Objective: Stavudine is a nucleoside reverse transcriptase inhibitor (NRTI) that is used in
the treatment of human immunodeficiency virus (HIV) infections. Stavudine exhibits
polymorphism and various polymorphic forms of stavudine are described in the literature,
however the available information on these solid states, at the start and during this study,
was limited. This study was conducted in order to (1) generate supplementary and/or
possibly new information on the physicochemical properties of the various polymorphs of
stavudine, (2) to possibly prepare and characterise a new polymorphic form of stavudine, (3)
to determine and compare the dissolution behaviour of the stavudine polymorphs and (4) to
investigate the possibility of applying analytical techniques to quantify the stavudine
polymorphs in solid state mixtures.
Methods: Various characterisation methods were used to determine the physicochemical
properties of the polymorphic forms of stavudine, including X-ray powder diffraction (XRPD);
variable temperature X-ray powder diffraction (VT-XRPD); diffuse reflectance infrared Fourier
transform spectroscopy (DRIFTS); differential scanning calorimetry (DSC); thermogravimetric
analysis (TGA); polarising optical microscopy; hot-stage microscopy (HSM); scanning
electron microscopy (SEM); as well as Karl Fischer (KF) analysis. The dissolution behaviour
of the various polymorphic forms of stavudine, that were prepared during this study, was also
determined, whilst quantitative XRPD and DRIFTS methods were developed for the
quantitative study.
Results: Polymorphic form I and form II of stavudine were prepared by recrystallisation of
stavudine raw material from various solvents, whereas form Ill (hydrate) and the N-methyl-2-pyrrolidone (NMP) solvate of stavudine were recrystallised from water and NMP respectively.
The results generated from the VT-XRPD analyses of form I and form II demonstrated that
these solid states are monotropically related (supportive of the findings of Mirmehrabi et al.
(2006:141)), and that form I and II do not interconvert to one another. The hydrate of
stavudine was not observed to convert to polymorphic form I upon heating, as was
determined by Gandhi et al. (2000:228). However, VT-XRPD analysis of form Ill and the
NMP solvate showed that upon heating, both these pseudopolymorphs interconvert to form a
polymorphic mixture consisting of form I and II. A glassy (amorphous) form of stavudine that
was previously not described in the available literature was also prepared and characterised
during this study.
Dissolution testing of polymorphic form I, form II, the glassy (amorphous) stavudine and the
form 1/11 mixture of stavudine revealed that a greater amount of the glassy stavudine
dissolved within one minute compared to the other polymorphic forms. A comparison of the
dissolution profiles, based on the requirements of the Medicines Control Council of South
Africa, indicated that the profiles of form I and form II, form I and the glassy stavudine, and
form I and the form 1/11 mixture are similar.
Two different methods (based on the analytical techniques of XRPD and DRIFTS) were
developed to quantify the amount of form I and form II of stavudine in solid state mixtures.
Each method was validated, and the results indicated that the quantitative DRIFTS method
showed the greatest agreement between the experimental and theoretical polymorphic
content. Preferred orientation was assumed to be the reason for the deviation of the
quantitative XRPD results, and it was suggested that this might be corrected by background
subtraction, Ka2 stripping and smoothing of the X-ray diffraction peaks. A test sample with an
unknown concentration was analysed using both methods, and the comparison between the
XRPD and DRIFTS results revealed that the DRIFTS method might be more accurate when
compared with the XRPD method.
Conclusion: Stavudine exhibits polymorphism and this study confirmed that the
physicochemical properties of the various polymorphs differ. A glassy (amorphous) form of
stavudine was, according to available literature, prepared and characterised for the first time
during this study. Two methods for quantifying the amount of form I and form II of stavudine
in mixtures comprising these two polymorphs were successfully developed and tested. The
DRIFTS method may have generated the more accurate results, since it shows the best
correlation between the experimental and theoretical results. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/1548 |
| Date | January 2007 |
| Creators | Strydom, Schalk Johannes |
| Publisher | North-West University |
| Source Sets | South African National ETD Portal |
| Detected Language | English |
| Type | Thesis |
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