Azelastine Hydrochloride: A Powder Diffraction and 13C CPMAS NMR Study of Its Anhydrous and Solvated Forms
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- 作者：Elisabetta Maccaroni ; Enrica Alberti ; Luciana Malpezzi ; Gabriele Razzetti ; Chiara Vladiskovic ; Norberto Masciocchi
- 刊名：Crystal Growth & Design
- 出版年：2009
- 出版时间：January 7, 2009
- 年：2009
- 卷：9
- 期：1
- 页码：517-524
- 全文大小：359K
- 年卷期：v.9,no.1(January 7, 2009)
- ISSN：1528-7505
文摘
Azelastine, a widely commercialized drug for the treatment of allergic asthma and rhinitis, has been commonly used as anhydrous hydrochloride salt, but it was found to form also hydrates or solvates upon recrystallization. The anhydrous form can be isolated also by precipitation from CH3CN solution or quantitatively generated from the hydrated form by heating it near 180 °C. The crystal structures of the anhydrous and of the three different solvated species have been determined by unconventional ab initio powder diffraction methods using laboratory data only, supported by solid state 13C NMR spectra and thermal analyses. Crystals of the anhydrous form are monoclinic, P21/n, a = 13.7858(9) Å, b = 16.3911(9) Å, c = 9.4085(5) Å, β = 97.540(4)°, V = 2107.6(2) Å3, Z = 4; the hydrated form crystallizes in the triclinic P space group, a = 9.5594(8) Å, b = 9.8208(8) Å, c = 14.644(1) Å, α = 86.726(5)°, β = 109.511(5)°, γ = 119.176(5)°, V = 1122.1(2) Å3, Z = 2. The stability of the two systems, in comparison with that of the known (hydrated) free base, is discussed in terms of molecular conformations, configurations, and packing environments. Two additional solvates have been prepared, a methanol adduct and a 2-butanone one, which were found to be isomorphous with the hydrated hydrochloride salt. Crystals data of the methanol adduct: a = 9.55957(7) Å, b = 9.8721(7) Å, c = 14.6792(9) Å, α = 86.412(5)°, β = 109.674(5)°, γ = 119.233(7)°, V = 1133.8(2) Å3, Z = 2. Those of the hemisolvated form with 2-butanone: a = 9.4080(6) Å, b = 9.9790(8) Å, c = 15.278(1) Å, α = 81.604(4)°, β = 111.138(4)°, γ = 118.928(4)°, V = 1170.2(1) Å3, Z = 2. In all these crystal forms, similar geometry and shape of the azelastine molecule are observed, with RS/SR (C16, N3) configuration and with the two flexible arms oriented almost parallel, with respect to each other, in a hairpin fashion.