The role of solvation in proton transfer reactions: implications for predicting salt/co-crystal formation using the ΔpKa rule.

The ΔpKa rule is commonly applied by chemists and crystal engineers as a guideline for the rational design of molecular salts and co-crystals. For multi-component crystals containing acid and base constituents, empirical evidence has shown that ΔpKa > 4 almost always leads to salts, ΔpKa < -1 almost always leads to co-crystals and ΔpKa between -1 and 4 can be either. This paper reviews the theoretical background of the ΔpKa rule and highlights the crucial role of solvation in determining the outcome of the potential proton transfer from acid to base. New data on the frequency of the occurrence of co-crystals and salts in multi-component crystal structures containing acid and base constituents show that the relationship between ΔpKa and the frequency of salt/co-crystal formation is influenced by the composition of the crystal. For unsolvated co-crystals/salts, containing only the principal acid and base components, the point of 50% probability for salt/co-crystal formation occurs at ΔpKa ≈ 1.4, while for hydrates of co-crystals and salts, this point is shifted to ΔpKa ≈ -0.5. For acid-base crystals with the possibility for two proton transfers, the overall frequency of occurrence of any salt (monovalent or divalent) versus a co-crystal is comparable to that of the whole data set, but the point of 50% probability for observing a monovalent salt vs. a divalent salt lies at ΔpKa,II ≈ -4.5. Hence, where two proton transfers are possible, the balance is between co-crystals and divalent salts, with monovalent salts being far less common. Finally, the overall role played by the "crystal" solvation is illustrated by the fact that acid-base complexes in the intermediate region of ΔpKa tip towards salt formation if ancillary hydrogen bonds can exist. Thus, the solvation strength of the lattice plays a key role in the stabilisation of the ions.

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

Salbutamol is an active pharmaceutical ingredient commonly used to treat respiratory distress and is listed by the World Health Organization as an essential medicine. Here, we establish the crystal structure of its oxalate form, salbutamol oxalate, and explore the nature of its crystallographic disorder by combined X-ray crystallography and 13C cross-polarization (CP) magic-angle spinning (MAS) solid-state NMR. The *C-OH chiral center of salbutamol (note that the crystal structures are a racemic mixture of the two enantiomers of salbutamol) is disordered over two positions, and the tert-butyl group is rotating rapidly, as revealed by 13C solid-state NMR. The impact of crystallization conditions on the disorder was investigated, finding variations in the occupancy ratio of the *C-OH chiral center between single crystals and a consistency across samples in the bulk powder. Overall, this work highlights the contrast between investigating crystallographic disorder by X-ray diffraction and solid-state NMR experiment, and gauge-including projector-augmented-wave (GIPAW) density functional theory (DFT) calculations, with their combined use, yielding an improved understanding of the nature of the crystallographic disorder between the local (i.e., as viewed by NMR) and longer-range periodic (i.e., as viewed by diffraction) scale.

Cediranib Maleate-From Crystal Structure Toward Materials Control.

Cediranib maleate is an active pharmaceutical ingredient (API) in phase III of development within AstraZeneca's oncology portfolio. Analysis of the crystal structure of this API confirmed that the selected salt form was robust. The salt formation step had to be redesigned to avoid an unwanted metastable polymorph. A solvate with a twist appeared during later development and was avoided using insights gained from its crystal structure. Differences between predicted and experimental aspect ratios correlate with weaker crystal interactions. Acceptable variability in particle size was defined and accommodated. The "Matwall" is introduced as a tool for building control of API performance from the crystal structure upward.