Fosinopril sodium, solid-state

As mentioned before, fosinopril sodium is known to be capable of existing in two polymorphic forms, and the diffuse reflectance IR spectra of the two forms indicated that the two structures differed in the conformation of one sidechain. The solid state 13C NMR spectra obtained on both forms were found to confirm this hypothesis [19]. As may be seen in Fig. 3, the significant spectral differences were all associated with nuclei contained within the acetal sidechain. 

Fig. 3 Solid state 13C NMR spectra obtained on the A-phase and B-phase polymorphs of fosinopril sodium, illustrating the differences observed in the CH aliphatic and CC aliphatic regions of the spectrum. (Data adapted from Ref. 19.)...

Analogous to the DuP 747 study, complete crystallographic information was not possible on the fosinopril sodium polymorphic system [25], Two known polymorphs (A and B) were studied via a multidisciplinary approach (XRD, IR, NMR, and thermal analysis). Complementary spectral data from IR and solid state 13C NMR revealed that the environment of the acetal sidechain of fosinopril sodium differed in the two forms. In addition, possible cis-trans isomerization about the CgN peptide bond may exist. These conformational differences are postulated as the origin of the observed polymorphism in fosinopril sodium in the absence of the crystallographic data for form B (single crystals not available). 

Fig. 3 Solid state 31P NMR spectra of fosinopril sodium acquired under single pulse, high-power proton decoupling and various conditions of magic-angle spinning (A) static, (B) 2.5 kHz, (C) 4.0 kHz, (D) 5.0 kHz, and (E) 6.0 kHz. The isotropic chemical shift is designated by an asterisk. (From Ref. 15.)...

Fig. 9 Examples of simplifying solid state NMR spectra by the TOSS and delayed decoupling pulse sequences. Shown is a comparison of the 31P CP/MAS NMR spectrum of fosinopril sodium utilizing the standard pulse sequence (A) and the TOSS routine (B). Also shown is the full 13C CP/MAS NMR spectrum of fosinopril sodium (C) and the nonprotonated carbon spectrum (D) obtained from the delayed decoupling pulse sequence utilizing a 80 /us delay time. Signals due to the methyl carbon resonances (0-30 ppm) are not completely eliminated due to the rapid methyl group rotation, which reduces the carbon-proton dipolar couplings.

In its simplest application, solid-state NMR spectra can be used to qualitatively differentiate between polymorphs or solvates, much in the manner described for vibrational spectroscopy. When detailed assignments of solid-state spectra have been made, the technique can be used to deduce differences in molecular conformation, which cause crystallographic variations to exist. During the development of fosinopril sodium, a crystal structure was solved for the most stable phase, but no such structure could be obtained for its... 

FIGURE 3 Solid-state C-NMR spectra obtained within the carbonyl region of fosinopril sodium upper trace, form A lower trace, form B. The data were adapted from reference 26. 

HG Brittain, KR Morris, DE Bugay, AB Thakur, ATM Serajuddin. Solid-state NMR and IR for the analysis of pharmaceutical solids Polymorphs of fosinopril sodium. J Pharm Biomed Anal 11 1063-1069, 1993. 

Using fosinopril sodium as the example, one can see evidence of such a relaxation transition. This was not observed in the final dosage form, but it probably would have occurred if the metastable form B had been chosen for development instead of the stable form A. In one study, a sample of form B was characterized by solid-state NMR, and then again after three months of storage at ambient laboratory conditions. As is evident from the data presented in Figs. 34a and b, the... 

Solid-state NMR spectra of fosinopril sodium, form A and form B (upper traces), showing the chemical shifts for the phosphorous nucleus in each form. The lower spectra show the partial interconversion from form B to form A after storage at room temperature and ambient humidity for three... 

Fosinopril sodium, an angiotensin-converting enzyme inhibitor, has been found to exist in two anhydrous polymorphic forms. No single crystal of sufficiently high crystallographic quality was obtained for the polymorphic phases and polymorphism was characterized by solid state and P NMR. The analysis of chemical shifts in C spectra suggested that polymorphism originates from conformational differences in the acetal side chains and/or cis-trans isomerization about the peptide C-N bond. The difference in chemical shift between P resonances in the two spectra is 2.2 ppm and demonstrates the existence of various envirorunents of phosphorus nuclei in each polymorph [43]. 

Brittain, H. G., Morris, K. R., Bugay, D. E., Thakur, A. B. and Serajuddin, A. T. M. Solid state characterization of fosinopril sodium polymorphs. J. Pharm. Biomed. Anal. 11 1063, 1993. Geppi, M., Guccione, S., Mollica, G., Pignatello, R. and Veracini, C. A. Molecular properties of ibuprofen and its solid dispersions with Eudragit RLIOO studied by solid-state nuclear magnetic resonance. Pharm. Res. 22 1544-1555, 2005. 

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