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Title: Stability of amorphous pharmaceuticals : calorimetric studies
Author: Alem, Naziha
ISNI:       0000 0004 2698 9574
Awarding Body: University College London
Current Institution: University College London (University of London)
Date of Award: 2010
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The amorphous form can offer a solution to poor solubility of BCS Class II drugs thanks to its higher apparent solubility compared with the crystalline form. However, this advantage is severely compromised by the inherent instability of the amorphous state. The understanding and prediction of the behaviour of this solid form can offer a good strategy towards the rational development of stable amorphous formulations. The work undertaken in this thesis aimed at exploring certain aspects of amorphous form stability using mainly isothermal microcalorimetry (IMC). The first area explored was the feasibility of using IMC to assess enthalpy relaxation of amorphous pharmaceutical materials. In the first study, relaxation profiles for amorphous indomethacin obtained by differential scanning calorimetry (DSC) and IMC were compared. The results showed that the two techniques measure the same molecular mobility as similar relaxation profiles were obtained. In the second study, IMC was used to assess the enthalpy relaxation of two-component amorphous pharmaceutical systems. Simulated and real calorimetric data for precharacterised 2-phase systems were fitted to 2- Kohlrasch-Williams-Watts (KWW) and 2- modified stretched exponential (MSE) models. The 2- KWW model was able to recover the correct relaxation parameters for simulated data but not for real calorimetric data due to inherent noise. The sensitivity of the MSE model seemed less prone to the effect of noise and any failings of this model to recover the expected values was taken as a sign of the two consisting components behaving differently from when they were aged individually. In the second section of the thesis, the dynamic behaviours of amorphous α and β lactose were compared. Enthalpy relaxation of the two milled anomers was assessed by IMC. Glass transition (Tg) width measurements were conducted using DSC. Moisture- solid interactions were also assessed using dynamic vapour sorption (DVS). The two anomers showed different enthalpy relaxation profiles. Tg width was the same for both anomers and this could be due to significant mutarotation during DSC measurements. Water sorption isotherms revealed that the anomeric configuration can only affect the physical stability of amorphous lactose above the Tg. In the last section, crystallisation from the amorphous state was explored using IMC. In the first study, the use of calculation methods based on the universal Sestak-Berggren equation to extract crystallisation parameters was examined. Calculation results were compared to those obtained by model-fitting approach. Simulated data revealed that a minimum of 15% data coverage is needed to recover the correct crystallisation parameters. Real data were obtained for crystallisation of indomethacin below its Tg; no trend was observed in terms of the success of the calculation method. This could be attributed to inherent noise in real calorimetric data. The second study of the last section examined the use of IMC to extract crystallisation kinetics of indomethacin above its Tg (60°C). Amorphous indomethacin was prepared either as film-like (AFI) or bulk (ABI) samples. Power-time profiles for two sample types were different reflecting differences in the crystallisation behaviours. This was speculated to be partly due to differences in the free surface areas between the two sample-types. AFI samples crystallisation at 60°C was also assessed with X-ray powder diffraction (XRPD) and polarised light microscopy (PLM). Quantitative analysis carried out with the Lorentzian model to deconvolute the calorimetric signal was reasonably consistent with the analysis undertaken with PLM and XRPD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available