Stability of Antimalarial Preparations

Rutendo Kuwana

Accra, December 2009

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PQ: Artemisin-derivative issuesPQ: 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 formsExpression of Interest – oral dosage forms

Artesunate* + AmodiaquineArtemether* + Lumefantrine*Artesunate* + MefloquineArtesunate* + 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 formsEOI – other dosage forms

Artemether Injection and rectal FPPsArtemotil (arteether) InjectionArtesunate 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

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 standardsInternational quality standards

Lumefantrine Pyrimethamine BP, PhEur, PhInt, USP Sulphadoxine BP, PhEur, PhInt, USP Piperaquine Dihydroartemisinin

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Other Antimalarial APIOther 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 derivativesProperties 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:

• - and -isomers are formed

1

2

34

5

65a

8a7

8

910

1112

12a

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ArtemisininArtemisinin

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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ArtesunateArtesunate

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 ArtesunateMetabolism of Artemether and Artesunate

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Mefloquine hydrochlorideMefloquine 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 informationPharmaceutical 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 ArtemisininsPotential 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 IIPotential 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 IIIPotential 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– -Arthemether, -Artheether– /-Dihydroartemisinin – -Artesunate

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Potential impurities of Artemisinins IVPotential 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 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 APIIncrease 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 TestingStress 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.