identification of a degradation product in stressed tablets of olmesartan medoxomil by the...

Journal of Pharmaceutical and Biomedical Analysis 47 (2008) 553559

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Identication of a degradation product in stressed tablets of olmesartanmedoxomil by the complementary use of HPLC hyphenated techniques

Tomonori Murakamia,, Hidetoshi Konnoa, Naoto Fukutsua, Michinobu Onoderaa,Takao Kawasakia,1, Fumiyo Kusub

a Analytical and Quality Evaluation Research Laboratories, Daiichi-Sankyo Co. Ltd., 1-12-1 Shinomiya, Hiratsuka, Kanagawa 254-0014, Japanb School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

a r t i c l e i n f o

Article history:Received 28 November 2007Received in revised form 13 February 2008Accepted 15 February 2008Available online 29 February 2008

Keywords:Olmesartan medoxomilDegradation productHPLC hyphenated techniqueLCMSLCNMRSolvent-elimination LCIR

a b s t r a c t

An unknown degradation product (DP-1) increased in olmesartan40 C/75% r.h., reaching 0.72% after 6 months. The molecular weightby LCMS suggested that DP-1 was a dehydrated dimer of olmesacarbonyl group was indicated by solvent-elimination LCIR analysis.

ticahniqu

2

1. Introduction

The identication and qualicpharmaceuticals are essential durdegradation products could affepharmaceuticals even in small amence on Harmonization of Techniof Pharmaceuticals for Humanguidelines regarding stability stuidentication and quantication of impurities in drug substancesand drug products [13]. These guidelines provide the reporting,identication and qualication thresholds for impurities based onthe total daily intake of the relevant drug. The identication ofdegradationproducts is also very effective for estimating the causesand pathways of the degradation oticals.

The isolation of degradation peral approach for structure elucidaand the use of several techniqu

Corresponding author. Tel.: +81 463 3E-mail address: murakami.tomonori.a

1 Present address: Institute of Applied MSapporo, Hokkaido 060-0002, Japan.

le exritiesuireion pts wof t

l havHPLCctur

the degradation products without complicated isolation processes.LCMS has been one of the powerful techniques for the identi-cation of small quantities of drug degradation products [57].Recently, LCNMR has been increasingly applied to obtain detailedstructural information on degradation products [813]. LCNMR

0731-7085/$ see front matter 2008 Eldoi:10.1016/j.jpba.2008.02.021f drug substances in pharmaceu-

roducts has been used as a gen-tion.However, considerable timees, such as a preparative scale

1 6447; fax: +81 463 31 [email protected] (T. Murakami).edicine, Inc., 32 Kita 2 Nishi 2, Chuo-ku,

experiments can be performed in on-ow, stopped-ow and loop-storage modes. However, stopped-ow or loop-storage LCNMRanalysis would be required for detailed structure elucidation dueto the relatively low sensitivity of NMR. LCIR can provide valuableinformation on the functional groups of the degradation prod-ucts [14]. Flow-cell and solvent-elimination interfaces have beenused in LCIR analysis and solvent-elimination LCIR has gener-ally been the tool of choice for structural analysis work becausethe obtainable spectral information and analytical sensitivity arelimited due to intense absorptions of the LC eluent in the ow-cell LCIR analysis [15,16]. Lately, multiple hyphenated techniques

sevier B.V. All rights reserved.of DP-1 as an esteried dimer of OL. Rapid and accurate idenachieved by the complementary use of HPLC hyphenated tecpurication processes.

ation of degradation products ining drug development, since suchct the efcacy and safety of theounts. The International Confer-

cal Requirements for RegistrationUse (ICH) has issued workabledies on pharmaceuticals and the

chromatography and multipsufcient quantities of impuMoreover, special care is reqin cases where the degradatdegradation of the degradantransesterication reactionssuch as candesartan cilexetiphase extraction process [4].widely utilized for the strumedoxomil (OLM) tablets stored atand fragment information obtainedrtan (OL) and the presence of esterLC1H NMR conrmed the structuretion of the degradation product wases without complicated isolation or

008 Elsevier B.V. All rights reserved.

tractions, are required to isolatefor spectroscopic identication.

d during the isolation processesroducts are labile, since furtherill occur. In fact, hydrolysis andhe ester group-containing drugse been observed during the solidhyphenated techniques are now

al analysis of trace amounts of

554 T. Murakami et al. / Journal of Pharmaceutical and Biomedical Analysis 47 (2008) 553559

Fig. 1. Chemical structures of OLM and OL.

such as LCNMRMS have been reported [17]. However, it is nec-essary to nd a compatible LC method for all the spectrometersin the hyphenated system to perform the analysis. By the comple-mentary use of these HPLC hyphstructures of the degradation prsignicantly shorter time withoprocesses.

