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Stability of Antimalarial Preparations. Rutendo Kuwana. Accra, December 2009. PQ: Artemisin-derivative issues. No innovator FPP registered in the ICH region. Therefore No comparator available for: Pharmaceutical equivalence studies Bioequivalence studies

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Stability of Antimalarial Preparations

Rutendo Kuwana

Accra, December 2009

pq artemisin derivative issues
PQ: Artemisin-derivative issues
  • No innovator FPP registered in the ICH region. Therefore No comparator available for:
    • Pharmaceutical equivalence studies
    • Bioequivalence studies
  • The APIs and FPPs not official in the internationally used major pharmacopoeias
  • WHO guides/SOPs apply to multisource FPPs.

ICH guides therefore used

expression of interest oral dosage forms
Expression of Interest – oral dosage forms
  • Artesunate*+ Amodiaquine
  • Artemether*+Lumefantrine*
  • Artesunate*+ Mefloquine
  • Artesunate*+ SP (sulphadoxine / pyrimethamine)
  • Dihydroartemisin+Piperaquine Phosphate*

*No comparator at the beginning *High quality-risk API

+ ... FDC or co-blistered (co-packaged) FPPs

* No comparator to date

eoi other dosage forms
EOI – other dosage forms
  • Artemether Injection and rectal FPPs
  • Artemotil (arteether) Injection
  • Artesunate Injection and rectal FPPs

Only FPPs listed in the EOI will be discussed.

availability of monographs for drug substances international pharmacopoeia
Availability of monographs for drug substances - International Pharmacopoeia
  • Artemether
  • Artemisinin
  • Artemotil
  • Artenimol
  • Artesunate
  • Mefloquine Hydrochloride
  • Proguanil Hydrochloride – Also in BP
  • Amodiaquine and Amodiaquine Hydrochloride – Also in USP
international quality standards
International quality standards
  • Lumefantrine
  • Pyrimethamine BP, PhEur, PhInt, USP
  • Sulphadoxine BP, PhEur, PhInt, USP
  • Piperaquine
  • Dihydroartemisinin
other antimalarial api
Other Antimalarial API
  • APIs described in monographs of major international pharmacopoeias ( 10 years)
    • Chloroquine, Dapsone, Quinine, Mefloquine, Trimethoprim
  • APIs not described in monographs of major international pharmacopoeias
    • Chlorproguanil,, Naphthoquine, Pyronaridine
properties of artemisinin derivatives
Properties of Artemisinin derivatives
















  • Artemisinin(C15H22O5)
    • 7 centres of asymmetry
    • 27 potential isomers
    • One isomer in biosynthesis
    • Chemical synthesis
      • Feasible
      • Economically unacceptable
  • Chemical derivatization at C-10 (carbonyl-moiety)converts C-10 into an additional stereoisomeric center:
      • a- and b-isomers are formed

Active antimalarial constituent of the traditional Chinese medicinal herb Artemisia annua L., Compositae

Although Artemisinin has seven (7) centers of assymetry Artemisia annua makes only one configuration

Practically insoluble in water

The bond energy of the O-O bond is ~30 kcal/mol

When the peroxide comes into contact with high iron concentrations, the molecule becomes unstable and "explodes" into free radicals.

The API, the capsules and the tablets are official in the Ph. Int. Not included in the current EOI.


Very slightly soluble in water

The ester linkage is inalpha configuration.

Both the API and the tablets are official in the Ph. Int.

Two functional groups are liable to decomposition

mefloquine hydrochloride
Mefloquine hydrochloride

Has an optically active carbon

Very slightly soluble in water

Has no reactive functional groups under general environmental conditions

pharmaceutical information
Pharmaceutical information
  • Artemisinin derivatives may have α- or β-configurationand each of them can exist in two conformations. The literature does not reveal any impact of the geometric isomerism on efficacy, safety or quality of artemisinins.
  • The internal peroxide bound is the most reactive part of the molecule. When the peroxide comes into contact with high iron concentrations, the molecule becomes unstable and "explodes" into free radicals.
  • The ester bond of artesunate is liable to hydrolysis.
  • The non-artemisinin APIs in the EoI are chemically stable.
potential impurities of artemisinins
Potential impurities of Artemisinins
  • Starting material (extracted from herbal sources)

Starting materials from vegetable origin should be fully characterized and a contaminant profile should be established

potential impurities of artemisinins ii
Potential impurities of Artemisinins II
  • Impurities contained in the "starting material" Artemisinin
    • Biosynthetic by-products
      • Arteannuin B , Artemisitene, Artemisinic acid,
        • Extraction from fresh leaves with CHCl3
      • Thujone (?)
    • Cultivation reagents
      • Pesticide residues, fumigants, mycotoxins
    • Solvents from the extraction process
      • Hexane, benzene, acetonitril, ether, pentane, chloroforme…..(?) diesel, fuel (?) [ICH Q3A (R)]
potential impurities of artemisinins iii
Potential impurities of Artemisinins III
  • Unreacted starting material
    • Artemisinin (starting material for derivatives)
    • Artemisinic acid (starting material for dihydroartemisinin)
    • Dihydroartemisinin (starting material for derivatives)
    • ….
  • Unreacted intermediates, by-products
    • a-Arthemether, a-Artheether
    • a/b-Dihydroartemisinin
    • b-Artesunate
potential impurities of artemisinins iv
Potential impurities of Artemisinins IV
  • Reagents, catalysts, residual solvents
    • Methanol, acetonitril, chloroforme, acetone …
    • NaBH4, succinic acid/anhydride, triethylamine, dimethylaminopyridine
  • Degradants
    • Stability of
      • ester-derivative (Artesunate)
      • ether-derivative (Artemether, Arteether)
      • lactone (Artemisinin)
    • Stability of artenimol (oxidation)
    • Susceptibility of endoperoxide bond to reduction
      • Deoxyartemisinine (loss of active principle)
c ompatibility of the api with excipients and diluents
Compatibility of the API with excipients and diluents
  • Select innovator excipients (WHOPAR, EPAR)
  • Magnesium stearate is incompatible with salts of weak bases and strong acids (e.g. Amodiaquine.2HCl) because the formed MgCl2 is highly hygroscopic and, as a result, its lubricant properties also change.
  • The compatibility and in-use stabilityof the FPP with reconstitution diluentsshould be addressed, e.g. in Artesunate injection.
increase in concentration of api
Increase in concentration of API

During some stability studies of Artesunate, the assay results were increasing. The hydrolysis may yield artenimol and succinic acid. The latter can justify the increase in assay. The assay method may be considered to be"stability indicating” but not specific.


stress testing
Stress Testing
  • Artesunate
  • The drug substance degrades readily at heat conditions in extreme of 100ºC, it is also unstable under light conditions and both acid and base conditions by hydrolysis. The α-epimer of dihydroartemesinin is the major degradant under light conditions.
  • α-Artemether is the major degradant under heat conditions in extreme of 100ºC although both the α and ß epimers of dihydroartemesinin are also significant degradants under this condition.