On the mechanism of solid-state phase transitions in molecular crystals - the role of cooperative motion in (quasi)racemic linear amino acids.

During single-crystal-to-single-crystal (SCSC) phase transitions, a polymorph of a compound can transform to a more stable form while remaining in the solid state. By understanding the mechanism of these transitions, strategies can be developed to control this phenomenon. This is particularly important in the pharmaceutical industry, but also relevant for other industries such as the food and agrochemical industries. Although extensive literature exists on SCSC phase transitions in inorganic crystals, it is unclear whether their classications and mechanisms translate to molecular crystals, with weaker interactions and more steric hindrance. A comparitive study of SCSC phase transitions in aliphatic linear-chain amino acid crystals, both racemates and quasi-racemates, is presented. A total of 34 transitions are considered and most are classified according to their structural change during the transition. Transitions without torsional changes show very different characteristics, such as transition temperature, enthalpy and free energy, compared with transitions that involve torsional changes. These differences can be rationalized using classical nucleation theory and in terms of a difference in mechanism; torsional changes occur in a molecule-by-molecule fashion, whereas transitions without torsional changes involve cooperative motion with multiple molecules at the same time.

Inhibition of the Vapor-Mediated Phase Transition of the High Temperature Form of Pyrazinamide.

Tailor-made additives can prove an effective method to prolong the lifetime of metastable forms of pharmaceutical compounds by surface stabilization. Pyrazinamide (PZA) is a pharmaceutical compound with four polymorphic forms. The high temperature γ form, which can be produced by spray drying or sublimation growth, is metastable at room temperature and transforms within days when produced by spray drying, and within several months up to years for single crystals produced by sublimation. However, when PZA is cospray dried with 1,3-dimethylurea (DMU), it has been reported to remain in its γ form for several years. Scanning electron microscopy (SEM) images reveal that the phase transition from γ-PZA to the low temperature forms involves a vapor-mediated recrystallization, while the reverse phase transition upon heating is a nucleation-and-growth solid-solid phase transition. The lifetime-extending effect of DMU on spray-dried PZA has been investigated in more detail and compared with high-energy ball milling of sublimation-grown γ-PZA crystals. Co-ball milling of PZA and DMU is found to extend the lifetime of the high temperature form of PZA to a few months, while separate ball milling leads to an extension of merely a few weeks. DMU acts as an additive that most likely stabilizes the surface of γ-PZA, which would reduce the vapor pressure of PZA, thereby reducing the transition rate. Alternatively, DMU could prevent nucleation of low temperature forms of PZA.