X-ray studies of molecular structure during the crystallisation of organic salts

Increasing numbers of pharmaceutical drugs are being produced in salt form to improve bioavailability, and handling and processing properties. Effective control of organic salt crystallisation from solution requires an improved understanding of the molecular-level interactions present in the solution before and during crystallisation. State-of-the-art X-ray techniques probe solution-phase systems at the short time- and length-scales required to reveal information about the chemical environment and local molecular structure of the solution. Core-level X-ray spectroscopy and X-ray diffraction, combined with computational analysis, have been used to characterise an organic salt in solution and the phase from which an organic salt crystallises. The near-edge X-ray absorption fine structure (NEXAFS) spectra of the C and N K-edges of aqueous imidazole (Imid) and imidazolium (ImidH+) are acquired using a novel combination of X-ray Raman scattering (XRS), near-ambient pressure X-ray photoelectron spectroscopy (NAP-XPS) and time-dependent density functional theory (TDDFT) calculations. C and N 1s core-level binding energies (from NAP-XPS) were used to assign relative ionisation potential energies. N-atom pseudoequivalence in ImidH+, defined by the single 1s to 1π* transition peak, contrasts with the two N moieties observed in Imid. TDDFT calculations revealed 1s to 3π* resonances in the ImidH+ C K-edge spectrum that are not present in the Imid spectrum. X-ray Pair Distribution Function (XPDF) patterns collected during the in situ cooling crystallisation of an aqueous solution of guanidine hydrochloride (GuHCl) indicate three distinct solution phases prior to crystallisation. For the first time, Empirical Potential Structure Refinement (EPSR) structural models, refined to experimental data, have been used to suggest the possible structural motifs that may dominate in the pre-crystallisation phases. The combined XPDF/EPSR approach was applied to the structures of 2, 4 and 6 M aqueous GuHCl solutions and suggested medium-range structural differences in Gdm+-Gdm+ interactions due to a critical solvation change between the 2 M solution, and higher-concentration solutions.