Olmesartan medoxomil (OLM4-yl)methoxy-4-(1-hydroxy-1-m(tetrazol-5-yl)-phenyl]phenyl}meangiotensin II receptor blocker [18of the pharmacologically active mThe chemical structures of OLM astability study of OLM tablets, twere observed during 6 monthsOne of the degradation productsOLM, and the other was an unknwhich reached a level of 0.5%. ADP-1 was observed only in OLMature and humidity, from a safetidentify this degradation product

In this study, the structurehyphenated techniques of LCMLCNMR using LC conditions coThe complementary use of HPLCadjustment of the HPLC separatiproved to be very effective incation of degradation productsprocesses.

2. Experimental

2.1. Chemicals and reagents

OLM5mg tabletsweremanufaJapan) and these tablets weremonths. Separately, OLM tabletsatmosphere at 70 C for 5 daysamount of DP-1 for the LCIR anreferred to as DP-1-enriched tDaiichi-Sankyo. Acetic acid, phosgen phosphate and triethylamineacetonitrile and methanol of HPWako Pure Chemical Industries(D2O, 99.9% D), deuterated acedeuteratedmethanol (CD3OD, 99bridge Isotope Laboratories (Andowith a Milli-Q Gradient A10 sUSA).

2.2. Sample preparation

One OLM tablet was dissolved in 5ml of methanol using anultrasonic bath (1mg OLM/ml). The homogenous suspension wascentrifuged at 3000 rpm (rotor radius 21.4 cm) for 10min witha Hitachi CF8DL centrifuge (Hitachi, Tokyo, Japan) and the clearsupernatant was subjected to LCUV and LCMS analyses.

Separately, two DP-1-enriched tablets were dissolved in 1ml ofmethanol (10mg OLM/ml) and ltered through a 0.45-m lter(13mmGD/X disposable lter, Whatman, SpringeldMill, UK) andthe ltrate was subjected to LCIR and LCNMR analyses.

For the acquisition of reference LCIR and LCNMR spectraof OL, an OL solution of 1mg/ml concentration in methanol wasprepared.

2.3. LCUV analysis of OLM tablets

rformantainarlate

th detogr150mn teH 3.9ceton25mby Uectedand tsoft

ses

h wPLCe useile pobileventacet

cial aole t, USAsed aratedesoand 2coneSmewerf apS op

widtes wne enintoters)edmenated techniques, the chemicaloducts could be elucidated in aut any isolation or purication

), (5-methyl-2-oxo-1,3-dioxolen-ethylethyl)-2-propyl-1-{4-[2-thylimidazol-5-carboxylate is an,19]. This drug is an ester prodrugetabolite olmesartan (OL) [20].

nd OL are shown in Fig. 1. In thewo major degradation productsof open storage at 40 C/75% r.h.was OL, an ester hydrolysate ofown degradation product (DP-1)lthough a signicant increase oftablets stored at a high temper-y standpoint it was important to.of DP-1 was elucidated by theS, solvent-elimination LCIR andmpatible with each technique.hyphenated techniques and the

on conditions for each techniquethe rapid and accurate identi-without isolation or purication

ctured byDaiichi-Sankyo (Tokyo,stored at 40 C/75% r.h. for 6

were stored in a water-saturatedin order to generate a sufcientd LCNMR analyses (hereinafterablets). OL was synthesized byphoric acid, potassium dihydro-(Et3N) of guaranteed grade, andLC grade were purchased from(Osaka, Japan), deuterium oxidetonitrile (CD3CN, 99.8% D) and.8% D)were purchased from Cam-ver,MA,USA).Waterwaspuriedystem (Millipore, Bedford, MA,

LCUV analyses were petem (Agilent Technologies, Sonline degasser G1379A, a bG1329A, a temperature regua UVvis variable-wavelengdetector G1315B. The chromacolumn, TSKgel ODS-100V (Tosoh, Tokyo, Japan); columphosphate buffer (15mM, pow rate, 0.8ml/min. The aearly from 35% to 80% inThe analytes were detectedonline UV spectra were collinjection volume was 10lChemstation version A.09.03sition.

