP:

quality target product profile

TDB:

trehalose-6,6′-dibehenate

VMD:

volumetric mean diameter

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Acknowledgments And Disclosures

Jukka Rantanen and Camilla Foged share senior authorship. The authors would like to acknowledge Dorthe Kyed Ørbæk (University of Copenhagen) for assistance with SEM and the Centre for Nano-Vaccines (CNV) and its members for the collaboration. The authors are grateful to The Danish Council for Strategic Research for funding the project (PTI). The funding source had no involvement in the study or the decision to submit the results for publication.

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Authors and Affiliations

  1. Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen O, Denmark

    Pall Thor Ingvarsson, Mingshi Yang, Helle Mulvad, Hanne Mørck Nielsen, Jukka Rantanen & Camilla Foged

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  1. Pall Thor Ingvarsson
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  2. Mingshi Yang
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  3. Helle Mulvad
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Correspondence to Jukka Rantanen.

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Ingvarsson, P.T., Yang, M., Mulvad, H. et al. Engineering of an Inhalable DDA/TDB Liposomal Adjuvant: A Quality-by-Design Approach Towards Optimization of the Spray Drying Process. Pharm Res 30, 2772–2784 (2013). https://doi.org/10.1007/s11095-013-1096-2

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  • DOI: https://doi.org/10.1007/s11095-013-1096-2

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