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IntroductionDithranol, also known as anthralin, is an anthrachi-none derivative which is used in the treatment of pso-riasis [1-3]. Topical application for 24 hours of dithra-nol in fatty bases has led to irritation on the non-affected skin. This irritation can be diminished byshortening the dithranol contact time without loss ofclinical efficacy. With the short-contact therapy oil-in-water creams became more popular because they caneasily be washed off after use. In our day-care centrepatients with psoriasis receive short-contact therapywith dithranol containing creams in increasing con-centrations, starting as low as 0.1% dithranol [4].

The stability of dithranol, especially in an aqueousenvironment, is poor. It easily decomposes into dan-throne and various dimers, which are ineffective [5 6].Therefore, oil-in-water creams usually contain stabilis-ers such as ascorbic acid and salicylic acid. Specialcare is needed during preparation of dithranol con-taining creams to prevent degradation by water, oxy-gen, high temperature and metal. Stability data oncreams have been published by Ros and Van der Meer[5], but concentrations lower than 0.5% were notinvestigated.

Since in our day-care centre lower concentrationsare applied, and since the stability of dithranol dimin-ishes with decreasing concentrations [7], we evaluat-ed the stability of dithranol in creams with 0.1, 0.3and 0.5% dithranol under various storage conditions.

Methods

Preparation of creamsDithranol, cetiol V, cetomacrogol wax, liquid paraffin,salicylic acid, sorbic acid and ascorbic acid were 275

PHAR 220 pips 246013

Stability of dithranol in creams• E .W. Wuis , D.M. Burger, M. Bee len and Y.A. Hekster

Pharm World Sci 1999;21(6): 275-277.© 1999 Kluwer Academic Publishers. Printed in the Netherlands.

E.W. Wuis (correspondence), D.M. Burger, M. Beelen andY.A. Hekster: 533 Department of Clinical Pharmacy,University Hospital Nijmegen St Radboud, P.O. Box 9101,6500 HB Nijmegen, the Netherlands

KeywordsAnthralinDithranolDrug stabilityShelf life

AbstractThe stability of the anthrachinone derivative dithranol increams was studied during storage at temperatures of 4°Cand 20°C. Aluminum-coated tubes with 0.1, 0.3 and 0.5%dithranol were stored and samples were analysedimmediately and after 3, 6 and 12 months of storage. The 0.3% dithranol cream was also stored in polypropylenetubes. Drug concentration was analysed by high-performance liquid chromatography. All concentrationstested were stable for 12 months of storage at 4°C inaluminum-coated tubes. This means that these lowconcentrations are sufficiently stable to be prepared inadvance for at least 12 months if prepared as described andkept refrigerated. Polypropylene tubes should not be used.

Accepted September 1999

obtained from Genfarma (Maarssen, theNetherlands). Aluminum tubes coated with epoxy-phenol and polypropylene tubes were obtained fromBlokland Pack (IJsselstein, The Netherlands).

The formulations of the creams we used weredesigned by Ros and Van der Meer [5] and are givenin Table 1. Preparation was as follows: cetiol V, ceto-macrogol wax and liquid paraffin were brought to atemperature of 70°C. Sorbic acid was dissolved inboiling distilled water; then ascorbic acid was addedand cooled down to 70°C; this solution was thenpoured in a weighed, pre-heated plastic mortar andsalicylic acid was added. Dithranol was added to thefat phase (50-70°C) and stirred with a high speed(Ultra Turrax) mixer until completely dissolved. Thewater phase (60-70°C) was added to the fat phaseand mixed shortly with the high speed mixer to pre-vent inclusion of air. Then the cream was mixed man-ually until cool, after which evaporated water wassubstituted. Immediately thereafter the cream waspacked in aluminum-coated tubes, avoiding theinclusion of air.The 0.3% dithranol cream was also prepared in poly-propylene tubes.

Drug stability during storageThe three different concentrations were studied induplicate at two temperatures: room temperature(20°C) and 4°C. Sampling times were immediately(t=0) and after 3, 6 and 12 months of storage. Foreach analysis a new tube was used to avoid any influ-ence of handling on the stability of dithranol. Theinfluence of opening and closing of the tube was test-ed separately by re-analysing all creams, which hadbeen opened at t=0, 1 month later.

