Thermal, X-ray Structural, and Dissolution Characteristics of Solid Forms Derived from the Anticancer Agents 2-Methoxyestradiol and 2-Methoxyestradiol-3,17-O,O-Bis-Sulfamate

The aim of the study was to generate alternative solid forms of 2-methoxyestradiol (2ME) and its sulfamoylated derivative 2-methoxyestradiol-3,17-O,O-bis-sulfamate (2MES), both of which are potent anticancer agents with no significant history of solid-state investigation. Screening for polymorphs and solvates by a variety of procedures yielded four distinct species: a crystalline form of 2ME, an amorphous form of 2ME, a chloroform solvate 2ME·(CHCl₃)₂, and the hemihydrate of the bis-sulfamate, 2MES·(H₂O)_0.5. Hydrogen-bonded assembly of 2ME molecules into layers in both crystalline 2ME and its chloroform solvate was established using single-crystal X-ray diffraction. This technique also revealed disorder of the sulfamate group at position 17 in both molecules comprising the asymmetric unit in the crystal of 2MES·(H₂O)_0.5. The thermal stabilities of the crystalline phases were recorded using hot-stage microscopy, thermogravimetry, and differential scanning calorimetry, and the results were reconciled with the crystal structures. Aqueous dissolution rates measured at 37°C generally decreased in the order 2MES·(H₂O)_0.5 > 2ME(amorphous) > 2ME(crystalline). © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3418–3425, 2015