Solid State Characterization of Sodium Eritadenate


Knowledge of the solid state is of great importance in the development of a new active pharmaceutical ingredient, since the solid form often dictates the properties and performance of the drug. In the present study, solid state characteristics of the sodium salt of the candidate cholesterol reducing compound eritadenine, 2(R), 3(R))-dihydroxy-4-(9-adenyl)-butanoic acid, were investigated. The compound was crystallized by slow cooling from water and various aqueous ethanol solutions, at different temperatures. Further, the compound solution was subjected to lyophilization and to high vacuum drying. The resulting solids were screened for polymorphism by micro Raman spectroscopy (λex = 830 nm) and the crystallinity was investigated by X-ray powder diffraction. Further, thermal analysis was applied to study possible occurrence of solvates or hydrates. Solids obtained from slow cooling showed crystallinity, whereas rapid cooling gave rise to more amorphous solids. Analysis of difference spectra of the Raman data for solids obtained from slow cooling of solution revealed subtle differences in the structures between crystals derived from pure water and crystals derived from aqueous ethanol solutions. Finally, from the thermal analysis it was deduced that crystals obtained from pure water were stoichiometrically dihydrates whereas crystals obtained from aqueous ethanol solutions were 2.5 hydrates; this formation of different hydrates were supported by the Raman difference analysis.

Share and Cite:

J. Enman, A. Patra, K. Ramser, U. Rova and K. Berglund, "Solid State Characterization of Sodium Eritadenate," American Journal of Analytical Chemistry, Vol. 2 No. 2, 2011, pp. 164-173. doi: 10.4236/ajac.2011.22019.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] A. W. Alberts, J. Chen, G. Kuron, V. Hunt, J. Huff, C. Hoffman, J. Rothrock, M. Lopez, H. Joshua, E. Harris, A. Patchett, R. Monaghan, S. Currie, E. Stapley, G. Albers-Schonberg, O. Hensens, J. Hirshfield, K. Hoogsteen, J. Liesch and J. Springer, “Mevinolin: A Highly Potent Competitive Inhibitor of Hydroxymethylglutaryl-Co-Enzyme a Reductase and a Cholesterol-Lowering Agent,” Proceeding of the National Academy of Sciences, Vol. 77, No. 7, 1980, pp. 3957-3961. doi:10.1073/pnas.77.7.3957
[2] I. Chibata, K. Okumura, S. Takeyama and K. Kotera, “Lentinacin: A New Hypocholesterolemic Substance in Lentinus Edodes,” Experientia, Vol. 25, No. 12, 1969, pp. 1237-1238. doi:10.1007/BF01897467
[3] T. Rokujo, H. Kikuchi, A. Tensho, Y. Tsukitani, T. Takenawa, K. Yoshida and T. Kamiya, “Lentysine: A New Hypolipidemic Agent from A Mushroom,” Life Sciences, Vol. 9, No. 7, 1970, pp. 379-385. doi:10.1016/0024-3205(70)90240-7
[4] Y. Kabir, M. Yamaguchi and S. Kimura, “Effect of Shiitake (Lentinus Edodes) and Maitake (Grifola Frondosa) Mushrooms on Blood Pressure and Plasma Lipids of Spontaneously Hypertensive Rats,” Journal of Nutritional Science and Vitaminology, Vol. 33, No. 5, 1987, pp. 341-346.
[5] T. Kaneda and S. Tokuda, “Effect of Various Mushroom Preparations on Cholesterol Levels in Rats,” Journal of Nutrition, Vol. 90, No. 4, 1966, pp. 371-376.
[6] S. Suzuki and S. Ohshima, “Influence of Shiitake (Lentinus Edodes) on Human Serum Cholesterol,” Proceedings of the 9th International Scientific Congress on the Cultivation of Edible Fungi, Tokyo, 1974, pp. 463-467.
