Drug Development
`
`and Industrial Pharmacy, 26(4), 451-453
`
`(2000)
`
`COMMUNICATION
`
`Diclofenac Sodium: Oxidative
`Degradation in Solution and Solid State
`
`Reynir Eyjolfsson
`
`Eyrarhoit 6, IS-220 Hafnarfjordur,
`
`Iceland
`
`ABSTRACT
`
`of two oxidative degradates of diclofenac in solution and the solid
`The formation
`state was demonstrated.
`Key Words: Diclofenac sodium; Stability; Tablets.
`
`INTRODUCTION
`
`MA TERIALS AND METHODS
`
`Although diclofenac (Fig. 1), mainly as sodium salt,
`has been used extensively and for a long time as a nonste-
`roidal anti-inflammatory
`drug (NSAlD),
`information on
`its stability is scarce. Two decades ago, the cyclization
`of diclofenac to an indolinone derivative (a lactam) (Fig.
`1) in acidic aqueous solutions was reported (1). Most of
`the experiments were carried out in 0.005-0.5 M hydro-
`chloric acid at 60°C. In 1993, it was shown that this de-
`gradate could only be detected in diclofenac tablets that
`had been stored at severe conditions (90°C/550/0 relative
`humidity [RH]) for 20 days, but not in samples kept at
`40°C/500/0 RH for 28 days or in commercial
`tablets (2).
`Recently, a paper was published stating the occurrence
`of two hydrolytic cleavage products of the indolinone de-
`rivative (i.e., oxindole and 2,6-dichlorophenol)
`(Fig. 1),
`in semiliquid formulations
`(gel ointments) of diclofenac
`that had been exposed to a high temperature (65°C) for
`prolonged periods of time (3).
`This communication
`presents evidence for an oxida-
`tive degradation of diclofenac in solution and the solid
`state that resulted in the formation of two degradates.
`
`raw materials used for tablet preparation were
`All
`pharmacopeial
`(EP) quality, and all other materials were
`analytical grade. Granulation was carried out
`in an in-
`tensive mixer
`(Gral-25, Collette, Belgium), and tablet
`compression was in a rotary tableting machine (Manesty
`B3B, Manesty, UK). High-performance
`liquid chroma-
`tography (HPLC) analyses were performed according to
`the method described in the BP (mobile phase of phos-
`phate buffer pH 2.5/methanol, 34/66, v/v) (4).
`
`EXPERIMENTAL
`Preparation of Tablets and Stability Trial
`
`Diclofenac tablets, batch size 5.4 kg, were prepared
`by wet granulation,
`followed by drying, sizing, mixing
`with magnesium stearate and talc, and compaction to a
`target
`tablet mass of 270 mg and a strength of 75 mg
`(diclofenac sodium). The main excipients were hydroxy-
`propyl methylcellulose
`(HPMC),
`lactose, microcrystal-
`line cellulose, and povidone. The tablets (Tl) were pack-
`
`Copyright © 2000 by Marcel Dekker,
`
`Inc.
`
`www.dekker.com
`
`451
`
`IPR2015-01099 IPR2015-01097
`IPR2015-01100 IPR2015-01105
`
`Lupin EX1170
`Page 1
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`

`
`452OCCOOH W
`
`LP NH
`
`D N
`
`CIOCI
`
`CIOCI
`
`0 Coo
`
`H
`
`OH
`
`CIOCI
`
`Oiclofenac
`
`Indolinone derivative
`
`Oxindole
`
`2,6-dichlorophenol
`
`Structure of diclofenae and its known decomposi-
`Figure 1.
`tion products,
`
`[polyvinylidene
`(AIIPVdC
`aluminum/PVdC
`into
`aged
`blisters,
`and a stability
`trial at 40eC/75% RH
`chloride])
`was conducted
`for 3 months.
`
`Eyjolfsson
`
`Hydrolytic Trials with Excipients
`
`sample H4
`trials with excipients,
`the hydrolytic
`For
`was diclofenac-Na
`100 mg, 100 mg HPMC, AND 1.0 ml
`at 40eC for 24 hr, cooled
`water, which was heated
`to
`room temperature,
`and analyzed
`by HPLC. For sample
`H5, diclofenac-Na
`100 mg, 100 mg lactose,
`and 1.0 ml
`at 40eC for 24 hr, cooled
`water were heated
`to room
`temperature,
`and analyzed
`by HPLC.
