Crystal transformations and crystallisation methodologies: polymorphic transformations of piracetam

The Ph.D project detailed in this thesis investigated the phenomena of crystallisation and polymorphism, focusing on 2-oxo-1-pyrrolidine acetamide (piracetam) as the model compound. The three polymorphs of practical relevance were isolated via different methods, and characterised using numerous analytical techniques. Solubility data was obtained between 5 and 50 °C for Form II and Form III in organic solvents. It was found that the solubility values correlated positively with solvent polar characteristics from a qualitative point of view; an increase in solubility was observed with increasing solvent polarity and solvent acidity. The metastable Form II has a slightly higher solubility than the stable Form III. A thorough investigation of the polymorphic transformations of the system was carried out, employing a combination of off-line and in-situ techniques. The solution mediated polymorphic transformation from Form II to Form III was investigated by monitoring the solution and solid phases. The effect of factors such as solvent, temperature, agitation, excess solid mass and specific surface area of the solid phase were examined. Solvent, temperature and agitation were all found to alter the transformation rate significantly due to their impact on the kinetics of the system. Increases in temperature and agitation increased the rate of the transformation. Indirectly, due to its impact on solubilities, temperature also influenced the driving force for the transformation. Solvent was found to affect the transformation rate both in terms of the solubility of piracetam in a particular solvent and the solvent-solute interactions. An insight into the mechanism of the transformation was also obtained. The transformation is governed by the nucleation and growth of the stable form, with nucleation likely to take place on the faces of the metastable form crystals. The solid state polymorphic transformations of piracetam were examined. Form II and Form III were each observed to transform directly to Form I upon heating, while Form I consistently transformed to Form II when cooled. Form II transforms to Form I at a slightly lower temperature than Form III. The transformation of both polymorphs to Form I was observed to cause physical cracking of the crystals as well as changing the optical properties. The molecular rearrangements required for the transformation from Form I to Form II were found to be more energetically favourable than those required for the transformation to Form III. The transformation from the metastable Form II to the stable Form III was not observed in the solid state. The true thermodynamic transition points of the three enantiotropically related polymorphs were probed in detail.