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

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