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Dependence of heterogeneous nucleation on hydrogen bonding lifetime and complementarity

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dc.contributor.author Verma, Vivek
dc.contributor.author Zeglinski, Jacek
dc.contributor.author Hudson, Sarah P.
dc.contributor.author Davern, Peter
dc.contributor.author Hodnett, Benjamin K.
dc.date.accessioned 2018-11-14T16:08:01Z
dc.date.issued 2018
dc.identifier.uri http://hdl.handle.net/10344/7311
dc.description peer-reviewed en_US
dc.description The full text of this article will not be available in ULIR until the embargo expires on the 19/09/2019
dc.description.abstract The crystallization of seven active pharmaceutical ingredients (APIs) (acetaminophen (AAP), carbamazepine (CBMZ), caffeine (CAF), phenylbutazone (PBZ), risperidone (RIS), clozapine base (CPB), and fenofibrate (FF)) was studied in the absence and presence of microcrystalline cellulose (MCC) which acted as a heterosurface. Two of the active pharmaceutical ingredients (APIs), namely, AAP and CBMZ, possess hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) functionalities, whereas the other five possess HBA functionality only. Density functional theory (DFT) and molecular dynamics calculations complemented the experimental study. The smallest nucleation rate enhancement was observed for CBMZ at 1.4 times, and the largest was observed for FF at 16 times. For all the APIs studied, the interfacial energy was similar for crystallizations performed in the presence and absence of the heterosurface. By contrast, the pre-exponential factor was larger by a factor of ca. 2 and more for crystallizations carried out in the presence of the heterosurface. Arising from this study, a model of heterogeneous crystallization was developed wherein two influencing factors were identified. The first involves the issue of hydrogen bond complementarity between heterosurface and API. Hence, a HBD rich heterosurface will provide a hydrogen-bond mediated option for API cluster formation that would otherwise not be specifically available in solution to APIs possessing HBAs only. The second factor identified is that the lifetime of the hydrogen bond made by an individual API molecule or small API cluster with the heterosurface is up to 1000 times longer than (i) the lifetime of API–API interactions in a solution phase, or (ii) the time required for an API molecule to add to a growing crystal. This lifetime effect arises from the greater stability of an adsorbed species, and this extended lifetime increases the probability that other molecules or small clusters of the API in solution will add to the already adsorbed or attached species, thus encouraging the heterogeneous route to crystallization. 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;18 (11), pp. 7158-7152
dc.relation.uri http://dx.doi.org/10.1021/acs.cgd.8b01302
dc.rights © 2018 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 see http://dx.doi.org/10.1021/acs.cgd.8b01302 en_US
dc.subject crystallization en_US
dc.subject pharmaceutical ingredients (APIs) en_US
dc.title Dependence of heterogeneous nucleation on hydrogen bonding lifetime and complementarity 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.8b01302
dc.contributor.sponsor SFI en_US
dc.contributor.sponsor Irish Government's Programme for Research in Third Level Institutions Cycle 5 en_US
dc.contributor.sponsor ERC en_US
dc.relation.projectid 12/RC/2275 en_US
dc.date.embargoEndDate 2019-09-19
dc.embargo.terms 2019-09-19 en_US
dc.rights.accessrights info:eu-repo/semantics/embargoedAccess en_US
dc.internal.rssid 2864222


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