Excipients are used in pharmaceutical formulations as fillers and drug carriers.
Their successful function is inextricably linked to their physicochemical
properties and, in turn, these properties are directly related to their structure. This
thesis is concerned with the structural and spectroscopic characterisation of a
selection of excipients by powder and single crystal X-ray diffraction, Raman and
IR spectroscopy and MASNMR and an investigation of their stability as a
function of temperature, humidity and particle size.
As well as being a well-known excipient used in the pharmaceutical industry,
lactose is also a common food additive. The diverse usage of lactose has led to a
wealth of contradictory information relating to both structure and properties of
this material. The first part of experimental work in this thesis identifies the four
real lactose polymorphs; the naturally occurring a-lactose monohydrate; the
anhydrous stable form of a-lactose; the hygroscopic unstable form of a-lactose;
and the anomeric equivalent, p-lactose using powder X-ray diffraction. The work
shows that anhydrous lactose formed by solvent dehydration often termed aM is
simply the anhydrous stable form of a-lactose formed via a different route.
Simple methods for discerning between the polymorphs using standard laboratory
equipment are suggested. IlC MASNMR data were collected on all four forms of
lactose for the first time and illustrate key differences between the four structures.
Single crystal data were successfully collected on the a-lactose monohydrate and
refinement carried at low temperature to determine the hydrogen bonded
arrangement for the first time. Rietveld refmement of the hygroscopic unstable
form of a-lactose using in-situ temperature resolved X-ray diffraction has shown
that the hygroscopic form can be produced as a single phase. Refinement of Plactose
using the Rietveld method has shown that powder diffraction data were
comparable with single crystal data, with respect to structure refinement but
attempts at both crystallisation and refinement of the stable anhydrous a-lactose
polymorph were unsuccessful due to the complexity of the structure.
Powder X-ray diffraction analysis was shown to be an effective tool in the
quantification of mixed phase lactose samples with respect to both mixed phase
stable anhydrous a-lactose and a-lactose monohydrate; and mixed p-Iactose and
a-lactose monohydrate samples. The accuracy of the technique was determined to
be at least 5%. Quantification was carried out using relative intensities of a well
resolved unique reflection for each phase within the system.
Dehydration techniques applied to lactose were applied to other hydrated
pharmaceutical sugars; trehalose dihydrate and raffmose pentabydrate. Solid state
techniques; powder X-ray diffraction, Raman and IR spectroscopy; showed that
discrimination of other sugar hydrates became more complex with increasing
levels of hydration.
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.