This study focused on two active pharmaceutical ingredients (APIs) that are used to treat two of the
most notorious diseases in Africa, i.e. human immunodeficiency virus/acquired immune deficiency
syndrome (HIV/AIDS) and malaria. It is well known that many African countries lack effective
regulatory control over medicines and patients are subsequently at risk of receiving sub-standard
treatments. This study set out to investigate how the modification of the crystal packing (i.e.
polymorphism) of these APIs may impact on their quality, safety and efficacy. Efavirenz (an
antiretroviral) and Pyrimethamine (an antimalarial) were selected as the two model APIs for
investigation during this study.
It was found that a novel amorphous form (Form A) of Efavirenz had been prepared during this study
through quench cooling. Form A was extensively characterised and compared to the preferred
crystalline Form I, with the aim of providing a means of distinguishing between these two Efavirenz
forms. In contrast to popular belief (that amorphous form should have improved dissolution and
solubility properties over the crystalline counterpart), the powder dissolution of Form A was
significantly lower than that of Form I. Further investigation indicated that this was due to the
occurrence of agglomeration and phase-mediated transformation. This observation had led to the
belief that Form A had poor thermodynamic stability.
The glass transition temperature and the crystallisation activation energy, required for the
recrystallisation of Form A, were subsequently determined in an attempt to elucidate its
thermodynamic stability. The glass transition temperature of Form A was found to be unfeasibly low,
hence confirming its tendency towards agglomeration. The crystallisation activation energy of Form A
was determined by non-isothermal determinations, using differential scanning calorimetry (DSC), hot
stage microscopy (HSM) and capillary melting point (CMP) analysis. These studies not only
elucidated the required activation energy for the conversion of Form A into Form I, but it also found
that the results from CMP were similar to those of the universally accepted DSC technique, allowing
for the proposal of CMP as a cost-effective alternative to DSC for the quantitative measurement of the
crystallisation of Efavirenz. Isothermal studies revealed that Form A had a short half-life, which,
together with its poor dissolution performance, exemplified why this form was unsuitable for
pharmaceutical use.
The Pyrimethamine study focused on recrystallisation as a means of modifying its crystal packing and
on an evaluation of the effect that such crystal modification may have on its safety and
manufacturability. Anhydrous Pyrimethamine was recrystallised, using methanol, acetone, n-propanol,
ethanol, N,N-dimethylformamide and N,N-dimethylacetamide. Ethanol, acetone and n-propanol
altered the crystal habit of Pyrimethamine, without any modification of its crystal lattice. The different
habits exhibited clear differences in flowability and compressibility, which could in turn affect
manufacturing and therefore the quality of the finished pharmaceutical product (FPP). These habits
were subsequently extensively characterised by means of in-silico molecular modelling predictions.
It was found that recrystallisation from methanol, N,N-dimethylformamide and N,N-dimethylacetamide
had resulted in solvatomorphism. These solvatomorphs contained their respective solvents in
concentrations exceeding the allowed residual solvent limits, as set by the International Conference
on Harmonisation (ICH) guidelines. These undesirable solvatomorphs were also comprehensively
characterised as a service to the pharmaceutical industry, in order to identify the distinct
characteristics that distinguish these forms from the preferred non-toxic form, and to provide
techniques for transforming the toxic forms into the non-toxic form. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2015
| Identifer | oai:union.ndltd.org:NWUBOLOKA1/oai:dspace.nwu.ac.za:10394/15497 |
| Date | January 2014 |
| Creators | Perold, Zak |
| Source Sets | North-West University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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