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Crystal Modifications of a Cyclic Guanosine Phosphorothioate Analogue, a Drug Candidate for Retinal Neurodegenerations
Chemical Processes and Pharmaceutical Development, Research Institutes of Sweden, Forskargatan 20 J, 151 36, Södertälje, Sweden, Forskargatan 20 J; Faculty of Pharmaceutical Sciences, University of Iceland, Sæmundargata 2, 102, Reykjavík, Iceland, Sæmundargata 2.
Chemical Processes and Pharmaceutical Development, Research Institutes of Sweden, Forskargatan 20 J, 151 36, Södertälje, Sweden, Forskargatan 20 J.
Chemical Processes and Pharmaceutical Development, Research Institutes of Sweden, Forskargatan 20 J, 151 36, Södertälje, Sweden, Forskargatan 20 J.
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Applied Physical Chemistry. Chemical Processes and Pharmaceutical Development, Research Institutes of Sweden, Forskargatan 20 J, 151 36, Södertälje, Sweden.ORCID iD: 0000-0003-2410-7366
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2023 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 12, no 12, article id e202300141Article in journal (Refereed) Published
Abstract [en]

In contribution to the pharmaceutical development of cyclic guanosine monophosphorothioate analogue cGMPSA as a potential active pharmaceutical ingredient (API) for the treatment of inherited retinal degenerations (IRDs), its neutral form (cGMPSA-H) and salts of sodium (-Na), calcium (-Ca), ammonium (-NH4), triethylammonium (-TEA), tris(hydroxymethyl)aminomethane (-Tris), benethamine (-Bnet), and benzathine (-BZ) were prepared. Their solid-state properties were studied with differential scanning calorimetry, thermogravimetric analysis, hot-stage microscopy, and dynamic vapor sorption, and their solubilities were measured in deionized H2O as well as aqueous HCl and NaOH buffers. A total of 21 crystal modifications of cGMPSA were found and characterized by X-ray powder diffraction. Despite their crystalline character, no API forms featured any observable melting points during thermal analyses and instead underwent exothermic decomposition at ≥163 °C. Both the vapor sorption behavior and solubility were found to differ significantly across the API forms. cGMPSA-BZ featured the lowest aqueous solubility and hygroscopicity, with 50 μg/mL and 5 % mass gain at maximum relative humidity. The synthesis and crystallization of some crystal modifications were upscaled to >10 g. Single crystal X-ray diffraction was performed which resulted in the first crystal structure determination and absolute configuration of a cyclic guanosine monophosphorothioate, confirming the RP- conformation at the phosphorus atom.

Place, publisher, year, edition, pages
Wiley , 2023. Vol. 12, no 12, article id e202300141
Keywords [en]
Configuration determination, Drug design, Neurological agents, Nucleotides, Solid-state structures
National Category
Physical Chemistry
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URN: urn:nbn:se:kth:diva-348438DOI: 10.1002/open.202300141ISI: 001090850300001PubMedID: 37877436Scopus ID: 2-s2.0-85174819785OAI: oai:DiVA.org:kth-348438DiVA, id: diva2:1877377
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QC 20240625

Available from: 2024-06-25 Created: 2024-06-25 Last updated: 2024-06-25Bibliographically approved

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Svensson, Per H.

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