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Understanding solid-state processing of pharmaceutical cocrystals via milling: role of tablet excipients

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dc.contributor.author Shaikh, Rahamatullah
dc.contributor.author Shirazian, Saeed
dc.contributor.author Guerin, Sarah
dc.contributor.author Sheehan, Eoin
dc.contributor.author Thompson, Damien
dc.contributor.author Walker, Gavin M.
dc.contributor.author Croker, Denise M.
dc.date.accessioned 2021-04-15T10:16:27Z
dc.date.available 2021-04-15T10:16:27Z
dc.date.issued 2021
dc.identifier.uri http://hdl.handle.net/10344/10001
dc.description peer-reviewed en_US
dc.description.abstract Discovery of novel cocrystal systems and improvement of their physicochemical properties dominates the current literature on cocrystals yet the required end-product formulation is rarely addressed. Drug product manufacturing includes complex API solid state processing steps such as milling, granulation, and tableting. These all require high mechanical stress which can lead to solid-state phase transformations into polymorphs and solvates, or lead to dissociation of cocrystals into their individual components. Here we measured the effect of tablet excipients on solid-state processing of a range of pharmaceutical cocrystal formulations. Our findings were rationalised using Density Functional Theory (DFT) calculations of intermolecular binding energies of cocrystal constituents and co-milling excipients. A 1:1 stoichiometric ratio of API Theophylline (THP) and co-former 4- Aminobenzoic acid (4ABA) was co-milled with five different excipients: hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), lactose, and microcrystalline cellulose (MCC). The experiments were carried out in 10 and 25 ml milling jars at 30 Hz for different milling times. Co-milled samples were characterised for formation of cocrystals and phase transformation using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Our data shows that co-milling in the presence of PEG, HMPC or lactose yields purer cocrystals, supported by the calculated stronger excipient interactions for PVP and MCC. We identify a suitably-prepared THP–4ABA pharmaceutical cocrystal formulation that is stable under extended milling conditions. en_US
dc.language.iso eng en_US
dc.publisher Elsevier en_US
dc.relation FENU-2020-0019 en_US
dc.relation.ispartofseries International Journal of Pharmaceutics;601, 120514
dc.subject Co-milling en_US
dc.subject Pharmaceutical cocrystals en_US
dc.subject Tablet excipients en_US
dc.title Understanding solid-state processing of pharmaceutical cocrystals via milling: role of tablet excipients 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 10.1016/j.ijpharm.2021.120514
dc.contributor.sponsor SFI en_US
dc.contributor.sponsor Government of the Russian Federation en_US
dc.relation.projectid 13/IA/1980 en_US
dc.relation.projectid RC/12/2275 en_US
dc.relation.projectid 15/CDA/3491 en_US
dc.rights.accessrights info:eu-repo/semantics/openAccess en_US
dc.internal.rssid 3006712


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