2.4. LCMS and MS/MS analy

The liquid chromatograpdescribed previously. The Hthe same conditions as thosfor the use of volatile mob2.0mm i.d. column at a min order to get efcient solmobile phases consisted ofadjusted to pH 3.9 with glawas 1l. A hybrid quadrupQ-Tof2 (Waters, Milford, MAionization (ESI) sourcewas uNitrogen was used with owfor cone gas, and 400 l/h fortion temperatures were 120voltage was 3.0 kV and theenergywas set to 10eV forMmeasurement. Mass spectra502000 with a resolution ohalf-maximum. For the MS/Mlision gas and the isolation1.7m/z units. Accurate massa reference compound, leucimolecule 556.2771) infusedMassLynx v 3.5 software (Waular formulas of theprotonatmass data.ed on an Agilent 1100 LC sys-Clara, CA, USA) consisting of an

y pump G1312A, an autosamplerd column compartment G1316A,tector G1314A and a diode arrayaphic conditions were as follows:m4.6mm, 3m particle size,

mperature, 40 C; mobile phase,)acetonitrile; gradient elution;itrile content was increased lin-in and held for 15min at 80%.V detection at 250nm and thebetween 200 and 400nm. The

he run time was 40min. Agilentware was used for the data acqui-

as the Agilent 1100 LC systemseparation was conducted underd for the LCUV analysis, excepthase modiers and the use of aphase ow rate of 0.2ml/min

evaporation and ionization. Theonitrile and 0.1% Et3N in watercetic acid. The injection volumeime-of-ight mass spectrometer) equipped with an electrospraynd operated in positive ESImode.s of 20 l/h for nebulization, 50 l/hlvation. The source and desolva-00 C, respectively. The capillaryvoltage was 35V. The collision

asurements, 25 eV for theMS/MSe acquired over an m/z range ofproximately 10,000 at full-widtheration, argon was used as a col-

hs of the parent ions were set toere measured by comparison tokephalin (m/z of the protonated

the lock spray reference channel.was used to calculate themolec-olecules according to theaccurate

T. Murakami et al. / Journal of Pharmaceutical and Biomedical Analysis 47 (2008) 553559 555

2.5. Solvent-elimination LCIR analysis

The HPLC separation was conducted under the same condi-tions as those used for the LCMS analysis. The injection volumewas 10l. The HPLC eluent was evaporated by nebulizing withcompressed air at a pressure of 30psi at a temperature of 150 Cusing an LC-Transform Series 600 interface (Lab Connections,Northborough, MA, USA). The resultant eluate was deposited ona 60mm o.d.2mm thickness rear-surface-aluminized germa-nium disk with a rotation rate of 10/min. The FT-IR spectra of thedeposited eluatewere recorded on a Spectrum100 FT-IR Spectrom-eter (PerkinElmer, Norwalk, CT, USA) equipped with a triglycinesulfate detector from 400 to 4000 cm1 with 4 cm1 resolution.The transient data of 10 scans was accumulated. As a check on thestability of the samples during the LCIR analysis, the depositedsamples were re-subjected to LCUV analysis after the IRmeasure-ments.

2.6. Stopped-ow LCNMR analysis

The LCNMR experiments were performed in the stopped-owmode on an Avance 600 spectrometer (Bruker BioSpin, Rheinstet-ten, Germany)working at 600.13MHz for 1H, coupled to theAgilent1100 LC system and a Bruker peak sampling unit (BPSU-12) inter-face. Two HPLC methods were used for the LCNMR analyses. Therst method was the same as that used for the LCUV analysis,except for the use of a 2.0mm i.d. column at a mobile phase owrate of 0.2ml/min in order to reduce the elution volume of thecomponent of interest and make sure that the maximum amount

Fig. 3. On-line UV spectra of OLM, OL and DP-1.

of the component was inside the ow cell for NMR detection. Inthe second method, methanol was used in place of acetonitrile asan organic component of the mobile phase and the methanol con-tent was increased linearly from 55% to 85% in 30min and held for20min at 85%. All the mobile phases were prepared using deuter-ated solvents (D2O, CD3CN and CD3OD) in order to minimize thesolvent background. The injection volume was 2l. For the NMRexperiments, a 1H13C/15N triple-resonance inverse (TCI) 5mmcryoprobe (active volume 60l) with cold 1H- and 13C-coils andpreampliers and a z-gradient accessory was used. The hyphen-ated system was controlled by Bruker Hystar software (version2.3). One-dimensional 1H NMR spectra were recorded using thedouble presaturation nuclear Overhauser effect spectroscopy pulse