HPLC analysis and validationThe concentration of dithranol was measured bystraight-phase high-performance liquid chromatogra-phy (HPLC) after an extraction procedure asdescribed in the British Pharmacopoeia [8].

An aliquot of the cream (containing 5mg of dithra-nol) was first extracted with 20ml of dichloromethaneand 5ml of demineralized water. The dichlorome-thane layer was quantitatively transferred to a 100mlvolumetric flask. The residue was then three timesextracted with 20ml of hexane. To the combinedextracts 1ml of glacial acetic acid was added and250microliter of a solution of nitro-aniline in metha-nol as the external standard (1g/10ml) and then filledup to volume with hexane (100.0ml). The solutionwas dried with anhydrous magnesium sulphate.

A 4.6x150mm Lichrosorb Si-60-5L column(Chrompack Nederland BV, Bergen op Zoom, theNetherlands) was used at ambient temperature. Themobile phase consisted of hexane-dichloromethane-glacial acetic acid: 82-5-1. The system was equippedwith a pump (Model P1000, Thermo SeparationsProducts, Breda, the Netherlands), an autosamplerequipped with a 20microliter loop (Model AS100,Thermo Separations Products), a variable wavelength

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ultraviolet (UV) detector (Model UV 1000, ThermoSeparations Products), and an integrator (ModelChromjet 4400, Thermo Separation Products). Theflow through the column was kept at 2.0ml/min, andeffluent was monitored at a wavelength of 354nm.For quantitation, the peak area relative to that of theexternal standard was determined. An one point cali-bration was used. As standard solution 5.0mg of dith-ranol dissolved in mobile phase was used.

The accuracy of the assay was assessed in duplicatefor two concentrations (0.1 and 0.5%) by measuringthe recovery from a placebo cream to which an exactamount of dithranol had been added.

The intraday precision of the assay was assessed bymeasuring six replicate samples of each concentration(creams 0.1, 0.3, and 0.5%); the interday precisionby measuring two concentrations (0.1 and 0.3%) induplicate on six separate occasions.

Results and discussionThe accuracy of the HPLC assay for dithranol creamwas 96.8 ± 0.4% and 97.1 ± 0.2% for 0.1% and 0.5%dithranol added to cream, respectively. The intradayprecision of the assay was 0.5%, 0.6% and 0.6%, for0.1%, 0.3% and 0.5% dithranol cream, respectively;the interday precision was 3.4% and 4.7% for 0.1 and0.3% dithranol cream, respectively.

The stability of the creams upon storage is given inTable 2. In Table 3 the influence of opening the tubeon the stability is shown. The found interday precisioncan explain a dithranol content of less than 100%directly after preparation at zero time (Table 2), aswell as a content in excess of 100% one month afteropening (Table 3).

All creams with dithranol prepared as describedunder Methods and packed in aluminum-coatedtubes were sufficiently stable for 12 months whenkept refrigerated (Table 2). The dithranol content of

Table 1 Formulations of 0.1, 0.3 and 0.5% dithranol creams according to [5]

0.1% 0.3% 0.5%

dithranol 3.00 9.00 15.0 gcetiol V 603 609 615 gcetomacrogol wax 450 450 450 gliquid paraffin 450 450 450 gsalicylic acid (pulv <90) 30.0 30.0 30.0 gsorbic acid 4.50 4.50 4.50 gascorbic acid 1.50 1.50 1.50 gwater, distilled up to 3000 3000 3000 g

Table 2 Stability of dithranol in creams in aluminum-coated and polypropylene tubes under various storageconditions

Storage time Storage Dithranol content (mean ± CV)temp.

cream 0.1% cream 0.3% cream 0.3%* cream 0.5%

0 months 20°C 94.7 ± 4.1% 94.2 ±1.6% 97.7% 92.8 ±2.1%3 months 20°C 84.1 ± 3.8% 87.0 ±1.3% 70.3% 87.7 ±0.9%6 months 20°C 39.6 ±14.6% 86.5 ±0.4% 49.0% 82.4 ±0.9%12 months 20°C 45.4 ±2.2% 90.9 ±0.3% 23.0% 85.0 ±6.6%

