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

Skotnicki, M.; Apperley, D.C.; Aguilar, J.A.; Milanowski, B.; Pyda, M.; Hodgkinson, P.

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


M. Skotnicki

D.C. Apperley

J.A. Aguilar

B. Milanowski

M. Pyda



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.


Skotnicki, M., Apperley, D., Aguilar, J., Milanowski, B., Pyda, M., & Hodgkinson, P. (2016). Characterization of Two Distinct Amorphous Forms of Valsartan by Solid-State NMR. Molecular Pharmaceutics, 13(1), 211-222.

Journal Article Type Article
Acceptance Date Nov 24, 2015
Online Publication Date Nov 24, 2016
Publication Date Jan 4, 2016
Deposit Date Jan 8, 2016
Publicly Available Date Nov 24, 2016
Journal Molecular Pharmaceutics
Print ISSN 1543-8384
Electronic ISSN 1543-8392
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 13
Issue 1
Pages 211-222
Keywords Valsartan, Amorphous form, cis−trans amide conformers, Solid-state NMR, Molecular mobility, Glass transition, Dissolution.


Accepted Journal Article (1.3 Mb)

Copyright Statement
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see

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