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Influence of Formulation Factors on the Aerosol Performance of Suspension and Solution Metered Dose Inhalers: A Systematic Approach

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Abstract

Metered dose inhalers (MDIs) are complex drug-device combination products widely used to treat pulmonary disorders. The efficacy, driven by aerosol performance of the products, depends on a multitude of factors including, but not limited to, the physicochemical properties of drug and nature and amount of excipient(s). Under the quality by design (QbD) paradigm, systematic investigations are necessary to understand how changes in critical quality attributes (CQAs) of formulation, device, and manufacturing process influence key product performance parameters, such as delivered dose (DD) and fine particle dose (FPD). The purpose of this work is to provide a better understanding of the effects of different levels of excipients and drug particle size distribution on the aerosol performance of MDI products, while using two fundamentally different MDI products as relevant model systems, Proventil® HFA (albuterol sulfate suspension) and Qvar® (beclomethasone dipropionate solution). These MDI products, as model systems, provided mid-points around which a design of experiments (DOE), consisting of 22 suspension and 9 solution MDI formulations, were defined and manufactured. The DOE included formulations factors with varying ethanol (2 to 20% w/w and 7 to 9% w/w for the suspension and solution, respectively) and oleic acid concentrations (0.005 to 0.25% w/w and 0 to 2% w/w for the suspension and solution, respectively) and drug volumetric median particle size distribution (PSD D50, 1.4 to 2.5 μm for the suspension). The MDI formulations were analyzed using compendial methods to elucidate the effect of these formulation variables (ethanol, oleic acid, and PSD D50) on DD and FPD. The outcomes of this study allowed defining design spaces for the formulation factors, such that DD and FPD would remain within specific pre-defined requirements. The systematic approach utilized in this work can contribute as a QbD tool to evaluate the extent to which the formulation factors govern the aerosol performance of MDI drug products, helping to design MDI formulations with desired product performance parameters.

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ACKNOWLEDGMENTS

Funding for this work was made possible, in part, by the Food and Drug Administration through grant 1U01FD004943-01. Views expressed in this publication do not necessarily reflect the official policies of the Department of Health and Human Services, nor does any mention of trade names, commercial practices, or organization imply endorsement by the US Government.

Author information

Author notes

  1. Jay T. Holt

    Present address: Aurobindo Pharma USA, Inc., Durham, North Carolina, USA

  2. Anthony J. Hickey

    Present address: RTI International, Research Triangle Park, North Carolina, USA

  3. Bhawana Saluja

    Present address: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

  4. Poonam Sheth, Dennis Sandell, and Denise S. Conti equally contributed to this work

Authors and Affiliations

  1. Recipharm, 511 Davis Drive, Suite 100, Morrisville, North Carolina, 27560, USA

    Poonam Sheth

  2. Cirrus Pharmaceuticals, Inc., Morrisville, North Carolina, USA

    Poonam Sheth, Jay T. Holt & Anthony J. Hickey

  3. S5 Consulting, Ekvägen 8, Blentarp, Sweden

    Dennis Sandell

  4. Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

    Denise S. Conti & Bhawana Saluja

Authors
  1. Poonam Sheth
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  2. Dennis Sandell
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  3. Denise S. Conti
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  4. Jay T. Holt
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  5. Anthony J. Hickey
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  6. Bhawana Saluja
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Corresponding author

Correspondence to Poonam Sheth.

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The opinions expressed in this paper by the authors do not necessarily reflect the views or policies of the Food and Drug Administration (FDA).

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Sheth, P., Sandell, D., Conti, D.S. et al. Influence of Formulation Factors on the Aerosol Performance of Suspension and Solution Metered Dose Inhalers: A Systematic Approach. AAPS J 19, 1396–1410 (2017). https://doi.org/10.1208/s12248-017-0095-3

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  • DOI: https://doi.org/10.1208/s12248-017-0095-3

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