`For
`sample H6,
`diclofenac-Na
`100 mg, 100 mg povidone,
`and 1.0 m! wa-
`at 40eC for 24 hr, cooled
`ter were heated
`to room tem-
`perature,
`and analyzed
`by HPLC.
`
`Hydrolytic Trials Without Excipients
`
`Oxidative Trials
`
`sample HI
`excipients,
`trials without
`For hydrolytic
`45 mg plus 30 ml 0.33 M hydrochloric
`was diclofenac-Na
`to
`acid, which was heated
`at 100ec
`for 60 min, cooled
`room temperature,
`and analyzed
`by HPLC. For
`sample
`H2, diclofenac-Na
`45 mg plus 30 m! 0.33 M sodium hy-
`droxide were heated at 100ec
`for 60 min, cooled to room
`temperature,
`and analyzed
`by HPLC.
`For
`sample H3,
`diclofenac-Na
`100 mg, 1.0 ml water,
`and 0.1 M sodium
`hydroxide
`to pH 10 were heated
`at 100ec
`for 30 min,
`cooled
`to room temperature,
`and analyzed
`by HPLC.
`
`sample 01 was diclofenac-Na
`trials,
`For the oxidative
`0.2 mg, 2 mg ferric chloride
`and 10 ml
`(FeCI), 6 H20),
`0.002 M hydrochloric
`acid, which was heated
`at 100ec
`for 25 min, cooled to room temperature,
`and analyzed
`by
`HPLC. For sample 02, diclofenac-Na
`7.5 mg plus 10 ml
`mobile
`phase were
`stored in a lOO-m! volumetric
`flask
`at room temperature
`in white
`light
`for 7 days
`and ana-
`lyzed by HPLC. For sample
`03, diclofenac-Na
`7.5 mg,
`10 mg sodium metabisulfite
`( Ta~S205)' and 10 ml mo-
`bile phase were
`stored
`in a IOD-ml volumetric
`flask at
`
`Table 1
`
`Indolinone Derivative, and Oxindole in
`Degradative Experiments with Diclofenac Sodium,
`Solution and Solid State
`
`Sample
`
`Temperature
`(0C)
`
`Time
`
`Results (HPLC)
`
`Tl Tablets in AI/PVdC blisters
`
`40175% RH
`
`3 months
`
`HI Die-Na + 0.33 M HCHI
`H2 Die-Na + 0.33 M NaOH
`H3 Dic-Na + H20, pH 10
`H4 Dic-Na + HPMC + H2O
`H5 Dic-Na + lactose + H2O
`H6 Dic-Na + povidone + H2O
`01 Die-Na + FeCI), pH 2.6
`
`a + mobile phase +
`02 Dic-
`air + light
`03 Dic-Na + mobile phase +
`aZS20l + air + light
`04 Indolinone derivative + mo-
`bile phase + air + light
`05 Oxindole + mobile phase +
`air + light
`
`100
`100
`100
`40
`40
`40
`100
`
`RT
`
`RT
`
`RT
`
`RT
`
`Deg-I 0.11 %; Deg-2 0.21 %; see
`Fig. 2, A
`No peaks
`No peaks
`No peaks
`No peaks
`No peaks
`No peaks
`Deg-I
`(large); Deg-2 (small);
`see Fig. 2, B
`Deg-l
`(large); Deg-2 (small);
`similar
`to Fig. 2, B
`Deg-2 only
`
`No peaks
`
`60 min
`60 min
`30 min
`24 hr
`24 hr
`24 hr
`25 min
`
`7 days
`
`7 days
`
`7 days
`
`7 days
`
`No peaks
`
`: Deg-2, degradate-Z: Dic-Na. diclofenac
`Deg-I, degradate-l
`lure. Percentages of degradates are relative 10 diclofenac.
