Utilizing Solid-State Techniques and Accelerated Conditions to Understand Particle Size Instability in Inhaled Drug Substances

Micronization by air jet milling is often used to produce drug substance particles of acceptable respirable size for use in dry powder inhaler formulations. The energy from this process often induces surface disordered sites on the micronized particles with potential consequences for the long-term s...

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Veröffentlicht in:Journal of pharmaceutical sciences 2021-08, Vol.110 (8), p.3037-3046
Hauptverfasser: Dobson, Daniel P., Yanez, Evelyn, Lubach, Joseph W., Stumpf, Andreas, Pellet, Jackson, Tso, Jerry
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container_end_page 3046
container_issue 8
container_start_page 3037
container_title Journal of pharmaceutical sciences
container_volume 110
creator Dobson, Daniel P.
Yanez, Evelyn
Lubach, Joseph W.
Stumpf, Andreas
Pellet, Jackson
Tso, Jerry
description Micronization by air jet milling is often used to produce drug substance particles of acceptable respirable size for use in dry powder inhaler formulations. The energy from this process often induces surface disordered sites on the micronized particles with potential consequences for the long-term stability of the drug substance. In this study, two lots of the same drug substance were qualitatively determined to have different extents of disordered surface using dynamic vapor sorption and scanning electron microscopy. These differences led to observable divergences in particle size and morphology between lots of drug substances on long-term and accelerated stability. The studies investigate the contribution of temperature and humidity, morphology prior to milling, and stability behavior post-micronization. The results highlight the importance of controlling the crystallization solvents upstream of micronization and their contribution to a material's susceptibility to milling-induced disorder on long-term physical stability. Furthermore, this work proposes an accelerated technique useful in predicting stability behavior of micronized drug substances in days rather than months, especially in cases where small differences cannot be detected by standard solid-state techniques.
doi_str_mv 10.1016/j.xphs.2021.05.006
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subjects Accelerated Stability
Crystallization
Dry Powder Inhaler
Micronization
Particle Size Fusion
Respirable Size
title Utilizing Solid-State Techniques and Accelerated Conditions to Understand Particle Size Instability in Inhaled Drug Substances
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