Abstract
Crystal polymorphism, where a molecule forms several different crystal lattices, is common, and often needs to be controlled. For example, crystalline drugs must be manufactured as one specified polymorph, so polymorph purity is essential to the pharmaceutical industry. This thesis is a quantitative study of the crystallization of glycine from aqueous solution, which focuses particularly on polymorphism. Crystallization is observed within a 96-well microplate, where each well is filled with 0.1 mL of supersaturated solution. We address the difficulty of obtaining reproducible nucleation data. This problem is difficult because induction times are extremely sensitive to factors such as how the crystallizing system is prepared, and small variations in the supersaturation. The appropriate statistical tests needed to show reproducibility are discussed. Glycine has two common polymorphs, alpha and gamma, the competition between these polymorphs is studied. We obtain data at multiple NaCl concentrations. Addition of NaCl is known to favour nucleation of the gamma polymorph. The polymorph of crystals are individually identified in-situ using Raman spectroscopy. At high salt concentrations, nucleation kinetics of the alpha and gamma polymorphs are qualitatively different. The gamma polymorph behaves like the hare in Aesop's story of the tortoise and the hare: Nucleation start off rapidly, but slows, while for the alpha polymorph, nucleation starts off slow but at later times almost overtakes that of the gamma polymorph. The opposite time dependencies of the nucleation of the competing polymorphs, allows optimisation of polymorph purity using time-dependent supersaturation. Growth of the two polymorphs is analysed. The alpha polymorph is observed to grow faster than the gamma polymorph. Growth rates were variable, so they were also analysed in relation to induction times and crystal habits. We show that crystals with long induction times tend to be needle-like, and needle-like morphologies tend to grow faster than non needle-like morphologies.