Vora, Ketan Lalit;
(2005)
The use of gravimetric and chromatographic analysis to study surface properties of powders.
Doctoral thesis (Ph.D.), University College London.
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Abstract
Pharmaceutical processing can affect the crystallinity of drug substances, leading to batch-to-batch variation and changes in the physicochemical behaviour of the final dosage form. The study of the effects of such processing is important to allow the control of manufacturing procedures in order to ensure the consistent quality of the finished product. The aims were to investigate and measure the changes in the surface properties of four compounds when subjected to pharmaceutical processing. The work also highlights the difficulties associated with the study of hydrates due to their water loss either by accident or intent when equilibrated prior to experimental analysis. Characterisation studies using a gravimetric approach coupled with near infrared spectroscopy showed the discovery of a new crystal transition for theophylline during hydration of the dehydrate lattice. A crystallisation type transition at 40-50% relative humidity occurred during rehydration. This suggested a probable "ghost hydrate structure" for the dehydrate packing. The sorption of water, during rehydration, allowed the structure to have sufficient mobility to transform back into the anhydrous form prior to hydrate formation. Such a technique can show real-time events of solid-state transitions for sophisticated powdered solids, and can thus help formulators monitor changes during manufacture of a product. Gravimetric analysis of compounds using a novel approach of probing the surface with solvents other than water provided useful data. It was possible to follow changes in non-micronised and micronised calcium mupirocin. Due to the hydrophilic nature of the compound it interacted with the polar probes to a greater extent. Once micronised the sample showed stronger wettability to all the probes probably due to amorphous regions, greater surface energy and/or larger surface areas created during micronisation. Interestingly, tests on the micronised sample after one year showed some recovery suggesting that increased surface area was not the only cause of the greater wetting but possibly also changes in the surface energy. Changes on the dihydrate form were not measurable due to the inability to retain the hydrate when water vapour was absent from the system. The method proved unsuitable for the other compounds due to minimal wetting or poor equilibration. This technique has allowed process-induced batch variability to be measured where conventional techniques such as x-ray diffractometry and solution calorimetry have failed. Chromatographic analysis of the surface of the compounds has proved successful especially where the gravimetric approach has shown limitations. Differences in surface energetics of both micronised and non-micronised forms of calcium mupirocin and nabumetone were attainable. Over time the surface energy of the samples recovered, suggesting the formation of a thermodynamically unstable surface state immediately after micronisation. Measurements of the hydrated forms (calcium mupirocin and theophylline) were possible chromatographically. Water into/onto the drugs reduced the dispersive and acidic components of the surface. Also the dehydrated form of theophylline showed very high surface energy values, corroborating the recognised instability of the lattice. Batch-to-batch variability between Sigma and Fluka forms of theophylline and magnesium stearate have also been highlighted by the differences in their respective surface energy values. Chromatography allows the determination of small changes in surface characteristics and has provided a new approach to successfully comparing hydrates for the first time. Gravimetric and chromatographic techniques have provided an alternative method to investigate process induced batch variability. Understanding the way surfaces interact with probes of varying polarity can help allow the selection of the appropriate solvent during processing in order to prevent undesirable changes to the original compound.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D. |
| Title: | The use of gravimetric and chromatographic analysis to study surface properties of powders. |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis Digitised by Proquest. |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10122297 |
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