Research Articles
Structural Study of Polymorphs and Solvates of Finasteride

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ABSTRACT

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 13C 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 13C 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 13C 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.

Section snippets

INTRODUCTION

Structural studies of solid pharmaceutical materials have traditionally relied on single-crystal diffraction experiments, with further characterisation involving, inter alia, thermal methods and vibrational spectroscopy. High-resolution NMR spectroscopy using cross polarisation (CP) and magic-angle spinning (MAS) was first applied1 to organic and pharmaceutical compounds soon after the CPMAS combination of techniques was introduced2 in 1976. For a number of years such applications were

Samples

Form I° was obtained from Hikma Pharmaceuticals, Jordan, and was used without further purification. It was originally produced by Hunan Steroids Chemicals Co., Ltd., China. Form II was prepared by dissolving about 1 g of Form I° in a solution of ethyl acetate containing water with a concentration of 24 mg/mL. The solution was then maintained at ambient temperature under stirring for an hour. The solution was left to evaporate overnight and then the solid was dried in a vacuum oven for 6 h at

Solid-State NMR of Forms I° and II, Together With Some Information For Two Further Forms

Figure 2 shows the 13C CPMAS NMR spectra of Forms I° and II of finasteride. As is usually the case with steroids, the quality of the spectra is high. The resolution is generally excellent because high-quality crystallites are readily obtained. Wenslow et al.22 reported some linewidths as low as 5 Hz in halfwidth. However, CH2 resonances are usually relatively broad for steroids34,35 (as in the present case) unless proton decoupling is especially efficient.36 The spectra of the two forms are

CONCLUSIONS

We have shown that finasteride exists in at least four polymorphic forms, though two of them have not yet been fully characterised. Two new solvate hydrates have been obtained and their structures, along with that of the dioxane solvate hydrate, determined by single-crystal X-ray methods. The four known solvate hydrates are isomorphous, with the solvate molecules residing in channels but in disordered fashion. Solid-state NMR is able to distinguish these forms though powder XRD is not. Evidence

ACKNOWLEDGMENTS

One of us (AO) thanks the Hikma Pharmaceuticals company for financial support to enable him to work towards a M.Sc. degree at the University of Durham. We are grateful to Dr. A.M. Kenwright for assistance with the solution-state NMR measurements. IRE thanks the EPSRC for an Academic Fellowship. We thank Dr. T.L. Threlfall for information about his work in advance of publication. We are greatly indebted to L. Emsley and B. Elena for the INADEQUATE spectrum of Form I (to the Access to Research

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    Published online in Wiley InterScience (www.interscience.wiley.com).

    Dedicated to the late Professor David J. W. Grant in tribute to his scientific achievements and in recognition of his great interest in the characterization of solid pharmaceutical compounds.

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