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Crystal Modifications of a Cyclic Guanosine Phosphorothioate Analogue, a Drug Candidate for Retinal Neurodegenerations
RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.ORCID iD: 0000-0002-4941-5915
RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.ORCID iD: 0000-0003-3401-0728
RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development.
RISE Research Institutes of Sweden, Bioeconomy and Health, Chemical Process and Pharmaceutical Development. KTH Royal Institute of Technology, 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
John Wiley and Sons Inc , 2023. Vol. 12, no 12, article id e202300141
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Medical Engineering
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URN: urn:nbn:se:ri:diva-68032DOI: 10.1002/open.202300141Scopus ID: 2-s2.0-85174819785OAI: oai:DiVA.org:ri-68032DiVA, id: diva2:1814252
Note

This research was funded by grants from the European Union (transMed: H2020‐MSCA‐765441, and TreatRP: EJP RD JTC 2020).

Available from: 2023-11-23 Created: 2023-11-23 Last updated: 2024-06-11Bibliographically approved

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Perez, OswaldoSchipper, NicolaasSvensson, Per H.Bollmark, Martin

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