Analysis of unstable degradation impurities of a benzodiazepine and their quantification without isolation using multiple linear regression
•Molibresib, a benzodiazepine, degrades reversibly in acidic conditions.•Two degradation impurities could not be isolated for relative response factor (RRF) determination by traditional means.•The RRFs of the impurities were determined without isolation using HPLC-UV data and multiple linear regress...
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| Veröffentlicht in: | Journal of pharmaceutical and biomedical analysis 2019-04, Vol.167, p.1-6 |
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| container_title | Journal of pharmaceutical and biomedical analysis |
| container_volume | 167 |
| creator | Campbell, John M. Grinias, Kaitie Facchine, Kevin Igne, Benoît Clawson, Jacalyn Peterson, John Wolters, Andy Barry, Jeremy Watson, Simon Leach, Kevin |
| description | •Molibresib, a benzodiazepine, degrades reversibly in acidic conditions.•Two degradation impurities could not be isolated for relative response factor (RRF) determination by traditional means.•The RRFs of the impurities were determined without isolation using HPLC-UV data and multiple linear regression analysis.
This manuscript presents a novel methodology for calculating the relative response factors (RRFs) of unstable degradation impurities of molibresib (1). The degradation impurities were observed by HPLC during stress testing and were accompanied by large mass balance deficits. However, the impurities could not be isolated for traditional RRF determination due to their instability. The RRFs of two degradation impurities were determined without isolation by multiple linear regression analysis of HPLC-UV data. The results permitted accurate quantification of the degradants. The benefits and drawbacks of the approach are discussed, including suggested validation acceptance criteria. |
| doi_str_mv | 10.1016/j.jpba.2019.01.028 |
| format | Article |
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This manuscript presents a novel methodology for calculating the relative response factors (RRFs) of unstable degradation impurities of molibresib (1). The degradation impurities were observed by HPLC during stress testing and were accompanied by large mass balance deficits. However, the impurities could not be isolated for traditional RRF determination due to their instability. The RRFs of two degradation impurities were determined without isolation by multiple linear regression analysis of HPLC-UV data. The results permitted accurate quantification of the degradants. The benefits and drawbacks of the approach are discussed, including suggested validation acceptance criteria.</description><identifier>ISSN: 0731-7085</identifier><identifier>EISSN: 1873-264X</identifier><identifier>DOI: 10.1016/j.jpba.2019.01.028</identifier><identifier>PMID: 30731352</identifier><language>eng</language><publisher>England: Elsevier B.V</publisher><subject>Forced degradation ; HPLC ; Impurities ; Mass balance ; Relative response factor ; Validation</subject><ispartof>Journal of pharmaceutical and biomedical analysis, 2019-04, Vol.167, p.1-6</ispartof><rights>2019 Elsevier B.V.</rights><rights>Copyright © 2019 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-8b009dcc8db6d89a7494e83d78c13af9e62492786ddeadf7eae15ab62331e0983</citedby><cites>FETCH-LOGICAL-c356t-8b009dcc8db6d89a7494e83d78c13af9e62492786ddeadf7eae15ab62331e0983</cites><orcidid>0000-0003-4096-8924</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jpba.2019.01.028$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30731352$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Campbell, John M.</creatorcontrib><creatorcontrib>Grinias, Kaitie</creatorcontrib><creatorcontrib>Facchine, Kevin</creatorcontrib><creatorcontrib>Igne, Benoît</creatorcontrib><creatorcontrib>Clawson, Jacalyn</creatorcontrib><creatorcontrib>Peterson, John</creatorcontrib><creatorcontrib>Wolters, Andy</creatorcontrib><creatorcontrib>Barry, Jeremy</creatorcontrib><creatorcontrib>Watson, Simon</creatorcontrib><creatorcontrib>Leach, Kevin</creatorcontrib><title>Analysis of unstable degradation impurities of a benzodiazepine and their quantification without isolation using multiple linear regression</title><title>Journal of pharmaceutical and biomedical analysis</title><addtitle>J Pharm Biomed Anal</addtitle><description>•Molibresib, a benzodiazepine, degrades reversibly in acidic conditions.•Two degradation impurities could not be isolated for relative response factor (RRF) determination by traditional means.•The RRFs of the impurities were determined without isolation using HPLC-UV data and multiple linear regression analysis.
