Investigations into the role of the water activity for the control of solid form during crystallisation procedures

• Main Author: Chiarella, Renato A
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2005
• Subjects: Chemical engineering; Pharmacology
• ISBN: 9780355476323; 0355476320

In the pharmaceutical industry it is important to control the crystal phase and understand the solid state behaviour of the drug substance at an early stage of drug development as this can affect its shelf life, solubility, formulation properties and processing. The formation of hydrates, solvates, or unknown polymorphic forms during manufacture can have a major impact on the drug development process and ultimately on regulatory approval. The work described in this thesis deals with factors affecting the isolation and stability of crystal hydrates, reporting experimental data on two materials, inosine and theophylline, which exist as both crystalline hydrates and anhydrates. In particular the role of water activity, in aqueous organic solvent mixtures, in defining the stability regime of the hydrates is studied, the kinetics of dehydration are measured and the solution crystallisation of hydrated and anhydrous phases has been explored. The effect of temperature and solvent composition on the phase transition points between hydrate and anhydrate were investigated and water activity was found to be a dominant effect, independent of solvent. The solubility of β inosine has been determined at various water-acetone concentrations and temperatures, and the non-ideality of the systems discussed. As a result of these experiments the ternary phase diagrams have been constructed. In crystallisation experiments with inosine it was found that water activity was the major factor determining the nature of the crystallising solid phase of inosine in organic solvent-water mixtures. In aqueous solution, lab based and synchrotron studies showed that while Ostwald's rule of stages was valid at high temperatures, at low temperatures the dihydrate was the only solid phase to nucleate. These results are discussed in the light of molecular self assembly from solution. The dehydration mechanics and kinetics have been investigated demonstrating the importance of the solution-mediated nature of the process.