Probing Intermolecular Crystal Packing in γ-Indomethacin by High-Resolution ¹H Solid-State NMR Spectroscopy

Abstract

An NMR crystallography approach that combines experimental solid-state magic-angle-spinning (MAS) NMR with calculation is applied to the  polymorph of the pharmaceutical molecule, indomethacin. First-principles calculations (GIPAW) for the full crystal structure and an isolated molecule show changes in the 1 H chemical shift for specific aliphatic and aromatic protons of over 1 ppm that are due to intermolecular CH- interactions. For the OH proton, 1 H double-quantum (DQ) CRAMPS (combined rotation and multiple-pulse spectroscopy) spectra reveal intermolecular H-H proximities to the OH proton of the carboxylic acid dimer as well as to specific aromatic CH protons.

Solid-State NMR Analysis of a Boron-Containing Pharmaceutical Hydrochloride Salt

“…Overall, the agreement between the 14 calculated and experimental values in Figure is relatively good, given the narrow 1 H chemical shift range and the imprecision of the 1 H δ iso measurements taken using the 2D CP–HETCOR spectrum. The agreement seen in Figure is similar to or better than the agreement between 1 H δ iso and σ iso (the latter calculated using GIPAW calculations) observed in other systems . It is known that improved agreement is possible if a series of variable‐temperature studies are performed and the experimental δ iso measurements obtained are used to extrapolate theoretical δ iso values at 0 K .…”

“…The agreement seen in Figure 8 is similar to or better than the agreement between 1 H * iso and F iso (the latter calculated using GIPAW calculations) observed in other systems. [49][50][51] It is known that improved agreement is possible if a series of variable-temperature studies are performed and the experimental * iso measurements obtained are used to extrapolate theoretical * iso values at 0 K. 49 This approach was not necessary with Form 1 given the clear assignments of the 14 observed 1 H positions.…”

Building solids inside nano-space: from confined amorphous through confined solvate to confined ‘metastable’ polymorph

“…[25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] Recent studies by Surwase et al reported new crystalline forms of IMC and water driven phase transitions from an amorphous phase, in spite of years of studies. 23 The thermodynamically most stable form of indomethacin (g-IMC) has the space group symmetry P% 1 with Z 0 = 1.…”

Benchmark fragment-based1H,13C,15N and17O chemical shift predictions in molecular crystals

“…Conversions to other chemical shift scales can be accomplished as described by Ref 37; for expediency, several of the most common conversions are given in the ESI. † The CSD reference codes and experimental references for NMR data for the three test sets are: Hydrogen (13 structures, 80 shifts): CIMETD, 1 INDMET, 38 URACIL, 39 co-crystal of 4,5-Dimethylimidazole and 3,5-Dimethylpyrazole, 40 AMBACO05, 41 PHBARB06, 42 IPMEPL, 7 COYRUD11, 43 FPAMCA11, 8 BAPLOT01, 8 WEZCOT, 8 FLUBIP, 44 ZIVKAQ. 45 …”