Structural study of polymorphs and solvates of finasteride.
NMR and XRD data are reported for several new forms of finasteride, including the results of complete structure determinations for three solvates. Form III of finasteride, hitherto only mentioned in the patent literature, and a new anhydrous form designated Form X, have been found in mixtures of polymorphs and their (13)C NMR chemical shifts obtained. The results demonstrate that the crystallographic asymmetric units contain three molecules and one molecule, respectively. Attempts to reproduce "Form H1", as described in a patent, resulted in a new IPA solvate hydrate. The previously-reported acetic acid, dioxane, and ethyl acetate solvates have been further characterised, and new THF and diethyl ether solvates prepared and characterised. The crystal structures of the dioxane, IPA, and THF solvates have been determined by single-crystal X-ray diffraction. All the solvates (except the acetic acid case) are found to be hemihydrates, to have a finasteride: solvent molar ratio of 2:1 and to have a common structure. The solvate molecules are highly disordered and sited in channels in the structure. The powder XRD patterns are characteristic of the common structure. These solvates may be distinguished by the characteristic CPMAS (13)C signals from the solvent molecules, but the resonances of the host finasteride structures differ only marginally, and powder XRD patterns are almost indistinguishable. Magic-angle spinning (MAS) proton spectra give sharp lines for the solvent peaks, confirming their high degree of mobility. This is further shown in one case by direct polarisation (13)C spectra. Mobility of the tert-butyl group is also implied. Thermal characteristics have been studied and TGA used (in conjunction with solution-state proton NMR) to estimate molar ratios.
Othman
Abdullah
A
Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, UK.
Evans
John S O
JS
Evans
Ivana Radosavljevic
IR
Harris
Robin K
RK
Hodgkinson
Paul
P
D019840:2-Propanol / Q000737:chemistry; D000085:Acetates / Q000737:chemistry; D019342:Acetic Acid / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D018360:Crystallography, X-Ray; D004146:Dioxanes / Q000737:chemistry; D004986:Ether / Q000737:chemistry; D018120:Finasteride / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D033362:Powder Diffraction; D011208:Powders; D012997:Solvents / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods*; D013818:Thermogravimetry
D000085:Acetates; D004146:Dioxanes; D011208:Powders; D012997:Solvents; D004986:Ether; D018120:Finasteride; C007650:ethyl acetate; C025223:1,4-dioxane; D019840:2-Propanol; D019342:Acetic Acid