`
`sodium; RH, relative humidity; RT. room tempera-
`
`Page 2
`
`

`
`453
`
`2A I were first discovered in HPLC stability testing of
`diclofenac tablets (Table 1, T I). Their possible identity
`with the previously known degradation products of diclo-
`fenac (Fig. 1) could safely be ruled out since the known
`degradation products have much shorter retention times
`in the HPLC system used [the RnO) values are about 0.2,
`0.35, and 0.5 for oxindole, 2,6-dichlorophenol,
`and the
`indolinone derivative,
`respectively]. Several hydrolytic
`experiments performed on diclofenac sodium with and
`without
`the presence of tablet excipients (Table I, Hl-
`H6) did not furnish any evidence on the formation of the
`degradates
`in question. By contrast, oxidation of diclo-
`fenac sodium with iron (I1I) in a moderately acidic aque-
`ous solution at 100°C (Table 1,01)
`resulted in practically
`complete loss of the drug. Instead,
`the appearance of an
`intense peak corresponding to degradate 1 and another.
`signal of low intensity conforming with degradate 2 was
`evident
`in the HPLC chromatogram of the reaction mix-
`ture (Fig. 2B). Both these peaks were also detected by
`HPLC in similar ratios in a solution of diclofenac sodium
`in the HPLC mobile phase on standing at room tempera-
`ture for 7 days in the presence of white light and atmo-
`spheric oxygen (Table 1,02). The presence of an antioxi-
`dant (sodium metabisulfite)
`in this solution prevented the
`formation of degradate 1, but had apparently little or no
`effect on degradate 2 (Table I, 03). The known degrada-
`tion products of diclofenac,
`the indolinone derivative and
`oxindole (Fig. 1), did not furnish either of the degradates
`on oxidation in solution with atmospheric oxygen (Table
`I, 04 and 05). Therefore,
`it appears that these two degra-
`dates are formed by oxidative attack on the diclofenac
`molecule itself.
`
`ACKNOWLEDGMENT
`
`The technical help of Mrs. Sveinbjorg Palmarsdottir,
`Ph.D.,
`is gratefully acknowledged.
`
`REFERE
`
`CES
`
`I. C. Larsen and H. Bundgaard, Arch. Pharrn. Chem. Sci. Ed.,
`8, 100 (1980).
`2. T. Kubala, B. Gambhir, and S. I. Borst, Drug Dev. Tnd.
`Pharm., 19, 749 (1993).
`I. Karamancheva,
`I. Dobrev, L. Brakalov, and A. Andeeva,
`Anal. Lett., 31, 117 (1998).
`4. British Pharmacopoeia
`1998. Her Majesty's
`Office, London, 1998, p. 1633.
`
`Stationery
`
`3.
`
`Il
`
`Diclofenac
`
`2'0 Time (min) d5
`
`Degradate-2
`
`Oxidative Degradation of Diclofenac Sodium
`
`A(
`
`Tablet powder)
`
`Abs.
`
`Degradate-1
`
`I
`
`15-.oxid.)
`
`Abs.
`
`Jada_te_-1
`
`_
`
`I
`15
`
`do Time (min) 2~
`
`Figure 2. HPLC chromatograrns of the two oxidative degra-
`dates of diclofenac.
`
`room temperature in white light for 7 days and analyzed
`by HPLC. For sample 04,
`indolinone derivative 0.75 mg
`and 1.0 ml mobile phase were stored in a lO-ml volumet-
`ric flask at room temperature
`in white light for 7 days
`and analyzed by HPLC. For sample 05, oxindole 7.5 mg
`and 10 ml mobile phase were stored in a 100-ml volumet-
`ric flask at room temperature
`in white light for 7 days
`and analyzed by HPLC.
`
`RESULTS
`
`The results of the experiments are enumerated in Ta-
`ble 1 in terms of the two unknown diclofenac degradates
`detected in HPLC chromatograms
`and having R,(D) (rela-
`tive to diclofenac) values of about 0.8 (degradate I) and
`1.1 (degradate 2) (Fig. 2).
`
`DISCUSSION AND CONCLUSIONS
`
`(relative to diclo-
`The two unknown degradates
`[R,(O)
`fenac) about 0.8 (degradate 1) and 1.1 (degradate 2), Fig.
`
`Page 3