Crystallization of bosutinib from a wide variety of solvents resulted in many distinct structures, and displayed difficulties to crystallize without solvent incorporation. We have prepared 23 solvated/hydrated and one anhydrous solid form and for 11 of them solved the crystal structures. With the goal of rationalizing the high propensity to solvate formation and exploring the stability relationships between the phases, the solid forms were characterized by different experimental and computational methods. Their stability was compared theoretically by calculating the packing efficiency in the crystal structures and the binding energy of the solvent in the crystal lattice using differential scanning calorimetry. Experimental studies were completed by analysing the forms' physical stability in solid state and in suspension and their intrinsic dissolution rate. The survey conducted on the inclusion compounds has resulted in basic understanding of the underlying factors affecting discriminative solvate formation: the solvents are utilised to satisfy previously unused hydrogen bonding capabilities in the host molecule.

The hydration/dehydration behavior of four distinct channel hydrates of sitagliptin L-tartrate (SLT) was investigated by thermoanalytical methods, dynamic vapour sorption analysis and variable humidity X-ray powder diffraction. The crystal structures were determined from single crystal and powder X-ray diffraction data. A survey of the forms revealed that SLT hydrates exhibit both stoichiometric and nonstoichiometric features demonstrating that the characterization of channel hydrates can be challenging as their behavior is not inevitably unambiguous. Upon dehydration, the parent hydrates retain their structures, and the lattices do not collapse; isostructural dehydrates are formed. The solved crystal structures of the packing polymorphs SLT phase 1 and phase 2 provide an effective basis to rationalize the observed hydration/dehydration pathways. The structures are dominated by infinite sheets formed by hydrogen tartrate anions, linked by hydrogen bonds. These layers separate the parallel, infinite chains of water molecules. The water molecules stabilize the structures by providing additional hydrogen bonds between the cation and the anion. This interaction substantiates the high affinity of water molecules to the API framework and explains the stoichiometric characteristics observed by solid state analytical methods. On the other hand, their non-stoichiometric character is evidenced by the non-destructive dehydration processes.

The crystallization of poorly soluble drug molecules with an excipient into new solid phases called cocrystals has gained a considerable popularity in the pharmaceutical field. In this work, the cocrystal approach was explored for a very poorly water soluble antifungal active, itraconazole (ITR), which was, for the first time, successfully converted into this multicomponent solid using an aromatic coformer, terephthalic acid (TER). The new cocrystal was characterized in terms of its solid-state and structural properties, and a panel of pharmaceutical tests including wettability and dissolution were performed. Evidence of the cocrystal formation was obtained from liquid-assisted grinding, but not neat grinding. An efficient method of the ITR–TER cocrystal formation was ball milling. The stoichiometry of the ITR–TER phase was 2:1 and the structure was stabilized by H-bonds. When comparing ITR–TER with other cocrystals, the intrinsic dissolution rates and powder dissolution profiles correlated with the aqueous solubility of the coformers. The rank order of the dissolution rates of the active pharmaceutical ingredient (API) from the cocrystals was ITR–oxalic acid > ITR–succinic acid > ITR–TER. Additionally, the ITR–TER cocrystal was stable in aqueous conditions and did not transform to the parent drug. In summary, this work presents another cocrystal of ITR that might be of use in pharmaceutical formulations.

Different approaches were utilized to assess the thermodynamic stability relationship between four distinct hemihydrates of sitagliptin L-tartrate (SLT). These phases are true polymorphs, having the same chemical composition and molar ratio of water, but different arrangement in the crystal lattice. The general approaches (Burger and Ramberger rules) have only limited applicability, but indicated a monotropic relationship between Phase 1 and Phase 2. The crystallisation and transformation behaviour of the polymorphs was strongly influenced by the solvent composition. As the stability thereof was found to be solvent-dependent, the application of the van't Hoff plot or the solvent-mediated transformation did not unambiguously reveal the relative stability of the forms. Experiments were carried out in an endeavour to determine the most suitable concentration trajectory for cooling crystallisation of the selected candidate and prevent concomitant crystallisation. The application of in situ monitoring techniques, such as FTIR-ATR and FBRM, offered great potential for process optimization and control.