The Complex Solid-State Landscape of Sodium Diatrizoate Hydrates.

Pharmaceutical sodium salts are prone to incorporate water into their crystal structures. The model compound diatrizoic acid monosodium salt, an X-ray contrast agent, has been investigated in depth towards its interaction with water in the solid state. Five hydrates with water content ranging from 0.3 to 8 molar equivalents of water show a high degree of interconvertibility, stoichiometric and non-stoichiometric behaviour, and potential of amorphisation during release of water. A DMSO/water mixed solvate further highlights the high attraction of this salt to incorporate water. All incorporated solvent coordinates to the sodium cation and can further interact and stabilise the respective crystal forms by hydrogen bonding. DTS thus highlights the importance of an in-depth investigation of sodium salts used pharmaceutically to guarantee dose uniformity and stability of final formulation.

Crystal nucleation from solutions--transition states, rate determining steps and complexity.

This introductory paper offers a contemporary view of crystal nucleation. We begin with a molecular interpretation of the transition state and then revisit the use of classical nucleation theory as a means of obtaining molecular scale information from kinetic data. Traditional physical organic chemistry has always utilised the combination of kinetics and thermodynamics in order to gain insight over reaction pathways. Here we demonstrate for the cases of sucrose and p-aminobenzoic acid how solution chemistry, crystallography and kinetics come together to provide self-consistent pictures of the molecular scale processes occurring during nucleation. In this and a number of other systems desolvation of specific functional groups is highlighted as the rate determining step. Finally we move on to discuss the question of complexity, both from a phase and molecular perspective.

The integration of solid-form informatics into solid-form selection.

OBJECTIVES: To demonstrate how the use of structural informatics during drug development assists with the assessment of the risk of polymorphism and the selection of a commercial solid form. METHODS: The application of structural chemistry knowledge derived from the hundreds of thousands of crystal structures contained in the Cambridge Structural Database to drug candidates is described. Examples given show the comparison of intermolecular geometries to database-derived statistics, the use of Full Interaction Maps to assess polymorph stability and the calculation of hydrogen bond propensities to provide assurance of a stable solid form. The software tools used are included in the Cambridge Structural Database System and the Solid Form Module of Mercury. KEY FINDINGS: The early identification of an unusual supramolecular motif in the development phase of maraviroc led to further experimental work to find the most stable polymorph. Analyses of two polymorphs of a pain candidate drug demonstrated how consideration of molecular conformation and intermolecular interactions were used for the assessment of relative stability. Informatics analysis confirmed that the solid form of crizotinib, a monomorphic system, had a low risk of polymorphism. CONCLUSIONS: The application of informatics-based assessment of new chemical entities complements experimental studies and provides a deeper understanding of the qualities of the structure. The information provided by structural analyses is incorporated into the assessment of risk. Informatics techniques are quick to apply and are straightforward to use, allowing an assessment of progressing drug candidates.

The isolation of a metastable conglomerate using a combined computational and controlled crystallization approach.

While the use of additives to control the crystallization of polymorphs is well known, similar methodology to promote the crystallization of a metastable conglomerate over a stable racemic compound in enantiomeric systems has not been reported. Here we demonstrate this phenomenon in the case of 2-chloromandelic acid.

Solubility, metastable zone width measurement and crystal growth of the 1:1 benzoic acid/isonicotinamide cocrystal in solutions of variable stoichiometry.

The solubility and crystal growth of the 1:1 cocrystal between benzoic acid and isonicotinamide from 95% ethanol was studied through the creation of a ternary phase diagram at differing temperatures and turbidity measurements. From the solubility measurements thermodynamic properties of the system were evaluated, which indicate little solution binding of the two components supported by in situ FT-IR spectra. Cooling crystallisation from solutions of differing composition suggests differing crystal growth characteristics. An excess of benzoic acid appears to increase the metastable zone width and reduce the crystal size through interactions along the fastest growth axis, while an excess of isonicotinamide decreases the metastable zone width with increased crystal size.