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Article: Stability studies of ionised and non-ionised 3,4-diaminopyridine: Hypothesis of degradation pathways and chemical structure of degradation products

TitleStability studies of ionised and non-ionised 3,4-diaminopyridine: Hypothesis of degradation pathways and chemical structure of degradation products
Authors
Keywords3,4-Diaminopyridine
HPLC-MS
Impurities
Stability studies
Stress condition
Issue Date2007
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jpba
Citation
Journal Of Pharmaceutical And Biomedical Analysis, 2007, v. 43 n. 1, p. 83-88 How to Cite?
Abstract3,4-Diaminopyridine is used to treat some symptoms met in Lambert-Eaton myasthenia syndrome. It was shown efficient to reduce a form of variable muscle weakness and fatigability typical of the disease and correlated to a block of acetylcholine release. In France, 3,4-diaminopyridine is nowadays given to patients under capsules form and the status of hospital preparation. Whatever the diluant used in the formulation, the stability period could not exceed 12 months. Preliminary studies were made on a salt form in order to test the influence of various stress factors and determine if there is interaction between them. From this study, the most influent stress condition, presence of hydrogen peroxide, was selected and a comparative study was performed to compare the stability of molecular and salt species. Solutions of each species were exposed to 5 or 15% of hydrogen peroxide and analyzed at 8, 24, 72 and 216 h of degradation by HPLC-UV. Fractions of detected impurities were purified and collected by semi-preparative HPLC-UV and analyzed by HPLC-UV-ESI-MS and IR spectroscopy in order to determine their structure hypotheses. Theses experiments demonstrate that the salt species were more stable under oxidative stress condition than molecular species. The two main degradation products were collected and identified as 4-amino, 3-nitropyridine and 3,4-diaminopyridine-N-oxide when the molecular form was degraded whereas only 4-amino, 3-nitropyridine was found in less quantity in the salt solutions. Nitrogen pyridine and pyridine amine could not easily be oxidized by hydrogen peroxide in salt comparatively to molecular species due to the lone pair of electron engaged in a bound with hydrogen in the first case and by resonance change of the pyridine in the second case. This modification of structure promoted different pathways of degradation for the salt form which are more dependent of energy. Owing to the better stability of the salt species, a new pharmaceutical form containing it was developed to assess its stability under ICH standard conditions allowing an industrial manufacture of this drug. © 2006 Elsevier B.V. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/134251
ISSN
2015 Impact Factor: 3.169
2015 SCImago Journal Rankings: 1.049
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorRaust, JAen_HK
dc.contributor.authorGoulayDufaÿ, Sen_HK
dc.contributor.authorLe Hoang, MDen_HK
dc.contributor.authorPradeau, Den_HK
dc.contributor.authorGuyon, Fen_HK
dc.contributor.authorDo, Ben_HK
dc.date.accessioned2011-06-14T08:52:27Z-
dc.date.available2011-06-14T08:52:27Z-
dc.date.issued2007en_HK
dc.identifier.citationJournal Of Pharmaceutical And Biomedical Analysis, 2007, v. 43 n. 1, p. 83-88en_HK
dc.identifier.issn0731-7085en_HK
dc.identifier.urihttp://hdl.handle.net/10722/134251-
dc.description.abstract3,4-Diaminopyridine is used to treat some symptoms met in Lambert-Eaton myasthenia syndrome. It was shown efficient to reduce a form of variable muscle weakness and fatigability typical of the disease and correlated to a block of acetylcholine release. In France, 3,4-diaminopyridine is nowadays given to patients under capsules form and the status of hospital preparation. Whatever the diluant used in the formulation, the stability period could not exceed 12 months. Preliminary studies were made on a salt form in order to test the influence of various stress factors and determine if there is interaction between them. From this study, the most influent stress condition, presence of hydrogen peroxide, was selected and a comparative study was performed to compare the stability of molecular and salt species. Solutions of each species were exposed to 5 or 15% of hydrogen peroxide and analyzed at 8, 24, 72 and 216 h of degradation by HPLC-UV. Fractions of detected impurities were purified and collected by semi-preparative HPLC-UV and analyzed by HPLC-UV-ESI-MS and IR spectroscopy in order to determine their structure hypotheses. Theses experiments demonstrate that the salt species were more stable under oxidative stress condition than molecular species. The two main degradation products were collected and identified as 4-amino, 3-nitropyridine and 3,4-diaminopyridine-N-oxide when the molecular form was degraded whereas only 4-amino, 3-nitropyridine was found in less quantity in the salt solutions. Nitrogen pyridine and pyridine amine could not easily be oxidized by hydrogen peroxide in salt comparatively to molecular species due to the lone pair of electron engaged in a bound with hydrogen in the first case and by resonance change of the pyridine in the second case. This modification of structure promoted different pathways of degradation for the salt form which are more dependent of energy. Owing to the better stability of the salt species, a new pharmaceutical form containing it was developed to assess its stability under ICH standard conditions allowing an industrial manufacture of this drug. © 2006 Elsevier B.V. All rights reserved.en_HK
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jpbaen_HK
dc.relation.ispartofJournal of Pharmaceutical and Biomedical Analysisen_HK
dc.rightsAppropriate Bibliographic Citation:Authors posting Accepted Author Manuscript online should later add a citation for the Published Journal Article indicating that the Article was subsequently published, and may mention the journal title provided that they add the following text at the beginning of the document: “NOTICE: this is the author’s version of a work that was accepted for publication in <Journal title>. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in PUBLICATION, [VOL#, ISSUE#, (DATE)] DOI#”-
dc.subject3,4-Diaminopyridineen_HK
dc.subjectHPLC-MSen_HK
dc.subjectImpuritiesen_HK
dc.subjectStability studiesen_HK
dc.subjectStress conditionen_HK
dc.titleStability studies of ionised and non-ionised 3,4-diaminopyridine: Hypothesis of degradation pathways and chemical structure of degradation productsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0731-7085&volume=43&spage=83&epage=88&date=Jan&atitle=Stability+studies+of+ionised+and+non-ionised+3,4-diaminopyridine:+Hypothesis+of+degradation+pathways+and+chemical+structure+of+degradation+products-
dc.identifier.emailGoulayDufaÿ, S: sdufay@hku.hken_HK
dc.identifier.authorityGoulayDufaÿ, S=rp01491en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.jpba.2006.06.007en_HK
dc.identifier.pmid16844337en_HK
dc.identifier.scopuseid_2-s2.0-33845237603en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33845237603&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume43en_HK
dc.identifier.issue1en_HK
dc.identifier.spage83en_HK
dc.identifier.epage88en_HK
dc.identifier.isiWOS:000243554900010-
dc.publisher.placeNetherlandsen_HK
dc.identifier.scopusauthoridRaust, JA=6603461316en_HK
dc.identifier.scopusauthoridGoulayDufaÿ, S=6507768346en_HK
dc.identifier.scopusauthoridLe Hoang, MD=6603079461en_HK
dc.identifier.scopusauthoridPradeau, D=7003279930en_HK
dc.identifier.scopusauthoridGuyon, F=7006952930en_HK
dc.identifier.scopusauthoridDo, B=7003399176en_HK

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