Transcript Stability of Antimalarial Preparations

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
 The APIs and FPPs not official in the internationally used major
pharmacopoeias
 WHO guides/SOPs apply to multisource FPPs.
ICH guides therefore used
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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
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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.
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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
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International quality standards





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Lumefantrine
Pyrimethamine BP, PhEur, PhInt, USP
Sulphadoxine BP, PhEur, PhInt, USP
Piperaquine
Dihydroartemisinin
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
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Properties of Artemisinin derivatives
 Artemisinin (C15H22O5)
– 7 centres of asymmetry
– 27 potential isomers
– One isomer in biosynthesis
– Chemical synthesis
• Feasible
• Economically unacceptable
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9
7
8a
12a
6
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11
12
5a
5
 Chemical derivatization at
C-10 (carbonyl-moiety) converts C-10 into
an additional stereoisomeric center:
• a- and b-isomers are formed
10
1
4
2
3
Artemisinin
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.
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Artesunate
 Very slightly soluble in water
 The ester linkage is in alpha
configuration.
 Both the API and the tablets
are official in the Ph. Int.
 Two functional groups are
liable to decomposition
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Metabolism of Artemether and Artesunate
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Mefloquine hydrochloride
 Has an optically active carbon
 Very slightly soluble in water
 Has no reactive functional
groups under general
environmental conditions
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Pharmaceutical information
 Artemisinin derivatives may have α- or β-configuration and 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.
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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
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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)]
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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
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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)
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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 stability of the FPP with
reconstitution diluents should be addressed, e.g. in
Artesunate injection.
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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.
+
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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.
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