The comparison of new structural data with crystal structures stored in the Cambridge Structural Database (CSD) is becoming ordinary when dealing with recognition and identification of new solid forms. Indeed,...

A new polymorph of tolfenamic acid, form IX, has been crystallised from a simple cooling crystallisation experiment raising the question as to why this polymorph had never been reported before.

Little is known about the relationship between the kinetic process of nucleation and the molecular and crystal structures of a crystallizing solute. Here we compare the behaviour of a series of benzoic acids with a focus on conformational effects.

Five organic salts of the antiplasmodial drug piperaquine (PQ, C 29 H 32 Cl 2 N 6 ) were synthesized and characterized by X-ray diffraction methods. The corresponding solubilities in water and acetic acid solutions were evaluated in the 20−50 °C (293−323 K) T range by UV−vis spectroscopy, with the aim of elucidating how they depend on chemical, structural, and thermodynamic factors. Experiments were complemented by DFT calculations, both in vacuo and in the solid state, to estimate changes in thermodynamic state functions related to the solvation process. It is demonstrated that solubility is mainly governed by the electronic and chemical properties of the anion, while lattice energies and packing effects, including in-crystal conformational changes of the drug, play a less important role. PQ salts generally conform to the predictions of hard and soft acid and bases (HSAB) theory, as less soluble compounds bear ions of comparable hardness, and vice versa. A remarkable exception is the PQ hydrogen sulfate salt, whose poor solubility can be ascribed to an exceptionally stable crystal lattice. Other factors, such as entropic effects related to solid-state disorder, can influence the response of solubility to temperature.

Organic compounds can crystallise in different forms known as polymorphs. Some polymorphs have disappeared from the physical world, never to be recrystallised again under the same conditions. The most infamous of these cases is that of the HIV drug ritonavir: once its reluctant stable form II was unwillingly nucleated for the first time, its desired but metastable form I could never be produced again with the same manufacturing process. The disappearance of metastable polymorphs remains a mysterious phenomenon, and the lack of control over it can be frustrating and costly for drug development. Here we show that Ritonavir’s extraordinary disappearing polymorph can be consistently produced by ball-mill grinding. Our work shows that not only crystal size, but also crystal shape and molecular conformation dictate polymorph stability switches in the mill. Through population balance modelling simulations, we also demonstrate how the size and shape of crystals at the steady state are determined by crystal breakage, dissolution and growth kinetics in the mill, which in turn can be controlled by the milling conditions. This work highlights the huge potential of mechanochemistry in polymorph discovery, and the manufacturing and control of complex flexible drug compounds such as Ritonavir.