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Title: The rational design of drug crystals to facilitate particle size reduction : investigation of crystallisation conditions and crystal properties to enable optimised particle processing and comminution
Author: Shariare, Mohammad Hossain
ISNI:       0000 0004 2717 131X
Awarding Body: University of Bradford
Current Institution: University of Bradford
Date of Award: 2011
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Micronisation of active pharmaceutical ingredients (APIs) to achieve desirable quality attributes for formulation preparation and drug delivery remains a major challenge in the pharmaceutical sciences. It is therefore important that the relationships between crystal structure, the mechanical properties of powders and their subsequent influence on processing behaviour are well understood. The aim of this project was therefore to determine the relative importance of particle attributes including size, crystal quality and morphology on processing behaviour and the characteristics of micronised materials. It was then subsequently intended to link this behaviour back to crystal structure and the nature of molecular packing and intermolecular interactions within the crystal lattice enabling the identification of some generic rules which govern the quality of size reduced powders. In this regard, different sieve fractions of lactose monohydrate and crystal variants of ibuprofen and salbutamol sulphate (size, morphology and crystal quality) were investigated in order to determine those factors with greatest impact on post-micronisation measures of particle quality including particle size, degree of crystallinity and surface energy. The results showed that smaller sized feedstock should typically be used to achieve ultrafine powders with high crystallinity. This finding is attributed to the reduced number of fracture events necessary to reduce the size of the particles leading to decreases in milling residence time. However the frequency of crystal cracks is also important, with these imperfections being implicated in crack propagation and brittle fracture. Ibuprofen crystals with a greater number of cracks showed a greater propensity for comminution. Salbutamol sulphate with a high degree of crystal dislocations however gave highly energetic powders, with reduced degree of crystallinity owing to the role dislocations play in facilitating plastic deformation, minimising fragmentation and extending the residence of particles in the microniser. Throughout these studies, morphology was also shown to be critical, with needle like morphology giving increased propensity for size reduction for both ibuprofen and salbutamol sulphate, which is related to the small crack propagation length of these crystals. This behaviour is also attributed to differences in the relative facet areas for the different morphologies of particles, with associated alternative deformation behaviour and slip direction influencing the size reduction process. Molecular modelling demonstrated a general relationship between low energy slip planes, d-spacing and brittleness for a range of materials, with finer particle size distributions achieved for APIs with low value of highest d-spacings for identified slip planes. The highest d-spacing for any material can be readily determined by PXRD (powder x-ray diffraction) which can potentially be used to rank the milling behaviour of pharmaceutical materials and provides a rapid assessment tool to aid process and formulation design. These studies have shown that a range of crystal properties of feedstock can be controlled in order to provide micronised powders with desirable attributes. These include the size, morphology and the density of defects and dislocations in the crystals of the feedstock. Further studies are however required to identify strategies to ensure inter-batch consistency in these attributes following crystallisation of organic molecules.
Supervisor: York, Peter ; De Matas, Marcel ; Blagden, Nicholas ; Leusen, Frank J. J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Crystallisation ; Micronisation ; Particle size and morphology ; Mechanical properties ; Crystallinity ; Surface free energy ; Dissolution ; Aerodynamic characteristics ; Molecular modelling ; Drug delivery