Thermodynamic and structural studies of 4-hydroxybenzaldehyde and simvastatin

Abstract

This thesis was focused on the study of 4-hydroxybenzaldehyde and simvastatin, from a thermodynamic and structural point of view. The work was part an ongoing investigation by the Molecular Energetics group on how structural changes affect the energetics of different molecular organic solids. Studies of the two known polymorphs of 4-hydroxybenzaldehyde (chapter 3) were carried out to complement a previous investigation of 4’-hydroxyacetophenone and address the question of how the substitution of a C(O)CH3 by a C(O)H group influenced polymorphism in hydroxybenzoil derivatives. This also led to the development of a methodology for the selective and reproducible preparation of the two 4-hydroxybenzaldehyde polymorphs and the determination of their stability domains represented in a Gibbs energy vs. temperature phase diagram. Simvastatin was structurally and energetically characterized from ambient temperature to the liquid state. The variation of its crystal structure with temperature, for the sub-ambient range, was also analyzed. These studies (chapters 4 and 5) led to the conclusion that previously reported phase transitions did not imply polymorphism (at least in the classical sense of the term) and were simply related to variations in the rotational freedom of the ester group present in simvastatin and not with crystal modifications. The thermal oxidative decomposition of simvastatin (chapter 6) was also studied. The main decomposition products were identified and the work conditions that can be used to prevent decomposition were determined. Finally (chapter 7), some exploratory studies to investigate if the solubility of simvastatin could be improved through the preparation of mixtures/dispersions in polyethylene glycols were also performed. This also included tests of the effect of compression on the stability of prepared materials, since compression is normally a fundamental step in the production of tablets.