여름정기학술대회
2022여름초록
발표자 및 발표 내용
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발표구분 |
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포스터발표 |
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Brief Oral Presentation 발표신청 | |
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주저자
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국가 |
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공동저자
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접수자
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According
to the International Conference on Harmonisation (ICH) Q3A (R2) guideline, the
identification threshold of an impurity for drug substance with a maximum daily
dose of 2 g or less is 0.1% or 1.0 mg whichever is lower. In addition, the
Ministry of Food and Drug Safety (MFDS) of Korea requires the submission of a
genotoxicity assessment report for any unspecified impurities above the
identification threshold. In the photostability test of dexamethasone drug
substance at UV 200 watt/m2, Vis 1,200,000 lux, two unspecified
impurities (i.e. unknown impurity 6 and unknown impurity 10) were detected
above the identification level (0.1%). The structures of the impurities were
predicted through literature research and identified through LC-MS/MS.
According to the LC-MS/MS results, the m/z values of the precursor ion of
dexamethasone API and unknown impurity 10 were 392.7 and 333.0, respectively.
The literature review confirmed that unknown 10 is a photodegradation product
("androderivative") of betamethasone, which is an epimer of
dexamethasone. The precursor ion of unspecified impurity 6 had an m/z value of
409.2, which implies that unknown impurity 6 would be a derivative of
dexamethasone with a hydroxyl (-OH) group. Considering that dexamethasone has
six positions where the hydroxyl group can be attached, a total of six
candidates were selected. The most likely structure of unknown impurity 6 among
the candidates was identified based on mass fragment matching and Log P value
(partition coefficient). The genotoxicity of the candidates for any unspecified
impurities (i.e. unknown 6, unknown 10) that are photodegradation products of
dexamethasone was evaluated using the Quantitative Structure Activity
Relationship (QSAR) program, and all of the impurities were class 5 compounds
with no risk of genotoxicity (ICH M7).
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