Mushtaq, Rayan
(2021)
Investigating the impact of the surface on the physical stability of drug: polymer amorphous solid dispersions.
PhD thesis, University of Nottingham.
Abstract
The formulation of drugs in the amorphous state offers potential advantages, including enhanced apparent solubility and hence bioavailability, although this comes at the cost of instability for recrystallisation. Recently, the importance of surface-enhanced crystallisation (SEC) mechanism on five amorphous drugs has been identified, in which crystal growth at an exposed surface is several orders of magnitude faster than growth in the bulk, and this occasionally affects the crystallisation polymorph and morphology at the surface. The aim of this thesis is to investigate the effect of the surface on the stability of other amorphous APIs against recrystallisation. If a different stability is seen, then these studies are to be extended to examine the influence of the SEC mechanism on the physical stability in the presence or absence of polymer additives.
Hot-stage polarised light microscopy (HS-PLM) was the primary technique used in this thesis to measure the recrystallisation behaviour. Confocal Raman spectroscopy was used to identify the polymorph of the crystals. Differential scanning calorimetry was employed to explore the miscibility between the drug and the polymer.
In Chapter 3, paracetamol (PCM) was selected as a model drug. Amorphous PCM exhibits low stability against recrystallisation, with different crystal polymorphs found on exposed surfaces compared to the bulk, and it was assumed that this might be due to SEC mechanism. Here, the crystallisation rates at the surface and in the bulk of amorphous PCM as a function of temperature were measured and compared for the first time. The crystallisation rate at the surface was found to be faster by an order of magnitude than that of the bulk at temperatures above the glass transition temperature (Tg), and faster by two orders of magnitude at temperatures slightly higher than Tg. Moreover, the crystallisation at the surface was discovered to be of Form II, while the bulk crystals existed in Form III. The results offer a solution to the long-standing puzzle of why slightly different crystallisation conditions can lead to different crystallisation outcomes, and also indicate that SEC may be more widespread and important in formulation than recognised to date.
In Chapter 4, the effect of the surface was studied on amorphous nifedipine (NIF) in the presence and absence of HPMC polymer to gain more understanding of the SEC mechanism. Amorphous NIF has no variance in the polymorphic form at the surface and in the bulk when it is recrystallised. The results in Chapter 4 reveal that mixing amorphous NIF with 1% HPMC inhibits the crystallisation rate at the surface by two orders of magnitude, but it has a significantly weak effect on crystal growth in the bulk at below Tg. In Chapter 5, a high throughput (HT) method for measuring the recrystallisation rates of amorphous drugs was established to obtain a crystallisation growth rate at various temperatures in one experiment using hot-stage microscopy. The recrystallisation rates of the HT method were generally comparable with those measured by the standard method. Hence, the HT method could be useful to screen how widespread the SEC mechanism is among other amorphous drugs, which could allow an understanding of the rationale behind the existence of the SEC phenomenon.
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