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Challenges with Developing In Vitro Dissolution Tests for Orally Inhaled Products (OIPs)

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Abstract

The purpose of this article is to review the suitability of the analytical and statistical techniques that have thus far been developed to assess the dissolution behavior of particles in the respirable aerodynamic size range, as generated by orally inhaled products (OIPs) such as metered-dose inhalers and dry powder inhalers. The review encompasses all analytical techniques publicized to date, namely, those using paddle-over-disk USP 2 dissolution apparatus, flow-through cell dissolution apparatus, and diffusion cell apparatus. The available techniques may have research value for both industry and academia, especially when developing modified-release formulations. The choice of a method should be guided by the question(s) that the research strives to answer, as well as by the strengths and weaknesses of the available techniques. There is still insufficient knowledge, however, for translating the dissolution data into statements about quality, performance, safety, or efficacy of OIPs in general. Any attempts to standardize a dissolution method for compendial inclusion or compendial use would therefore be premature. This review reinforces and expands on the 2008 stimulus article of the USP Inhalation Ad Hoc Advisory Panel, which “could not find compelling evidence suggesting that such dissolution testing is kinetically and/or clinically crucial for currently approved inhalation drug products.”

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Abbreviations

ACI:

Andersen Cascade Impactor

API:

active pharmaceutical ingredient

APSD:

aerodynamic particle size distribution

BDP:

beclomethasone dipropionate

COPD:

chronic obstructive pulmonary disease

DDW:

double distilled water

DPI:

dry powder inhaler

DPPC:

dipalmitoylphosphatidylcholine

ELF:

epithelial lung fluid

FP:

fluticasone propionate

ICS:

inhaled corticosteroid

IPAC-RS:

International Pharmaceutical Aerosol Consortium on Regulation and Science

IVIVC:

in vivo in vitro correlation

LABA:

long-acting beta agonist

MDI:

metered dose inhaler

NGI:

Next Generation Pharmaceutical Impactor

OIP:

orally inhaled product

PBS:

phosphate-buffered saline

PC:

phosphatidylcholine

PD:

pharmacodynamic

PK:

pharmacokinetic

PVDF:

polyvinylidene difluoride

SLF:

simulated lung fluid

USP:

US Pharmacopeia

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Author information

Author notes

  1. Andrew Cooper

    Present address: Non-Clinical Statistics, Merck, Kenilworth, New Jersey, USA

Authors and Affiliations

  1. Inhaled Product & Device Technology, GlaxoSmithKline, Hertfordshire, UK

    Trevor Riley

  2. Nonclinical and Pharmaceutical Sciences Statistics, Merck, West Point, Pennsylvania, USA

    David Christopher

  3. Analytical Development Respiratory R&D, Teva, Haarlem, The Netherlands

    Jan Arp

  4. Drug Product Development R&D CMC, Chiesi, Parma, Italy

    Andrea Casazza

  5. Pharmaceutical Development, AstraZeneca, Mölndal, Sweden

    Agnes Colombani

  6. Global Respiratory Group, Mylan, Sandwich, UK

    Andrew Cooper

  7. Non-Clinical Statistics, Merck, Kenilworth, New Jersey, USA

    Monisha Dey

  8. Pharmaceutical and Analytical Development, Novartis, Horsham, UK

    Janet Maas

  9. Trudell Medical International, London, Ontario, Canada

    Jolyon Mitchell

  10. Respiratory Drug Delivery, Boehringer Ingelheim, Ingelheim am Rhein, Germany

    Maria Reiners

  11. Respiratory Product Development, Merck, Summit, New Jersey, USA

    Nastaran Sigari

  12. CMC Development, Boehringer Ingelheim, Ridgefield, Connecticut, USA

    Terrence Tougas

  13. Pharmaceutical Practice Group, Drinker Biddle & Reath LLP, 1500 K Street NW, Washington, District of Columbia, 20005-1209, USA

    Svetlana Lyapustina

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  1. Trevor Riley
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  2. David Christopher
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Correspondence to Svetlana Lyapustina.

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Riley, T., Christopher, D., Arp, J. et al. Challenges with Developing In Vitro Dissolution Tests for Orally Inhaled Products (OIPs). AAPS PharmSciTech 13, 978–989 (2012). https://doi.org/10.1208/s12249-012-9822-3

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