Decreasing particle size helps to preserve metastable polymorphs. A case study of dl-cysteine

Abstract

The contribution describes the effect of particle size on the interconversion between the high-temperature (I) and the low-temperature (II) polymorphs of crystalline DL-cysteine (⁺NH₃–CH(CH₂SH)–COO⁻) studied by X-ray powder diffraction, Raman spectroscopy, differential scanning calorimetry, scanning electron microscopy. Crystalline DL-cysteine undergoes a phase transition on cooling related to the rotation of its side-chain and a rearrangement of the H-bond network. For the crystals larger than ∼1 μm, the transition could be observed in the range 250–200 K and was characterized by a large (up to 110 K) hysteresis. If (I) was obtained as crystalline particles with characteristic size of ∼1 μm by grinding, no transformation into (II) was observed on cooling down even to 10 K. (I) was preserved down to 200 K, after which another low-temperature phase, (I)′, appeared, which was structurally related to (I), but with strongly disordered (possibly modulated) sulfhydryl side-chains. Nevertheless, (II) could be prepared as small (∼0.1 to 1 μm) particles directly at low temperatures by freeze-drying of DL-cysteine aqueous solutions. The sample could be then preserved as a metastable low-temperature polymorph on heating up to ∼333 K, and transformed completely to (I) at 373 K only. The small particles of (I) obtained by heating from small particles of (II) then transformed completely back to (II) on cooling down to 183 K. The effects are interpreted in terms of kinetic control of the polymorphic transitions and the relation between particle size, nucleation of a new phase, and relaxation of mechanical stresses.