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Influence of impurities on the solubility, nucleation, crystallization and compressibility of paracetamol

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dc.contributor.author Keshavarz, Leila
dc.contributor.author Steendam, René R.E.
dc.contributor.author Blijlevens, Melian A.R.
dc.contributor.author Pishnamazi, Mahboubeh
dc.contributor.author Frawley, Patrick J.
dc.date.accessioned 2019-10-08T14:43:05Z
dc.date.issued 2019
dc.identifier.uri http://hdl.handle.net/10344/8125
dc.description peer-reviewed en_US
dc.description.abstract The striking ability of impurities to significantly influence crystallization processes is a topic of paramount interest in the pharmaceutical industry. Despite being present in small quantities, impurities tend to considerably change a crystallization process as well as the final crystalline product. In the present work, the effect of two markedly different impurities 4-nitrophenol and 4′-chloroacetanilide on the solubility, nucleation, and crystallization of paracetamol is described. In the first part of this work, the fundamentals are outlined and show that, although each impurity led to a small increase in solubility of paracetamol, their effect as a nucleation inhibitor was much more pronounced. Induction time experiments were used in conjunction with the classical nucleation theory to show that the impurities did not affect the solid−liquid interfacial energy but instead significantly reduced the kinetic factor, overall resulting in reduced nucleation rates. Intriguingly, both impurities influenced the solubility and nucleation of paracetamol in a similar fashion despite their significant differences in terms of molecular structure, solubility, and ability to incorporate into the crystal structure of paracetamol. In the second part of this work, the incorporation of 4′-chloroacetanilide into the solid phase of paracetamol was investigated. The presence of 4′-chloroacetanilide in the solid phase of paracetamol significantly increased the compressibility of paracetamol, resulting in improved processability properties of paracetamol. The compressibility efficiency of paracetamol could be controlled using the amount of incorporated 4′-chloroacetanilide. Therefore, an experimental design space was developed and utilized to select the most important process parameters for impurity incorporation. Intriguingly, the number of carbon atoms in the aliphatic chain of the alcohol solvent strongly correlated to the impurity incorporation efficiency. As a result, it was feasible to accurately control the compressibility and the amount of 4′-chloroacetanilide in the solid phase of paracetamol by simply choosing the required alcohol as the solvent for crystallization. Thus, the present work comprehensively shows how different impurities impact the key crystallization mechanisms and properties of a pharmaceutical product. Rational process control over the incorporation of impurities and additives allows for advanced manufacturing of products with tailored specifications. en_US
dc.language.iso eng en_US
dc.publisher American Chemical Society en_US
dc.relation 12RC2275 en_US
dc.relation.ispartofseries Crystal Growth and Design;19 (7), pp. 4193-4201
dc.relation.uri https://doi.org/10.1021/acs.cgd.9b00490
dc.rights © 2019 ACS This document is the Accepted Manuscript version of a Published Work that appeared in final form in Crystal Growth and Design, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work seehttps://doi.org/10.1021/acs.cgd.9b00490 en_US
dc.subject paracetamol en_US
dc.subject crystallization en_US
dc.title Influence of impurities on the solubility, nucleation, crystallization and compressibility of paracetamol en_US
dc.type info:eu-repo/semantics/article en_US
dc.type.supercollection all_ul_research en_US
dc.type.supercollection ul_published_reviewed en_US
dc.identifier.doi 10.1021/acs.cgd.9b00490
dc.contributor.sponsor SFI en_US
dc.relation.projectid 12/RC/2275 en_US
dc.date.embargoEndDate 2020-05-22
dc.embargo.terms 2020-05-22 en_US
dc.rights.accessrights info:eu-repo/semantics/openAccess en_US


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