Search for: All records

This paper reports the principal values of the¹³C chemical shift tensors for five nitrogen‐dense compounds (i.e., cytosine, uracil, imidazole, guanidine hydrochloride, and aminoguanidine hydrochloride). Although these are all fundamentally important compounds, the majority do not have¹³C chemical shift tensors reported in the literature. The chemical shift tensors are obtained from¹H→¹³C cross‐polarization magic‐angle spinning (CP/MAS) experiments that were conducted at a high field of 18.8 T to suppress the effects of¹⁴N‐¹³C residual dipolar coupling. Quantum chemical calculations using density functional theory are used to obtain the¹³C magnetic shielding tensors for these compounds. The best agreement with experiment arises from calculations using the hybrid functional PBE0 or the double‐hybrid functional PBE0‐DH, along with the triple‐zeta basis sets TZ2P or pc‐3, respectively, and intermolecular effects modeled using large clusters of molecules with electrostatic embedding through the COSMO approach. These measurements are part of an ongoing effort to expand the catalog of accurate¹³C chemical shift tensor measurements, with the aim of creating a database that may be useful for benchmarking the accuracy of quantum chemical calculations, developing nuclear magnetic resonance (NMR) crystallography protocols, or aiding in applications involving machine learning or data mining. This work was conducted at the National High Magnetic Field Laboratory as part of a 2‐week school for introducing undergraduate students to practical laboratory experience that will prepare them for scientific careers or postgraduate studies.

 

Competitive milling (CM) and stability milling (SM) mechanochemical reactions are used to comprehensively assess the relative thermodynamic stabilities and cocrystallization affinities of three pharmaceutical cocrystals (PCCs) of fluoxetine HCl ( X ) with three different pharmaceutically acceptable coformers (PACs, i.e. , benzoic acid ( B ), fumaric acid ( F ), and succinic acid ( S )). CM reactions, which involve milling X in the presence of two or more different PACs, were used to determine cocrystallization affinities, whereas SM reactions, which involve milling a PCC of X with a different coformer, were used to determine relative thermodynamic stabilities. In certain cases, SM reactions exhibited a remarkable solid-state exchange of coformers, yielding new cocrystalline forms. 35 Cl (spin I = 3/2) SSNMR is used as the primary probe of the products of CM and SM reactions, providing a reliable means of identifying and quantifying chloride ions in unique hydrogen bonding environments in each reaction mixture ( 13 C SSNMR spectra and pXRD patterns are used in support of these data). On the basis of these reactions and data, the PAC cocrystallization affinities with X are B > F ≈ S (most to least preferred), and the PCC stabilities are XB > X 2 F ≈ X 2 S (most to least preferred), corresponding to enthalpies of cocrystallization ranked as Δ H CCXB < ≈ . PAC affinities and PCC stabilities were found to be the same for products of analogous slow evaporation experiments and mechanochemical reactions with extended milling times ( i.e. , 90 minutes). Preliminary plane-wave DFT-D2* calculations are supportive of cocrystal formation; however, challenges remain for the quantification of relative enthalpies of cocrystallization. This work demonstrates the great potential of CM and SM reactions for providing pathways to the rational design, discovery, and manufacture of new cocrystalline forms of APIs. 

There are currently no methods for the acquisition of ultra-wideline (UW) solid-state NMR spectra under static conditions that enable reliable separation and resolution of overlapping powder patterns arising from magnetically distinct nuclei. This stands in contrast to the variety of techniques available for spin-1/2 or half-integer quadrupolar nuclei with narrow central transition patterns under magic-angle spinning (MAS). Resolution of overlapping signals is routinely achieved in MRI and solution-state NMR by exploiting relaxation differences between nonequivalent sites. Preliminary studies of relaxation assisted separation (RAS) for separating overlapping UWNMR patterns using pseudo-inverse Laplace Transforms have reported two-dimensional spectra featuring relaxation rates correlated to NMR interaction frequencies. However, RAS methods are inherently sensitive to experimental noise, and require that relaxation rates associated with overlapped patterns be significantly different from one another. Herein, principal component analysis (PCA) denoising is implemented to increase the signal-to-noise ratios of the relaxation datasets and RAS routines are stabilized with truncated singular value decomposition (TSVD) and elastic net (EN) regularization to resolve overlapped patterns with a larger tolerance for differences in relaxation rates. We extend these methods for improved pattern resolution by utilizing 3D frequency- R 1 – R 2 correlation spectra. Synthetic and experimental datasets, including 35 Cl ( I = 3/2), 2 H ( I = 1), and 14 N ( I = 1) NMR of organic and biological compounds, are explored with both regularized 2D RAS and 3D RAS; comparison of these data reveal improved resolution in the latter case. These methods have great potential for separating overlapping powder patterns under both static and MAS conditions.