| Summary: | Methods of recrystallisation from solution using various solvents as well as physical
vapour deposition (PVD) methods were employed in an attempt to create different
polymorphic forms of the anti-tuberculosis drug ethionamide.
Through recrystallisations a variety of products were obtained, though not a single
form proved to be a different polymorphic form. A single form obtained from N,Ndimethylformamide
(DMF) was proven to be a non-stoichiometric solvate through
thermogravimetric (TGA) and infrared (IR) analyses. This clathrate showed improved
water solubility in comparison with the raw material (RM), though the toxicological
attributes of the solvent makes the product pharmaceutically non-applicable.
The physical vapour deposition methods used led to the formation of at least one
novel polymorphic form, though the methods employed to isolate this form
demonstrated some less than ideal results. The influence of variation in temperature
and pressure proved to produce some varying patterns in the attributes of the
products formed and the methods used were shown to deliver reproducible results.
Thermal and diffraction analyses were utilised for the characterisation of the physicochemical
properties of the various forms obtained.
Tendencies of phase transitions occurring during the heating of the raw material,
observed through differential scanning calorimetry (DSC), were explored and this
method was used to identify possible phase transitions and the conditions needed to
manipulate the sample into going through these transitions. Thermal microscopy
(TM) in combination with polarised light microscopy was used to visualise the
occurrences observed in the DSC traces. Sublimation of the RM and subsequent
recrystallisation was observed and various methods were employed to manipulate
this process.
The DSC traces of the various forms were investigated and compared to results
obtained from the TM and crossed polarisers combination. The influences of the
variable conditions used to create the various vapour deposition products were
studied and patterns in properties altered by these variations, such as melting point,
were identified. Variable temperature X-ray diffractometry (VTXRD) was used to
verify whether the conclusions made were consequential of the alteration of the molecular coordination found within the crystals. These results were not decisive, as
the variation in heating rates used made comparison of the events seen in the DSC
traces impossible. This is because the heating rates used proved to have an effect
on the kinetics of the phase transitions occurring with these crystal structures.
Another aspect thought to affect the results obtained through powder X-ray
diffractometry (XRPD) and VTXRD was that the samples were milled in preparation
for this method. The effect of milling on a specific form obtained was shown to alter
the properties of this form in a way that indicated possible phase transitions induced
by this method. Comprehensive characterisation of the molecular coordinations of
the various forms obtained through the PVD methods was not achievable since
these methods and the small crystal sizes rendered single crystal X-ray
diffractometry (SCXRD) impossible.
The hypothesis was made that the various forms obtained were either different ratios
of two polymorphic forms; each having a unique internal molecular packing
arrangement or a mixture of various ratios of more than two separate polymorphic
forms.
A presumed more stable form (i.e. a form having a higher melting point) was
obtained on separate occasions. Isolation of this form was not accomplished, though
not proven to be unattainable. Through optimisation of experimental conditions, it
should be possible to prepare and isolate this solid-state form. === Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013
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