[7] Y. Shimada, T. Morita and K. Sugiyama, “Eritadenine-Induced Alterations of Plasma Lipoprotein Lipid Concentrations and Phosphatidylcholine Molecular Species Profile in Rats Fed Cholesterol-Free and Cholesterol-Enriched Diets,” Bioscience, Biotechnology and Biochemistry, Vol. 67, No. 5, 2003, pp. 996-1006. doi:10.1271/bbb.67.996
[8] K. Sugiyama, A. Yamakawa, H. Kawagishi and S. Saeki, “Dietary Eritadenine Modifies Plasma Phosphatidylcholine Molecular Species Profile in Rats Fed Different Types of Fat,” Journal of Nutrition, Vol. 127, No. 4, 1997, pp. 593-599.
[9] K. Takashima, K. Izumi, H. Iwai and S. Takeyama, “The Hypocholesterolemic Action of Eritadenine in the Rat,” Atherosclerosis, Vol. 17, No. 3, 1973, pp. 491-502. doi:10.1016/0021-9150(73)90039-7
[10] K. Takashima, C. Sato, Y. Sasaki, T. Morita and S. Takeyama, “Effect of Eritadenine on Cholesterol Metabolism in the Rat,” Biochemical Pharmacology, Vol. 23, No. 2, 1974, pp. 433-438. doi:10.1016/0006-2952(74)90434-1
[11] S. R. Byrn, R. R. Pfeiffer, G. Stephenson, D. J. W. Grant and W. B. Gleason, “Solid-State Pharmaceutical Chemistry,” Chemistry of Materials, Vol. 6, No. 8, 1994, pp. 1148-1158. doi:10.1021/cm00044a013
[12] J. Lu and S. Rohani, “Polymorphism and Crystallization of Active Pharmaceutical Ingredients (Apis),” Current Medicinal Chemistry, Vol. 16, No. 7, 2009, pp. 884-905. doi:10.2174/092986709787549299
[13] A. Hakkinen, K. Pollanen, M. Karjalainen, J. Rantanen, M. Louhi-Kultanen and L. Nystrom, “Batch Cooling Crystallization and Pressure Filtration of Sulphathiazole: The Influence of Solvent Composition,” Biotechnology and Applied Biochemistry, Vol. 41, No. 1, 2005, pp. 17-28. doi:10.1042/BA20040044
[14] M. Kitamura, “Polymorphism in the Crystallization of L-Glutamic Acid,” Journal of Crystal Growth, Vol. 96, No. 3, 1989, pp. 541-546. doi:10.1016/0022-0248(89)90049-3
[15] S. Byrn, R. Pfeiffer and J. Stowell, “Solid State Chemistry of Drugs,” 2nd Edition, SSCI, Inc., West Lafayette, 1999.
[16] J. Enman, U. Rova and K. A. Berglund, “Quantification of the Bioactive Compound Eritadenine in Selected Strains of Shiitake Mushroom (Lentinus Edodes),” Journal of Agricultural Food Chemistry, Vol. 55, No. 4, 2007, pp. 1177-1180. doi:10.1021/jf062559+
[17] N. J. Leonard and K. L. Carraway, “5-Amino-5-Deoxyribose Derivatives. Synthesis and Use in the Preparation of ‘Reversed’ Nucleosides,” Journal of Heterocyclic Chemistry, Vol. 3, No. 4, 1966, pp. 485-489.
[18] P. A. Levene and E. T. Stiller, “Acetone Derivatives of d-Ribose. Ⅱ.,” Journal of Biological Chemistry, Vol. 106, 1934, pp. 421-429.
[19] M. Kawazu, T. Kanno, S. Yamamura, T. Mizoguchi and S. Saito, “Studies on the Oxidation of ‘Reversed Nucleosides’ in Oxygen. I. Synthesis of Eritadenine and Its Derivatives,” Journal of Organic Chemistry, Vol. 38, No. 16, 1973, pp. 2887-2890. doi:10.1021/jo00956a033
[20] P. H. C. Eilers, “A Perfect Smoother,” Analytical Chemistry, Vol. 75, No. 14, 2003, pp. 3631-3636.
