Dynamic NMR study and theoretical calculations on the conformational exchange of valsartan and related compounds

Li, Fang; Zhang, Huiting; Jiang, Ling; Zhang, Weinong; Nie, Jing; Feng, Yu‐Qi; Yang, Minghui; Liu, Maili

doi:10.1002/mrc.2072

Cited by 17 publications

(20 citation statements)

References 25 publications

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“…Comparing the valsartan spectra is more difficult due to the presence of two conformers in solution associated with hindered rotation of its amide bond, see Refs. ( 56 , 57 ). Changes are seen for the carbonyl group (C-5) and in the aromatic region (Table IS , supplementary material).…”

Section: Resultsmentioning

confidence: 99%

Bisoprolol and Bisoprolol-Valsartan Compatibility Studied by Differential Scanning Calorimetry, Nuclear Magnetic Resonance and X-Ray Powder Diffractometry

et al. 2014

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PurposeThe objective of this study was to evaluate the thermal behavior of crystalline and amorphous bisoprolol fumarate and its compatibility with amorphous valsartan. This pharmacologically relevant drug combination is a potential candidate for fixed-dose combination formulation.MethodsDSC and TMDSC were used to examine thermal behavior of bisoprolol fumarate. SSNMR and XRPD were applied to probe the solid state forms. The thermal behavior of physical mixtures with different concentrations of bisoprolol and valsartan were examined by DSC and TMDSC, and the observed interactions were investigated by XRPD, solution- and solid-state NMR.ResultsThe phase transitions from thermal methods and solid-state NMR spectra of crystalline and amorphous bisoprolol fumarate are reported. Strong interactions between bisoprolol fumarate and valsartan were observed above 60 C, resulting in the formation of a new amorphous material. Solution- and solid-state NMR provided insight into the molecular nature of the incompatibility.ConclusionsA combined analysis of thermal methods, solution- and solid-state NMR and XRPD experiments allowed the investigation of the conformational and dynamic properties of bisoprolol fumarate. Since bisoprolol fumarate and valsartan react to form a new amorphous product, formulation of a fixed-dose combination would require separate reservoirs for bisoprolol and valsartan to prevent interactions. Similar problems might be expected with other excipients or APIs containing carboxylic groups.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-014-1471-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Bisoprolol and Bisoprolol-Valsartan Compatibility Studied by Differential Scanning Calorimetry, Nuclear Magnetic Resonance and X-Ray Powder Diffractometry

et al. 2014

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“…Numbering scheme used as in Refs. 20,21 The dihedral angle C-6-N-1-C-5-O-1, τ, that determines the amide cis (τ ≈180°) vs trans (τ ≈ 0°) conformation, as defined in Ref. 21 , is shown.…”

Section: Valsartan (Valmentioning

confidence: 99%

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

et al. 2015

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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.

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“…13 C NMR and two-dimensional analysis showed two rotational isomers of CA-sar-TFMA. Thus, like other drugs, for example, valsartan, 31 CA-sar-TFMA appears to have two different rotational states around a tertiary amide bond that yields split peaks for carbon atoms. Tertiary amide bonds often give rise to rotamers because of the inherent flexibility of the bond, and the inability to form stabilizing hydrogen bonds.…”

Section: Synthesis Of Ca-sar-tfmamentioning

confidence: 96%

Design and Evaluation of a Novel Trifluorinated Imaging Agent for Assessment of Bile Acid Transport Using Fluorine Magnetic Resonance Imaging

Vivian

Cheng

Khurana

et al. 2014

Journal of Pharmaceutical Sciences

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Previously, we developed a trifluorinated bile acid, CA-lys-TFA, with the objective of noninvasively assessing bile acid transport in vivo using 19F magnetic resonance imaging (MRI). CA-lys-TFA was successfully imaged in the mouse gallbladder, but was susceptible to deconjugation in vitro by choloylglycine hydrolase (CGH), a bacterial bile acid deconjugating enzyme found in the terminal ileum and colon. The objective of the present study was to develop a novel trifluorinated bile acid resistant to deconjugation by CGH. CA-sar-TFMA was designed, synthesized, and tested for in vitro transport properties, stability, imaging properties, and its ability to differentially accumulate in the gallbladders of normal mice, compared with mice with known impaired bile acid transport (deficient in the apical sodium-dependent bile acid transporter, ASBT). CA-sar-TFMA was a potent inhibitor and substrate of ASBT and the Na+/taurocholate cotransporting polypeptide. Stability was favorable in all conditions tested, including the presence of CGH. CA-sar-TFMA was successfully imaged and accumulated at 16.1-fold higher concentrations in gallbladders from wild-type mice compared with those from Asbt-deficient mice. Our results support the potential of using MRI with CA-sar-TFMA as a noninvasive method to assess bile acid transport in vivo.

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Dynamic NMR study and theoretical calculations on the conformational exchange of valsartan and related compounds

Cited by 17 publications

References 25 publications

Bisoprolol and Bisoprolol-Valsartan Compatibility Studied by Differential Scanning Calorimetry, Nuclear Magnetic Resonance and X-Ray Powder Diffractometry

Bisoprolol and Bisoprolol-Valsartan Compatibility Studied by Differential Scanning Calorimetry, Nuclear Magnetic Resonance and X-Ray Powder Diffractometry

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

Design and Evaluation of a Novel Trifluorinated Imaging Agent for Assessment of Bile Acid Transport Using Fluorine Magnetic Resonance Imaging

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