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 |
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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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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. 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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.</description><subject>Accelerated Stability</subject><subject>Crystallization</subject><subject>Dry Powder Inhaler</subject><subject>Micronization</subject><subject>Particle Size Fusion</subject><subject>Respirable Size</subject><issn>0022-3549</issn><issn>1520-6017</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kMFu1DAURS1ERactP8ACeckm4TmOnURiUw1QKlVqpemsLcd-YTzKOIPtINoF346jKSxZWbbPvU_vEPKOQcmAyY_78tdxF8sKKlaCKAHkK7JiooJCAmtekxVAVRVc1N05uYhxD5kAId6Qc14D1BXrVuT3NrnRPTv_nW6m0dlik3RC-ohm592PGSPV3tJrY3DEkH8sXU_euuQmH2ma6NZbDDEt0IMOyZkR6cY9I731-bXP3emJOp-vOz3m9Ocw50lzv0QMxityNugx4tuX85Jsv355XH8r7u5vbtfXd4XhQqaC1QK4EA3vW20l7wAHxhvZ90wOONQ1ly1oyWzTGdOZgTMr2x41k80ATd0gvyQfTr3HMC1bJXVwMe80ao_THFUlqraDtmlERqsTasIUY8BBHYM76PCkGKjFu9qrxbtavCsQKlvNofcv_XN_QPsv8ld0Bj6dAMxb_nQYVDQOswLrApqk7OT-1_8HoIqVmw</recordid><startdate>20210801</startdate><enddate>20210801</enddate><creator>Dobson, Daniel P.</creator><creator>Yanez, Evelyn</creator><creator>Lubach, Joseph W.</creator><creator>Stumpf, Andreas</creator><creator>Pellet, Jackson</creator><creator>Tso, Jerry</creator><general>Elsevier Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7694-3118</orcidid><orcidid>https://orcid.org/0000-0001-5681-5880</orcidid></search><sort><creationdate>20210801</creationdate><title>Utilizing Solid-State Techniques and Accelerated Conditions to Understand Particle Size Instability in Inhaled Drug Substances</title><author>Dobson, Daniel P. ; Yanez, Evelyn ; Lubach, Joseph W. ; Stumpf, Andreas ; Pellet, Jackson ; Tso, Jerry</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-145035573b8ad6390ef1376bb16fef443680a61d79cc9cf31d68bea167f0747e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Accelerated Stability</topic><topic>Crystallization</topic><topic>Dry Powder Inhaler</topic><topic>Micronization</topic><topic>Particle Size Fusion</topic><topic>Respirable Size</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dobson, Daniel P.</creatorcontrib><creatorcontrib>Yanez, Evelyn</creatorcontrib><creatorcontrib>Lubach, Joseph W.</creatorcontrib><creatorcontrib>Stumpf, Andreas</creatorcontrib><creatorcontrib>Pellet, Jackson</creatorcontrib><creatorcontrib>Tso, Jerry</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of pharmaceutical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dobson, Daniel P.</au><au>Yanez, Evelyn</au><au>Lubach, Joseph W.</au><au>Stumpf, Andreas</au><au>Pellet, Jackson</au><au>Tso, Jerry</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Utilizing Solid-State Techniques and Accelerated Conditions to Understand Particle Size Instability in Inhaled Drug Substances</atitle><jtitle>Journal of pharmaceutical sciences</jtitle><addtitle>J Pharm Sci</addtitle><date>2021-08-01</date><risdate>2021</risdate><volume>110</volume><issue>8</issue><spage>3037</spage><epage>3046</epage><pages>3037-3046</pages><issn>0022-3549</issn><eissn>1520-6017</eissn><abstract>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. 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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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