[21] A. Cao, A. K. Pandya, G. K. Serhatkulu, R. E. Weber, H. Dai, J. S. Thakur, V. M. Naik, R. Naik, G. W. Auner, R. Rabah and D. C. Freeman, “A Robust Method for Automated Background Subtraction of Tissue Fluorescence,” Journal of Raman Spectroscopy, Vol. 38, No. 9, 2007, pp. 1199-1205.
[22] R. Suryanarayanan and S. Rastogi, “Encyclopedia of Pharmaceutical Technology,”2006.
[23] A. P. Ayala, “Polymorphism in Drugs Investigated by Low Wavenumber Raman Scattering,” Vibrational Spectroscopy, Vol. 45, No. 2, 2007, pp. 112-116. doi:10.1016/j.vibspec.2007.06.004
[24] S. D. Clas, “The Importance of Characterizing the Crystal Form of the Drug Substance During Drug Development,” Current Opinion in Drug Discovery and Development, Vol. 6, No. 4, 2003, pp. 550-560.
[25] E. Fukuoka, M. Makita and Y. Nakamura, “Glassy State of Pharmaceuticals. 5. Relaxation During Cooling and Heating of Glass by Differential Scanning Calorimetry,” Chemical and Pharmaceutical Bulletin, Vol. 39, No. 8, 1991, pp. 2087-2090.
[26] P. Tong and G. Zografi, “Solid-State Characteristics of Amorphous Sodium Indomethacin Relative to Its Free Acid,” Pharmaceutical Research, Vol. 16, No. 8, 1999, pp. 1186-1192.
[27] L. Yu, “Amorphous Pharmaceutical Solids: Preparation, Characterization and Stabilization,” Advanced Drug Delivery Reviews, Vol. 48, No. 1, 2001, pp. 27-42. doi:10.1016/S0169-409X(01)00098-9
[28] B. C. Hancock and M. Parks, “What Is the True Solubility Advantage for Amorphous Pharmaceuticals?,” Pharmaceutical Research, Vol. 17, No. 4, 2000, pp. 397-404. doi:10.1023/A:1007516718048
[29] T. Vasconcelos, B. Sarmento and P. Costa, “Solid Dispersions as Strategy to Improve Oral Bioavailability of Poor Water Soluble Drugs,” Drug Discovery Today, Vol. 12, No. 23-24, 2007, pp. 1068-1075. doi:10.1016/j.drudis.2007.09.005
[30] J. Enman, K. Ramser, U. Roval and K. A. Berglund, “Raman Analysis of Synthetic Eritadenine,” Journal of Raman Specroscopy, Vol. 39, No. 10, 2008, pp. 1464-1468.
[31] Y. Huang, J. Komoto, Y. Takata, D. Powell, T. Gomi, H. Ogawa, M. Fujioka and F. Takusagawa, “Inhibition of S-Adenosylhomocysteine Hydrolase by Acyclic Sugar Adenosine Analogue D-Eritadenine-Crystal Structure of S-Adenosylhomocysteine Hydrolase Complexed with D-Eritadenine,” Journal of Biological Chemistry, Vol. 277, No. 9, 2002, pp. 7477-7482. doi:10.1074/jbc.M109187200
[32] S. R. Vippagunta, H. G. Brittain and D. J. W. Grant, “Crystalline Solids,” Advanced Drug Delivery Reviews, Vol. 48, No. 1, 2001, pp. 3-26. doi:10.1016/S0169-409X(01)00097-7
[33] A. Nangia and G. R. Desiraju, “Pseudopolymorphism: Occurrences Of Hydrogen Bonding Organic Solvents in Molecular Crystals,” Chemical Communications, No. 7, 1999, pp. 605-606. doi:10.1039/a809755k

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.