Preparation of Single Crystal of Inosine Induced by Sulfosalicylic Acid
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reparation of Single Crystal of Inosine Induced by Sulfosalicylic Acid Y. N. Zhanga,*, Y. L. Liua, L. X. Liua, Y. R. Fenga, L. L. Wua, L. Zhanga, Y. J. Zhanga, D. Y. Zoua, L. Changa, X. Sua, X. S. Zhangb, G. D. Chenga, and C. X. Wanga a College
b The
of Pharmacy, Jiamusi University, Jiamusi, 154007 China First Affiliated Hospital of Jiamusi University, Heilongjiang Province, Jiamusi, 154007 China *e-mail: [email protected] Received May 18, 2020; revised July 20, 2020; accepted July 30, 2020
Abstract—For improving solubility of inosine, its β-form has been designed and prepared from inosine powder upon induction by sulfosalicylic acid. A single crystal of β-form inosine has been grown. The structure of β-form inosine has been characterized by XRPD, NMR and single-crystal X-ray crystallography. The crystal structure of β-form inosine demonstrates the layered structure based on a primary asymmetric cyclic hydrogen-bonded tetramer R44(14) based on the hetero-nitrogen and the hydroxyl group of inosine molecules. The single crystal exhibits the spiral structure along b axis formed due to O–H···O and O–H···N hydrogen bonds. As a result, water solubility under 37°C of inosine β-form is higher than that of inosine powder, and β-form inosine is hygroscopically more stable at 98% RH with respect to inosine powder. The β-form of inosine demonstrates the improved in vitro activity against liver cancer cells compared to inosine powder. Keywords: inosine powder, β-form inosine, solubility
DOI: 10.1134/S1070363220100205 INTRODUCTION Inosine (Scheme 1), also known as hypoxanthine nucleoside, possesses a variety of interesting biological activities, including antiviral and antitumor [1, 2]. The above activity is retarded by its low solubility and biological availability [3, 4]. At present, few different methods of improving solubility of solid drugs, such as adding surfactants, preparing liposomes and applying nanotechnology, have been introduced [5–8]. However, the above methods suffer from some drawbacks. For instance, adding surfactants or preparing liposomes can increase drug solubility while reducing drug permeability [7, 8], or preparation of nanoparticles can lead to sedimentation [9, 10]. Therefore, it was a challenge to design the crystal form of inosine based on its original structure without affecting its properties. Scheme 1. Molecular structure of inosine.
Over recent years, application of inducers for regulating nucleation and growth of crystals, that modified their crystal form and crystal morphology, has become an efficient method of controlling polymorphic crystals [11–13]. Selection of inducers depends mostly upon the following factors: (1) good solubility [14, 15]; (2) meeting the medicinal requirements [16] including solubility in solutions [17]; (3) likelihood to intermolecular interactions with organic solvents (H-bonds, aryl packing and electrostatic interactions), thus suppressing formation of H-bonds among medicine molecules [18]; (4) structural similarity with the medicine molecules, thus supporting
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