| Summary: | Malaria has been responsible for the deaths of thousands of people annually and is
considered one of the biggest health challenges globally. In order to ensure that
patients in malaria affected areas receive products of suitable quality, it is important
that effective pharmacopoeial monographs for these medicines are available for
distinguishing between good and inferior quality products, prior to distribution to the
public.
With artemether and lumefantrine forming part of the current, most effective treatment
regimes against malaria, the development of monographs for the lumefantrine active
pharmaceutical ingredient (API) (a monograph already exists for the artemether API)
and for artemether/lumefantrine combination dosage forms, has become a high priority
to the World Health Organization (WHO) for inclusion in the International
Pharmacopoeia (Ph.Int.).
During this study, both APIs were also evaluated for the possible occurrence of
polymorphism, in order to provide manufacturers with additional information regarding
identified polymorphic forms.
During the polymorphic screening of artemether, the physico-chemical properties of the
different recrystallisation products demonstrated results similar to those of the raw
materials tested. Although the polymorphic screening of lumefantrine revealed no new
polymorphic forms, it was found that the X-ray powder diffraction (XRPD) patterns were
influenced by preferred orientation and that the variation in melting points obtained,
correlated well with differences observed in particle size and/or morphology. It
therefore illustrated the importance for manufacturers of lumefantrine to consider the
possibility of the melting point being influenced by crystal habit and particle size, and
would it be advisable not to characterise and identify lumefantrine, based on the
melting point alone.
The physico-chemical analytical results obtained during the polymorphic screening of
artemether and lumefantrine furthermore revealed that only one crystal packing for
each API exists.
Methods for the two new monographs were developed in accordance with WHO
requirements and were validated compliant with the International Conference on
Harmonisation (ICH) guidelines on the validation of methods.
The methods developed for lumefantrine during this study, included the following: The
chosen identification tests comprised a standalone infrared method, or as an alternative a combination of ultraviolet spectrophotometry (UV-VIS) and thin layer
chromatography (TLC) methods. The standard pharmacopoeial methods for heavy
metals, sulfated ash (residue on ignition) and loss on drying were proposed. For the
determination of the related substances (impurities from synthesis and degradation
products), a high performance liquid chromatography (HPLC) method and a newly
developed TLC method were included, with the monograph allowing a choice.
Furthermore, a titration with perchloric acid was decided upon for the assay of the
lumefantrine API. An alternative UV spectrophotometric assay method (not included in
the Ph.Int. monograph) was developed using a UV spectrophotometric method where
the A1%/1cm value in methanol was established as 331.4.
For the monographs of artemether/lumefantrine tablets and powder for oral suspension
two identification tests were developed for use in combination, namely TLC and HPLC
methods.
A TLC limit test was developed for the related substances of artemether, which proved
to be less stable than lumefantrine. The developed method made the simultaneous
assaying of artemether and lumefantrine, using HPLC, possible.
The proud outcome of this research project was the adoption of the final proposed
monographs for the lumefantrine API and artemether/lumefantrine combination dosage
forms, during the 42nd meeting of the WHO’s Expert Committee on Specifications for
Pharmaceutical Preparations (July 2008, Geneva), for inclusion in the Ph.Int.
The methods for identification, assay and related substances of the
artemether/lumefantrine tablets monograph were verified by an independent
surveillance study, during which the results demonstrated that the methods were easily
transferable between quality control (QC) laboratories. During this study, the proposed
monograph was used to test 108 batches of artemether/lumefantrine tablets, sourced
by the WHO. The generated results were able to identify batches of substandard
quality and thus proved the monograph methods to be suitable for distinguishing
between suitable or inferior quality, and even counterfeit batches.
The conclusion that could be drawn from the outcomes of this study was that the use of
the methods in these monographs during quality control testing, should indeed result in
a reduction in substandard and/or counterfeit products being distributed to the public,
thus in reducing the number of malaria related deaths and the escalating occurrence of
resistance against antimalarial treatment regimes. === Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011
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