Influence of the Crystallisation Solution Environment on the Structural Pathway from Solute Solvation to the Polymorphic Forms of Tolfenamic Acid

The influence of the solution environment on the solution crystallisation of the conformational polymorphic forms I and II of tolfenamic acid is assessed through integration of multi-scale (molecular, cluster and crystallographic) modelling with polymorphic screening using polythermal crystallisation as a function of solvent selection. Solid-state analysis reveals the contrasting crystal chemistry with the strongest synthon involving hydrogen bonding synthons and π–π van der Waals interactions for forms I and II, respectively. Analysis of the molecular conformational energies reveals molecular structures for forms I and II to be very close which is matched by their calculated lattice energies. Crystallisation as a function of both solute concentration and solution cooling rate reveals form II to be mostly more preferred than form I. The higher stability of the form II conformer together with its easier conformational adjustment during the formation of form II crystals, is consistent with its greater crystallisability compared to the more stable form I. Solute concentration analysis of the relative stabilities of the two forms as a function of their sizes reveals that smaller cluster sizes are required to stabilise the crystal structure for form I with respect to form II. Polymorphic screening as a function of solvent confirms the predicted poor crystallisability of form I whose crystallisation is preferred at higher initial solute concentrations and lower cooling rates in polar solvents but less so for the more apolar solvent toluene, the latter being consistent with π–π solute/solvent interactions promoting the formation of hydrogen bonded solute/solute synthons at the expense of π–π interactions. Modelling work correlates well with the observed crystallisation behaviour, highlighting the importance of understanding solvent selection and solution state structure at the molecular-scale level for directing polymorphic outcomes, as confirmed by the higher crystallisability of the metastable form II.