This manuscript presents a novel methodology for calculating the relative response factors (RRFs) of unstable degradation impurities of molibresib (1). The degradation impurities were observed by HPLC during stress testing and were accompanied by large mass balance deficits. However, the impurities could not be isolated for traditional RRF determination due to their instability. The RRFs of two degradation impurities were determined without isolation by multiple linear regression analysis of HPLC-UV data. The results permitted accurate quantification of the degradants. The benefits and drawbacks of the approach are discussed, including suggested validation acceptance criteria.</description><subject>Forced degradation</subject><subject>HPLC</subject><subject>Impurities</subject><subject>Mass balance</subject><subject>Relative response factor</subject><subject>Validation</subject><issn>0731-7085</issn><issn>1873-264X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp9kctu1jAQhS1ERX8KL8ACeckmwZdcbIlNVXGTKnXTSuwsx5608ytxUtuhal-BlyYhhSWrkWa-c0Yzh5B3nJWc8ebjsTzOnS0F47pkvGRCvSAHrlpZiKb68ZIcWCt50TJVn5LXKR0ZYzXX1StyKreJrMWB_DoPdnhMmOjU0yWkbLsBqIfbaL3NOAWK47xEzAh_EEs7CE-TR_sEMwagNnia7wAjvV9syNij23UPmO-mJVNM07B3loThlo7LkHFelwyr3EYa112Q0gq8ISe9HRK8fa5n5ObL5-uLb8Xl1dfvF-eXhZN1kwvVMaa9c8p3jVfatpWuQEnfKsel7TU0otKiVY33YH3fggVe264RUnJgWskz8mH3neN0v0DKZsTkYBhsgGlJRnAludJabajYURenlCL0Zo442vhoODNbCOZothDMFoJh3KwhrKL3z_5LN4L_J_n79RX4tAOwXvkTIZrkEIIDjxFcNn7C__n_BioYnSY</recordid><startdate>20190415</startdate><enddate>20190415</enddate><creator>Campbell, John M.</creator><creator>Grinias, Kaitie</creator><creator>Facchine, Kevin</creator><creator>Igne, Benoît</creator><creator>Clawson, Jacalyn</creator><creator>Peterson, John</creator><creator>Wolters, Andy</creator><creator>Barry, Jeremy</creator><creator>Watson, Simon</creator><creator>Leach, Kevin</creator><general>Elsevier B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-4096-8924</orcidid></search><sort><creationdate>20190415</creationdate><title>Analysis of unstable degradation impurities of a benzodiazepine and their quantification without isolation using multiple linear regression</title><author>Campbell, John M. ; Grinias, Kaitie ; Facchine, Kevin ; Igne, Benoît ; Clawson, Jacalyn ; Peterson, John ; Wolters, Andy ; Barry, Jeremy ; Watson, Simon ; Leach, Kevin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-8b009dcc8db6d89a7494e83d78c13af9e62492786ddeadf7eae15ab62331e0983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Forced degradation</topic><topic>HPLC</topic><topic>Impurities</topic><topic>Mass balance</topic><topic>Relative response factor</topic><topic>Validation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Campbell, John M.</creatorcontrib><creatorcontrib>Grinias, Kaitie</creatorcontrib><creatorcontrib>Facchine, Kevin</creatorcontrib><creatorcontrib>Igne, Benoît</creatorcontrib><creatorcontrib>Clawson, Jacalyn</creatorcontrib><creatorcontrib>Peterson, John</creatorcontrib><creatorcontrib>Wolters, Andy</creatorcontrib><creatorcontrib>Barry, Jeremy</creatorcontrib><creatorcontrib>Watson, Simon</creatorcontrib><creatorcontrib>Leach, Kevin</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of pharmaceutical and biomedical analysis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Campbell, John M.</au><au>Grinias, Kaitie</au><au>Facchine, Kevin</au><au>Igne, Benoît</au><au>Clawson, Jacalyn</au><au>Peterson, John</au><au>Wolters, Andy</au><au>Barry, Jeremy</au><au>Watson, Simon</au><au>Leach, Kevin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Analysis of unstable degradation impurities of a benzodiazepine and their quantification without isolation using multiple linear regression</atitle><jtitle>Journal of pharmaceutical and biomedical analysis</jtitle><addtitle>J Pharm Biomed Anal</addtitle><date>2019-04-15</date><risdate>2019</risdate><volume>167</volume><spage>1</spage><epage>6</epage><pages>1-6</pages><issn>0731-7085</issn><eissn>1873-264X</eissn><abstract>•Molibresib, a benzodiazepine, degrades reversibly in acidic conditions.•Two degradation impurities could not be isolated for relative response factor (RRF) determination by traditional means.•The RRFs of the impurities were determined without isolation using HPLC-UV data and multiple linear regression analysis.
This manuscript presents a novel methodology for calculating the relative response factors (RRFs) of unstable degradation impurities of molibresib (1). The degradation impurities were observed by HPLC during stress testing and were accompanied by large mass balance deficits. However, the impurities could not be isolated for traditional RRF determination due to their instability. The RRFs of two degradation impurities were determined without isolation by multiple linear regression analysis of HPLC-UV data. The results permitted accurate quantification of the degradants. The benefits and drawbacks of the approach are discussed, including suggested validation acceptance criteria.</abstract><cop>England</cop><pub>Elsevier B.V</pub><pmid>30731352</pmid><doi>10.1016/j.jpba.2019.01.028</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0003-4096-8924</orcidid></addata></record> |
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| language | eng |
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| source | Access via ScienceDirect (Elsevier) |
| subjects | Forced degradation HPLC Impurities Mass balance Relative response factor Validation |
| title | Analysis of unstable degradation impurities of a benzodiazepine and their quantification without isolation using multiple linear regression |
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