Crystal Modifications of a Cyclic Guanosine Phosphorothioate Analogue, a Drug Candidate for Retinal NeurodegenerationsShow others and affiliations
2023 (English)In: ChemistryOpen, ISSN 2191-1363, Vol. 12, no 12, article id e202300141
Article 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
Identifiers
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
Note
QC 20240625
2024-06-252024-06-252024-06-25Bibliographically approved