Danielle Giron

Crystal structure elucidation and morphology study of pharmaceuticals in development

The structural characterization of drug substances by X-ray diffraction plays a central role during the development of pharmaceuticals. While powder diffraction is usually employed for the identification of solid phases, the single crystal technique yields detailed structural information, which is needed for purity control, understanding of polymorphism or pseudo-polymorphic behavior, physico-chemical property elucidation and morphology characterization. The structure determination of three active ingredients is discussed in this context. In the first case, we have solved the structure directly from high-resolution powder X-ray data, using the ‘direct-space’ methodology. The polymorphic behavior of the second substance has been rationalized by analyzing the intermolecular interactions and packing motifs of the two modifications in the solid state. For the third compound, we have predicted the morphology from the knowledge of its crystal structure. Solvent mixtures have been used to control the external crystal habit, based upon a detailed analysis of chemical groups emerging from the cleaved crystal surfaces of the calculated morphology.

5.21 – Solid-State Physicochemistry

Most drugs are administrated orally. If the absorption of the drug substance in the body is limited by its solubility, the properties of the solid state can have an influence on the dissolution rate and solubility. The interface between drug discovery and development is very critical to optimize candidate selection in order to reduce considerably the number of projects rejected during development. The ‘developability assessment’ has become an increasingly important criterion in addition to traditional drug efficacy and toxicity evaluation. The physicochemical properties in solid state of acidic or basic compounds can be modified by salt formation. However, an organic compound can have several solid forms, crystalline or not, and its physical properties in the solid state will depend on these solid forms. The relevance of polymorphic behavior is now recognised as a critical factor. A well known example is the market withdrawal of ritonarvir one year after its launch, caused by its far too slow dissolution rate due to an insoluble stable polymorph not found during development. Therefore the choice of a salt form has to be done in correlation with its ‘polymorphic’ behavior. This chapter summarizes the thermodynamic rules which are the driving force of polymorphism, pseudo-polymorphism and apomorphism and the solid state parameters affected by these phenomena e.g. solubility, dissolution rate, hygroscopicity, chemical stability and effect of aging due to kinetic factors. This chapter also points to some strategies to overcome solubility problems by modification of salt form, crystal form, particle size, complexes, co-crystals or formulations. Various examples in development illustrate this chapter.