Crystal Structure and Tautomerism of Capecitabine
The crystal and molecular structure of capecitabine, an anticancer pharmaceutical substance, was solved and refined using single-crystal X-ray diffraction. The compound was synthesized from a derivative of cytidine by a modified method. The crystal of capecitabine for X-ray study was grown by seedle...
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| Veröffentlicht in: | Journal of pharmaceutical sciences 2014-02, Vol.103 (2), p.587-593 |
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| creator | Malińska, Maura Krzeczyński, Piotr Czerniec-Michalik, Ewelina Trzcińska, Kinga Cmoch, Piotr Kutner, Andrzej Woźniak, Krzysztof |
| description | The crystal and molecular structure of capecitabine, an anticancer pharmaceutical substance, was solved and refined using single-crystal X-ray diffraction. The compound was synthesized from a derivative of cytidine by a modified method. The crystal of capecitabine for X-ray study was grown by seedless crystallization from a single solvent. The low and room temperature single-crystal X-ray crystallographic study revealed that capecitabine exists in the solid state exclusively in one of the two possible prototropic tautomers. In the molecular structure of this tautomer, the hydrogen atom is attached to the N3 nitrogen atom of the pyrimidine ring (imine tautomer) and not to the N(4) nitrogen of the carbamate (carbamate tautomer), as has been widely reported up to the present. The imine tautomer was also found to be thermodynamically preferred in the ab initio calculations. This finding indicates that the reported structural formula of capecitabine, as well as its systematic chemical name, must be revised. |
| doi_str_mv | 10.1002/jps.23831 |
| format | Article |
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The compound was synthesized from a derivative of cytidine by a modified method. The crystal of capecitabine for X-ray study was grown by seedless crystallization from a single solvent. The low and room temperature single-crystal X-ray crystallographic study revealed that capecitabine exists in the solid state exclusively in one of the two possible prototropic tautomers. In the molecular structure of this tautomer, the hydrogen atom is attached to the N3 nitrogen atom of the pyrimidine ring (imine tautomer) and not to the N(4) nitrogen of the carbamate (carbamate tautomer), as has been widely reported up to the present. The imine tautomer was also found to be thermodynamically preferred in the ab initio calculations. This finding indicates that the reported structural formula of capecitabine, as well as its systematic chemical name, must be revised.</description><identifier>ISSN: 0022-3549</identifier><identifier>EISSN: 1520-6017</identifier><identifier>DOI: 10.1002/jps.23831</identifier><identifier>PMID: 24382662</identifier><identifier>CODEN: JPMSAE</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>ab initio calculations ; ab initiocalculations ; Alcohols - chemistry ; Antimetabolites, Antineoplastic - chemistry ; Capecitabine ; Crystallization ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - chemistry ; Fluorouracil - analogs & derivatives ; Fluorouracil - chemistry ; Models, Molecular ; Molecular Conformation ; stability ; Stereoisomerism ; structure ; tautomerism ; X-ray crystallography ; X-Ray Diffraction</subject><ispartof>Journal of pharmaceutical sciences, 2014-02, Vol.103 (2), p.587-593</ispartof><rights>2014 Wiley Periodicals, Inc. and the American Pharmacists Association</rights><rights>2013 Wiley Periodicals, Inc. and the American Pharmacists Association</rights><rights>2013 Wiley Periodicals, Inc. and the American Pharmacists Association.</rights><rights>Copyright © 2013 Wiley Periodicals, Inc., A Wiley Company</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3971-da1c8c3cef1ac412e5f9b93c80958049f23af772aaaa3661cbe2b6d74b89a61f3</citedby><cites>FETCH-LOGICAL-c3971-da1c8c3cef1ac412e5f9b93c80958049f23af772aaaa3661cbe2b6d74b89a61f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjps.23831$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjps.23831$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24382662$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Malińska, Maura</creatorcontrib><creatorcontrib>Krzeczyński, Piotr</creatorcontrib><creatorcontrib>Czerniec-Michalik, Ewelina</creatorcontrib><creatorcontrib>Trzcińska, Kinga</creatorcontrib><creatorcontrib>Cmoch, Piotr</creatorcontrib><creatorcontrib>Kutner, Andrzej</creatorcontrib><creatorcontrib>Woźniak, Krzysztof</creatorcontrib><title>Crystal Structure and Tautomerism of Capecitabine</title><title>Journal of pharmaceutical sciences</title><addtitle>J Pharm Sci</addtitle><description>The crystal and molecular structure of capecitabine, an anticancer pharmaceutical substance, was solved and refined using single-crystal X-ray diffraction. The compound was synthesized from a derivative of cytidine by a modified method. The crystal of capecitabine for X-ray study was grown by seedless crystallization from a single solvent. The low and room temperature single-crystal X-ray crystallographic study revealed that capecitabine exists in the solid state exclusively in one of the two possible prototropic tautomers. In the molecular structure of this tautomer, the hydrogen atom is attached to the N3 nitrogen atom of the pyrimidine ring (imine tautomer) and not to the N(4) nitrogen of the carbamate (carbamate tautomer), as has been widely reported up to the present. The imine tautomer was also found to be thermodynamically preferred in the ab initio calculations. This finding indicates that the reported structural formula of capecitabine, as well as its systematic chemical name, must be revised.