0 months 4°C 93.4 ±0.6% 95.9 ±1.3% 96.7% 94.0 ±0.8%3 months 4°C 89.6 ±3.1% 90.5 ±0.6% 88.9% 96.8 ±2.2%6 months 4°C 87.5 ±0.0% 90.8 ±0.0% 86.7% 97.4 ±0.7%12 months 4°C 89.5 ±0.3% 90.6 ±1.9% 68.4% 98.4 ±2.1%

*packing material polypropylene tube, n=1

Table 3 Stability of dithranol in creams in aluminum-coated and polypropylene tubes 1 month after opening

Storage temp. % Initial dithranol content remaining*

cream 0.1% cream 0.3% cream 0.3%** cream 0.5%

20°C 94.6% 101.3% 91.6% 105.6%4°C 97.2% 100.7% 100.2% 105.3%

* the content of drug in samples at time zero was designated as 100%**packing material polypropylene tube

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all three concentrations at all times tested remainedabove 85%, the lower limit of acceptance of theBritish Pharmacopoeia [8]. Ros and van der Meer [5]have shown dithranol in creams to be stable at roomtemperature for 12 months at concentrations of 0.5%and higher. Our data show that 0.3% was also stableat room temperature for 1 year; creams with 0.1%have a much shorter storage time at room tempera-ture (Table 2). In polypropylene tubes dithranoldeclined much faster, therefore these tubes are notrecommended as packing material. Possible explana-tions for this fast degradation are the presence of anti-static components which could promote this process,and the transmission of light and air by syntheticmaterial [7]. This was not further investigated.

Dithranol was stable for 1 month after the tubeshad been opened. The influence of daily opening thetubes remains to be investigated. This influence wassubstantial in dithranol creams of slightly differentcomposition, i.e. 10% degradation within 3 weeks [7].

All stability data can only be used to justify thegiven storage when preparation is exactly asdescribed. Preparation time should be kept as short aspossible to avoid degradation by air, light and elevat-ed temperature [5]. Also, the use of metal utensilsshould be avoided.

In conclusion, dithranol creams with concentra-tions as low as 0.1% can be stored up to 12 monthsat 4°C when packed in aluminum-coated tubes.Special care must be taken when preparing thesecreams.

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AcknowledgementA. van Mameren is thanked for preparing the differentcream batches.

References1 de Vet AAMW, Pennings BJH, van de Kerkhof PCM.

Behandeling van psoriasis met ditranol (Treatment of psoria-sis with dithranol). Ned Tijdschr Geneesk 1992;136:214-7.

2 Lantinga H, Ek JW, Nijman FC, Antonietti-Barels IH, Nijssen JP,Bos D et al. NHG-standaard psoriasis (Dutch PhysiciansStandard psoriasis). Huisarts Wetensch 1994;37:111-9.

3 Peterse MTM. NHG-standaard “Psoriasis” (Dutch PhysiciansStandard “Psoriasis”). Pharm Weekbl 1994;129:726-9.

4 Prins M, Bouwhuis S, de Gast MJ, van der Valk PGM. Klinischeervaringen met ditranolcrème in twee formuleringen(Clinical experience with dithranol creams in two formulas).Pharm Weekbl 1998;133;1508-11.

5 Ros JJW, van der Meer YG. Preparation, analysis and stabilityof oil-in-water dreams containing dithranol. Eur J HospPharm 1991;1:77-84.

6 Ros JJW, Boer Y. Bereiding van ditranolbevattende preparaten(Preparation of dithranol containing compounds). PharmWeekbl 1998; 133:1504-7.

7 Anonymous. Ditranolcrème (Dithranol cream). FormulariumNederlandse Apothekers (Formulary Dutch Pharmacists),Koninklijke Nederlandse Maatschappij ter bevordering derPharmacie (Royal Society of Dutch Pharmacists), The Hague,1999.

8 Anonymous. British Pharmacopoeia, London, 1993:888.

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