Characterization of Two Distinct Amorphous Forms of Valsartan by Solid-State NMR

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• 作者：Marcin Skotnicki ; David C. Apperley ; Juan A. Aguilar ; Bart?omiej Milanowski ; Marek Pyda ; Paul Hodgkinson
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：January 4, 2016
• 年：2016
• 卷：13
• 期：1
• 页码：211-222
• 全文大小：631K
• ISSN：1543-8392

文摘

Valsartan (VAL) is an antihypertensive drug marketed in an amorphous form. Amorphous materials can have different physicochemical properties depending on preparation method, thermal history, etc., but the nature of such materials is difficult to study by diffraction techniques. This study characterizes two different amorphous forms of valsartan (AR and AM) using solid-state NMR (SSNMR) as a primary investigation tool, supported by solution-state NMR, FT-IR, TMDSC, and dissolution tests. The two forms are found to be clearly distinct, with a significantly higher level of structural arrangement in the AR form, as observed in ¹³C, ¹⁵N, and ¹H SSNMR. ¹³C and ¹⁵N NMR indicates that the fully amorphous material (AM) contains an approximately equal ratio of cis–trans conformers about the amide bond, whereas the AR form exists mainly as one conformer, with minor conformational “defects”. ¹H ultrafast MAS NMR shows significant differences in the hydrogen bonding involving the tetrazole and acid hydrogens between the two materials, while ¹⁵N NMR shows that both forms exist as a 1,2,3,4-tetrazole tautomer. NMR relaxation times show subtle differences in local and bulk molecular mobility, which can be connected with the glass transition, the stability of the glassy material, and its response to aging. Counterintuitively the fully amorphous material is found to have a significantly lower dissolution rate than the apparently more ordered AR material.