Taming the dynamics in a pharmaceutical by cocrystallization: investigating the impact of the coformer by solid-state NMR

Abstract

Pharmaceuticals in their crystalline state may display a range of dynamics that can affect their physicochemical properties and chemical stability. With pharmaceutical cocrystals continuing to gain attention, there is an...

Discovering the Solid-State Secrets of Lorlatinib by NMR Crystallography: To Hydrogen Bond or not to Hydrogen Bond

“…Our work complements ongoing developments in the application of fast MAS to pharmaceuticals to show the power of NMR crystallography for characterising the solid-state forms of pharmaceutical molecules. 38,41,43,44,46,58,59,67,109…”

“…50,51 A recent example for a pharmaceutical salt shows how specific packing effects can be understood in this way. 58 In further examples of applying NMR crystallography to pharmaceuticals, solidstate NMR can probe proton transfer that distinguishes co-crystal or salt formation [59][60][61][62] and test the validity of structures determined by powder X-ray diffraction. 63 Moreover, a GIPAW-trained machine learning approach for the prediction of chemical shifts, ShiftML, has recently been presented.…”

A toolbox for improving the workflow of NMR crystallography

“…(d) Asymmetric unit of (Efavirenz)(L-proline) with the carbon atoms coloured based on the RMSENMR using the "NMR_Colouring" scripts (section 2.2.3). The experimental and GIPAW-calculated NMR data is taken from Szell et al [109]…”

Combining X-ray and NMR Crystallography to Explore the Crystallographic Disorder in Salbutamol Oxalate

“…Solid-state NMR can be used to gain insights into crystallographic disorder occurring in bulk pharmaceuticals ,− and can be combined with gauge-including projector-augmented-wave (GIPAW) calculations to verify and refine the crystal structure, that is, NMR crystallography. ,,,− As a technique that observes the bulk sample, solid-state NMR can be used to validate the occurrence of crystallographic disorder and determine its nature. ,, The disorder caused by dynamics can be investigated by solid-state NMR, − offering qualitative information through line-shape analysis, chemical shift measurement, and dipolar coupling measurements. , In addition, quantitative information on the thermodynamic parameters of the dynamics can be obtained through relaxation time measurements. ,,, There are limits to the ability of solid-state NMR to investigate disorder, which may arise due to the nature of the technique. Examples of this may arise from an insufficient resolution required to adequately resolve the crystallographic disorder, the disorder involving unreceptive nuclei or potentially missing the presence of dynamics occurring at a timescale distinct from that of the one-dimensional NMR experiment.…”

“…61,81 In addition, quantitative information on the thermodynamic parameters of the dynamics can be obtained through relaxation time measurements. 61,71,72,75 There are limits to the ability of solid-state NMR to investigate disorder, which may arise due to the nature of the technique. Examples of this may arise from an insufficient resolution required to adequately resolve the crystallographic disorder, the disorder involving unreceptive nuclei or potentially missing the presence of dynamics occurring at a timescale distinct from that of the onedimensional NMR experiment.…”