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Tadalafil-malonic acid cocrystal: Physicochemical characterization, pH-solubility and supersaturation studies
Luleå University of Technology, Department of Health Sciences, Medical Science. Luleå University of Technology, Department of Civil, Environmental and Natural Resources Engineering, Chemical Engineering.ORCID iD: 0000-0001-7469-4197
Luleå University of Technology, Department of Health Sciences, Medical Science.ORCID iD: 0000-0002-2273-457x
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor.
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor.
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2018 (English)In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 18, no 8, p. 4378-4387Article in journal (Refereed) Published
Abstract [en]

The purpose of this study was to enhance the solubility and dissolution of a poorly water-soluble drug, tadalafil (TDF), by cocrystal formation with malonic acid (MOA), to characterize the cocrystal structure, and to quantify the cocrystal solution behavior. The crystal structure revealed a 1:1 stoichiometry wherein the TDF molecules form a double layered structure through N–H…O=C interactions linked to a catemeric chain of MOA molecules via O-H…O hydrogen bonds. Cocrystal solubility advantage (SA defined as Scocrystal/Sdrug) or supersaturation index was determined from eutectic point measurements to be 102 to 129 in the pH range of 1 to 3. Cocrystal dissolution generated supersaturation levels (Cmax/Sdrug) of 30 in buffer and 120 in the presence of a nucleation inhibitor, HPMC. The amorphous form of TDF generated supersaturation 3 times lower than cocrystal in buffer, and not significantly different from cocrystal in the presence of HPMC. Thus, supersaturation index is a valuable metric for assessing the risk of cocrystal conversion during kinetic studies and for predicting conditions when the usage of a precipitation inhibitor may significantly increase cocrystal exposure levels.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018. Vol. 18, no 8, p. 4378-4387
National Category
Other Health Sciences Physical Chemistry
Research subject
Health Science; Chemistry of Interfaces
Identifiers
URN: urn:nbn:se:ltu:diva-69663DOI: 10.1021/acs.cgd.8b00362OAI: oai:DiVA.org:ltu-69663DiVA, id: diva2:1220704
Note

Validerad;2018;Nivå 2;2018-08-02 (rokbeg)

Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-08-02Bibliographically approved

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Shimpi, Manishkumar R.Al-Hayali, AmaniVelaga, Sitaram P.

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