</description><subject>ab initio calculations</subject><subject>ab initiocalculations</subject><subject>Alcohols - chemistry</subject><subject>Antimetabolites, Antineoplastic - chemistry</subject><subject>Capecitabine</subject><subject>Crystallization</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Deoxycytidine - chemistry</subject><subject>Fluorouracil - analogs & derivatives</subject><subject>Fluorouracil - chemistry</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>stability</subject><subject>Stereoisomerism</subject><subject>structure</subject><subject>tautomerism</subject><subject>X-ray crystallography</subject><subject>X-Ray Diffraction</subject><issn>0022-3549</issn><issn>1520-6017</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMtKw0AUhgdRbK0ufAEJuNFF2rlkksxSglcKCq3rYTI5gSm5OZMofXtH07oQPZuzON_5-fkQOid4TjCmi03n5pSljBygKeEUhzEmySGa-hsNGY_EBJ04t8EYx5jzYzShEUtpHNMpIpndul5Vwaq3g-4HC4FqimCthr6twRpXB20ZZKoDbXqVmwZO0VGpKgdnuz1Dr3e36-whXD7fP2Y3y1AzkZCwUESnmmkoidIRocBLkQumUyx4iiNRUqbKJKHKD4tjonOgeVwkUZ4KFZOSzdDVmNvZ9m0A18vaOA1VpRpoBycJx1HEBU0Tj17-QjftYBvfTpJIEOaVMO6p65HStnXOQik7a2plt5Jg-eVReo_y26NnL3aJQ15D8UPuxXlgMQIfpoLt_0ny6WW1j2TjB3hp7wasdNpAo6EwFnQvi9b8UeQTqoaMmA</recordid><startdate>201402</startdate><enddate>201402</enddate><creator>Malińska, Maura</creator><creator>Krzeczyński, Piotr</creator><creator>Czerniec-Michalik, Ewelina</creator><creator>Trzcińska, Kinga</creator><creator>Cmoch, Piotr</creator><creator>Kutner, Andrzej</creator><creator>Woźniak, Krzysztof</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201402</creationdate><title>Crystal Structure and Tautomerism of Capecitabine</title><author>Malińska, Maura ; Krzeczyński, Piotr ; Czerniec-Michalik, Ewelina ; Trzcińska, Kinga ; Cmoch, Piotr ; Kutner, Andrzej ; Woźniak, Krzysztof</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3971-da1c8c3cef1ac412e5f9b93c80958049f23af772aaaa3661cbe2b6d74b89a61f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>ab initio calculations</topic><topic>ab initiocalculations</topic><topic>Alcohols - chemistry</topic><topic>Antimetabolites, Antineoplastic - chemistry</topic><topic>Capecitabine</topic><topic>Crystallization</topic><topic>Deoxycytidine - analogs & derivatives</topic><topic>Deoxycytidine - chemistry</topic><topic>Fluorouracil - analogs & derivatives</topic><topic>Fluorouracil - chemistry</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>stability</topic><topic>Stereoisomerism</topic><topic>structure</topic><topic>tautomerism</topic><topic>X-ray crystallography</topic><topic>X-Ray Diffraction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Malińska, Maura</creatorcontrib><creatorcontrib>Krzeczyński, Piotr</creatorcontrib><creatorcontrib>Czerniec-Michalik, Ewelina</creatorcontrib><creatorcontrib>Trzcińska, Kinga</creatorcontrib><creatorcontrib>Cmoch, Piotr</creatorcontrib><creatorcontrib>Kutner, Andrzej</creatorcontrib><creatorcontrib>Woźniak, Krzysztof</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of pharmaceutical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Malińska, Maura</au><au>Krzeczyński, Piotr</au><au>Czerniec-Michalik, Ewelina</au><au>Trzcińska, Kinga</au><au>Cmoch, Piotr</au><au>Kutner, Andrzej</au><au>Woźniak, Krzysztof</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Crystal Structure and Tautomerism of Capecitabine</atitle><jtitle>Journal of pharmaceutical sciences</jtitle><addtitle>J Pharm Sci</addtitle><date>2014-02</date><risdate>2014</risdate><volume>103</volume><issue>2</issue><spage>587</spage><epage>593</epage><pages>587-593</pages><issn>0022-3549</issn><eissn>1520-6017</eissn><coden>JPMSAE</coden><abstract>The crystal and molecular structure of capecitabine, an anticancer pharmaceutical substance, was solved and refined using single-crystal X-ray diffraction. 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| subjects | ab initio calculations ab initiocalculations Alcohols - chemistry Antimetabolites, Antineoplastic - chemistry Capecitabine Crystallization Deoxycytidine - analogs & derivatives Deoxycytidine - chemistry Fluorouracil - analogs & derivatives Fluorouracil - chemistry Models, Molecular Molecular Conformation stability Stereoisomerism structure tautomerism X-ray crystallography X-Ray Diffraction |
| title | Crystal Structure and Tautomerism of Capecitabine |
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