Fig. 2. Typical HPLC chromatograms: (a) (pho(b) stressed OLM tablets (6 months at 40 3.9-aanalyzed by LC-NMR methods using (c) astressed OLM tablets (6 months at 40 C/75% r.h.) analyzed by the LC-UV methodC/75% r.h.) analyzed by the LC-MS method (triethylamine/acetic acid solution pHcetonitrile eluent and (d) methanol eluent.sphate buffer pH 3.9-acetonitrile eluent),cetonitrile eluent), DP-1 enriched tablets


Fig. 4. (a) LC-MS and (b) LC-MS/MS spectra of DP-1. *Signals of the protonatedmolecule of triethylamine in the mobile phase.

sequencewith shapedpulses for suppressionof the acetonitrile andthe water signals. Spectra were acquired with a 12 019Hz spectralwidth and 16K data points, giving digital resolution of 0.73Hz perpoint. A total of 256512 scans were accumulated. All the spectrawere processed with an exponen1Hz and a zero lling factor of 2.

Fig. 6. Solvent-elimination LC-IR spectra of (a) OL and (b) DP-1.

All NMR spectra were recorded at a constant temperature of25 C, and the chemical shifts were referenced to the methyl sig-nal of the residual acetonitrile at 1.93ppm or that of the residualmethanol at 3.30ppm.

3. Results and discussion

3.1. LCUV analysis of stressed OLM tablets

In the LCUV analysis, an unknown degradation product DP-1 was detected at 0.72% by the peak area percent at 250nm inOLM 5mg tablets stored at 40 C/75% r.h. for 6 months. OL wasalso detected as another major degradation product formed bythe ester hydrolysis of OLM. There was no loss of mass balance inthe stressed tablets. A typical HPLC chromatogram of the stressedtablets and the online UV spectra of OLM, OL and DP-1 are shownin Figs. 2a and 3, respectively. DP-1, as well as OL, did not show theintensive UV absorption maximum at 260nm characteristic of the5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl group (ester moiety) inOLM, suggesting that DP-1 lacks the ester moiety.

3.2. Identication of DP-1

nalydevetial function, a line broadening of In the LCMS and LCIR avolatile mobile phases wasFig. 5. Proposed fragmentation scheme for DP-1 in the LC-MS/MS analysis.ses, a separation condition usingloped and the resulting separa-


Fig. 7. LC-1H-NMR spectra of (A) DP-1 obtained using CD3CN eluent, (B) DP-1 obtained using CD3OD eluent and (C) OL obtained using CD3OD eluent. The relative integralintensities for the resonances are indicated below the axis.


tion (Fig. 2b) was equivalent to that obtained in the LCUV analysis(Fig. 2a). Comparative chromatograms of the DP-1-enriched tabletsobtained by the LCNMRmethods using acetonitrile eluent (Fig. 2c)and methanol eluent (Fig. 2d) showed that the use of methanolchanged the retention order and caused little peak broadening,however, a sufcient separation of main impurities in the DP-1enriched tablets was achieved.

3.2.1. LCMS and MS/MS analysesThe accurate mass spectrum of DP-1 exhibited a protonated

molecule [M+H]+ and an Et3N adduct ion [M+H+Et3N]+ at m/z875.4122 and 976.5380, respectively (Fig. 4a). In the MS/MS spec-trum (Fig. 4b), the product ions equivalent to the protonatedmolecule of the OL substructure and the dehydrated ion of theprotonated molecule of DP-1 was detected at m/z 447.2140 and857.3998, respectively. All the other product ions detected in theMS/MS spectrum of DP-1 at m/z 429.2031, 385.2146 and 207.0922werealsodetected in theMS/MSspectrumofOL. Fromthese results,DP-1 was estimated to be a dehydrated condensation product(C48H50N12O5, calculatedmass foof two OL molecules and the pposed as shown in Fig. 5. Howevstructures formed as reaction pof one of the OL molecules withdazole moiety, with the secondamoiety, or with the carboxyl gror acid anhydride formation) anholic group on the imidazole mowith the secondary amino grouother.

3.2.2. Solvent-elimination LCIR aIn the LCIR spectrum, DP-1 s

tern to OL except for the band corstretching (C O) (Fig. 6a and b)tionwith the LCMS results, DP-1dimer of OL.

