Detection And Identification Of Photodegradation Products Of Flucytosine And Griseofulvin

Degradation products of drug substances can be responsible for unwanted side effects. Therefore the detection and identification of the degradation products of flucytosine and griseofulvin are of interest (Figure 13). Both are some of the few drug substances used for the systemic therapy of mycotic infections.

Flucytosine is orally or parenterally applied for generalised mycoses. 5-Fluorouracil is known as a toxic degradation product of flucytosine. Therefore pharmacopoeias like the Ph. Eur. 97 and the USP 23 demand for flucytosine the testing of the absence of 5-fluorouracil.

For griseofulvin, it has been known since 1960 that degradation products can cause toxic side effects. Nevertheless, until now, the structures of these photolytic degradation products are not clear nh2 0

O^NH

flucytosine-* photoproduct griseofluvin

5-fluorouracil

Figure 13 Chemical structure of flucytosine, its degradation product 5-fluorouracil and of griseofulvin

After 6 min of irradiation 80% of flucytosine was degraded in methanolic solution. After a longer irradiation of 16 h of an aqueous solution 5 degradation products were detected in the HPLC chromatogram. The chromatogram of a standard solution of 5-fluorouracil corresponds exactly with the peak of the photodegradation product W3 (retention time 4.18 min) (Figure 14).

Figure 15 Influence of the solvent on the photodegradation of griseofulvin (lOmg/lOOml, SuntestCPS, UVfilter).

Figure 15 Influence of the solvent on the photodegradation of griseofulvin (lOmg/lOOml, SuntestCPS, UVfilter).

time (min)

Photodegradation of flucytosine in methanoiic solution (10 mg/100 ml, Suntest CPS, UV-filter)

Degradation products of flucytosine in H2O (16 h, Suntest CPS, UV-filter) 2,98 min: W1 8,88 min: W6

6,28 min: flucytosine 13,08 min: W9

Figure 14 Photodegradation of flucytosine in methanoiic solution (10 mg/ loo ml, Suntest CPS, UV-filter) and detection of 5 photodegradation products of flucytosine after 16 h irradiation (aqueous solution 100 mg / ml, Suntest CPS, UV filter).

For griseofiilvin it was found that its photodegradation occurs faster in alcoholic solutions than in water. The photolysis of griseofiilvin in methanolic solution resulted in a degree of about 50% of the initial drug content after 1 h irradiation. After 3 h the residual drug content was below 10%. The decomposition in an ethanol solution was similar to that of a methanolic solution. In aqueous solution the drugs substance was significantly more photostable. After 1 h only 30% were destroyed, after 3 h the residual drug content still amounted to 25% (Figure 15).

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Figure 17 Mass spectra of irradiated griseofiilvin in ethanol solution: (lOOmg/100ml, 16h) (Suntest CPS, UVfilter)

A Total ion-chromatogram after 16 h irradiation B mass-spectrum of photoproduct E2 (RT 8.5 min) C mass-spectrum of photoproduct E3 (RT 12.0 min)

100 200 300

Figure 17 Mass spectra of irradiated griseofiilvin in ethanol solution: (lOOmg/100ml, 16h) (Suntest CPS, UVfilter)

A Total ion-chromatogram after 16 h irradiation B mass-spectrum of photoproduct E2 (RT 8.5 min) C mass-spectrum of photoproduct E3 (RT 12.0 min)

Because of this fact it was of interest as to whether the different degradation kinetics are caused by different degradation pathways.

It is conspicuous, that the number of degradation products in the methanolic solution is higher than in the other solutions (Figure 16).

By means of the HPLC-MS technique the photodegradation products after irradiation of an ethanol solution were partly identified. The MS spectrum of the degradation product El proves its identity as dechlorogriseofulvin. This spectrum is not shown here. Two of the photodegradation products are formed only by irradiation of griseofulvin in ethanol solution, because ethanol takes part in the photochemical reaction as a reaction partner. The MS spectra of these two degradation products are shown in Figure 17. E2 is the ethyl ester of griseofulvin, E3 the corresponding dechlorinated product.

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