3.2.3. Stopped-ow LCNMR analyFurther conrmation was per

NMR spectrum of DP-1 obtainedponent of themobile phase is shoprotons which appeared in the 1Hative integral intensities of the prthat expected from the estimateH-D exchangeable 4). One possibmethyl signal of the residual acetnals of DP-1. Further LCNMR anusing CD3OD in place of CD3CNmobile phase. The LC1H NMR spent is shown in Fig. 7b. A signal ofin the analysis using CD3CN eluesignal was overlapped with theLC1H NMR spectrum of DP-1 was well as the UV and IR spectramore singlet signals at 2.0 and 5of the isopropanol moiety and thThe peak integrals from DP-1 spber of protons observed in each4, 6 from the lower eld to the h(4, 4, 2, 2, 6, 2, 3). These results cof OL and that the newly formedmolecules shifted the resonanceof H13 and the resonance of HH4.

Fig. 8. Chemical structure of DP-1.

Thus, DP-1 was successfully identied as an esteried dimer ofOL by the complementary use of HPLC hyphenated techniques, asshown in Fig. 8, and all the results of the on-line and at-line spec-troscopic and spectrometric anal

uctuypherefergrou

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. LCubstralysistrucLCNitateithouMRe, e.overan ber the

to thnc. for [M+H]+ 875.4105, error 1.9ppm)roduct ions of DP-1 were pro-er, there were 6 possible dimerroducts of the carboxylic groupthe alcoholic group on the imi-ry amino group of the tetrazoleoup of the others (ester, amide,d reaction products of the alco-iety of one of the OL moleculesp of the tetrazole moiety of the

nalysishowed a similar absorption pat-responding to the ester carbonyl. From these results, in conjunc-was estimated to be an esteried

sisformed by LCNMR. The LC1Husing CD3CN as an organic com-wn in Fig. 7a. The total number ofspectrum obtained from the rel-oton signals (40) was 6 less thand dimeric structure (46, total 50,le explanation for this is that theonitrile overlapped with the sig-alyses were therefore performedas an organic component of theectrum of DP-1 using CD3OD elu-6 protons at 2.0ppmnot observednt was noted, indicating that thisresidual acetonitrile signal. Theas similar to that of OL (Fig. 7c), except for the presence of two.6ppm due to the methyl groupse methylene group, respectively.ectrum indicated that the num-resonance region (8, 8, 4, 4, 12,igher eld) is double that of OLonrmed that DP-1 was a dimerester bond between the two OLof H13 to a lower eld than that4 to a higher eld than that of

quite consistent with this stridentication using HPLC htion was presumed to be pcompounds containing estersuch as hydrolysis.

Two dimeric degradatiostressed tablets (3 years atangiotensin II receptor blockdehydrated dimers of losartaalcoholic group on the imidaality at the tetrazole [21]. Itdimer of OL,was predominanthe DP-1 formation reactionlosartan lacks occurredmorer.h. On the other hand, the fdegradation products, acetylacid, has been reported in theieshave suggested thatbasicin tablets accelerate the degrsuggested to have a similar etablets.

4. Conclusions

This investigation has didentication of the degradatof OLM was achieved by thsolvent-elimination LCIR anpatible with each techniquethe molecular formula and sdation product and LCIR anester functional group. Thewas denitely conrmed byhyphenated techniques facilof the degradationproductwlation processes. In the LCNmodier of the mobile phasbe efcient for resolving thesolvents. These approaches ctical development process foof degradation products.

Acknowledgments

The authors would likeShukichiOchiai of S.T. Japan Iyses (UV, MS, IR and NMR) werere. As things turned out, the rapidnated techniques without isola-able, since it is well known thatps are susceptible to degradation,

roducts were observed in theC/75% r.h.) of losartan, the rstbe marketed. However, the two

ere formed by the reaction of themoiety and the amine function-

assumed that DP-1, the esteriedrmed in theOLM tablets becauselving the carboxylic group whichly during the storage at 40 C/75%tion of similar esteried dimericylsalicylic acid and salicylsalicylicof aspirin tablets and those stud-cants suchasmagnesiumstearateions [2224]. Basic lubricants areon the formation of DP-1 in OLM

nstrated that the unambiguousroduct formed in stressed tabletsphenated techniques of LCMS,NMR using LC conditions com-MS and MS/MS spectra provideductural information of the degra-s determined the presence of theture of the degradation productMR. Complementary use of thesed the rapid structure elucidationt complicatedpurication or iso-analysis, a change of the organicg. from CD3CN to CD3OD, wouldlapping signals of the sample andvery effective in the pharmaceu-rapid and accurate identication

ank Dr. Akira Yanagawa and Dr.r their support in the LCIRdeter-


mination. Thanks are also due to Mr. Philip Snider for proofreadingthis manuscript.

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identification of a degradation product in stressed tablets of olmesartan medoxomil by the...

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