Available online at www.sciencedirect.com
Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 247253
Drug safety, drug quality, d
Budap2 Octer 200
Controllin ringproperties of samequality of bu d toare identity, ity iselucidation) cts, tdrug materials can be avoided or at least controlled/minimized.
The deveand requirePharmacopoare observaused. Sincerecommend
The effecis that dueattribute for
It is recomfor more im 2007 Els
The aimone senten
The aianalysis) i
bulk dru the inter product drug for
Tel.: +36E-mail ad
0731-7085/$doi:10.1016/jlopment in the field of chromatographic and spectroscopic methods in the last decades has led to changes in the philosophy, structurements in the monographs of drug materials in the principal pharmacopoeias. Although the approaches of the European and USeias are somewhat different, a common feature is the shift of focal point toward purity tests. In contrast to this, relatively few changes
ble in the field of the assay methods for bulk drug materials: non-selective titrimetric and spectrophotometric methods are still widelythe results of these do not contribute to the safety issue, the omission of these tests and substitution by the mass balance concept ised.tiveness of the tendency of replacing non-selective methods by selective ones (mainly HPLC) is also questionable. The reason for thisto the limited precision of the HPLC assay the drug content obtained by the mass balance concept is a much better quality controlbulk drug materials than that obtained by HPLC.mended that classical assay methods (including HPLC) be used in exceptional cases only and the time and energy thus spared be used
portant impurity-related issues that directly contribute to the safety of drug therapy.evier B.V. All rights reserved.
rug quality; Drug safety; Drug purity; Drug analysis; Assay
and scope of drug analysis
s and scope of drug analysis can be summarized ince as follows:m of drug analysis (with emphasis on industrial drugs the analytical investigation of
g materials,mediates of their syntheses,s of drug research (potential pharmacons),mulations,
1 4314620; fax: +36 1 4315284.dress: firstname.lastname@example.org.
the impurities and degradation products of drugs, biological samples containing the drugs and their metabolites.
with the aim of obtaining data which can contribute to
the high quality, the maximum efficacy and maximum safety of drug therapy and the maximum economy of the production of drugs .
This sentence contains the three main issues incorporatedin the title of the paper: safety, quality and analysis of drugs.The aim of this paper is to describe the authors views on thecorrelation of these with the eyes of a pharmaceutical analyst,i.e. how to optimize the contribution of analytical chemistryin assuring maximum safety of drug therapy. The scope of the
see front matter 2007 Elsevier B.V. All rights reserved..jpba.2007.10.038Sandor Gorog Gedeon Richter Plc., P.O.B. 27, H-1475
Received 2 October 2007; accepted 1Available online 13 Novemb
g and minimizing the side effects of drugs are the key issues in assuthe drug material, these cannot be influenced by drug analysts. At thelk drug materials and drug formulations and this is also closely relatestrength and purity. Of these, in the case of bulk drug materials, purand quantitative determination of the impurities and degradation produrug analysis
est, Hungaryober 20077
the safety of drug therapy. Since side effects are inherenttime drug analysts play a predominant role in assuring thethe safety issue. The three main attributes of drug qualityof prominent importance: by the identification (structurehe risk of their contribution to the side effect profile of the
248 S. Gorog / Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 247253
paper is restricted to bulk drug materials with small molecules:biomacromolecules and drug formulations will not be dealtwith.
The Fooships of ththe safety odrugs. . . bemine that thcausing sid
The efcgists, biolotaking partpharmaceucan only inaiming at in.
So mucanalytical cshows thateffect prolpropertiestheir benefithe duty oftration ageof a new ddecision.
On thedegradationAvoiding oassuring thtion to toxand regulanant role inmaterial.
The defiConferencesuitabilityintended usstrength anability of thin the earlytion was bainfrared sping with refnot necessan importaever of prmaterials, icontent is, eically 98.0potentially
composition of (100 active ingredient content)% = impurities.With other words this means that of the three attributes in
A/ICH definition purity is of prominent importancemajority of cases the only really important quality
the t. (1)ventand. Thabovtee tdrugmuc
igind ofuritifactothe omendstryuencingpurit) anre e
es inain,ty pdete
impat in], aa) gee imimpuaperdea] ca], anle ority pticalsafety
d and Drug Administration (FDA), one of the flag-e drug safety issue describes its own role regardingf drug therapy as follows: . . . FDA. . . requires thatproven safe and effective. . . .FDA. . . must deter-e drug produces the benefits it is supposed to withoute effects that would outweigh those benefits .acy of drug therapy depends mainly on pharmacolo-
gists, biochemists, synthetic chemists, and cliniciansin the development of the drug. Although the role oftical analysts is not negligible even in this field, theydirectly contribute to the success of drug researchtroducing new, highly effective drugs into the therapy
h the greater is the importance of the activities ofhemists in safety issues. The definition cited above
the safety of drug therapy mainly depends on the sidee of the drug. As it is known, side effects are inherentof the drug material. The examination of the ratio ofcial actions and the risks caused by the side effects ispharmacologists, toxicologists, clinicians and regis-
ncies before making decision about the introductionrug: analytical chemists do not play any role in this
other hand physiologically active impurities andproducts can contribute to the side effect profile.
r at least minimizing this contribution is a key issue ine reproducibility and safety of drug therapy. In addi-icologists, process chemists, formulation scientiststion agencies, analytical chemists play a predomi-
this by controlling the quality (purity) of the drug
nition of drug quality in a FDA-ICH (Internationalon Harmonisation) document  is as follows: The
of either a drug substance or drug product for itse. This term includes such attributes as the identity,d purity. Of the three attributes improving the reli-e identication tests used to be of great importanceperiod of pharmaceutical analysis when identifica-
sed on specific colour reactions. Nowadays, however,ectroscopy and/or chromatographic retention match-erence standards create a firm basis for identification
itating further developments. Strength is of coursent quality attribute of drug formulations. It is, how-actically no importance in the case of bulk drug.e. it is not important whether the active ingredient.g. 98.5 or 99.5% within the acceptance criteria (typ-
102.0% or even stricter.) The only important pointinfluencing drug safety is the quantity, nature and
the FD(in theattribu
Of, i.eual solmetalslimitedin theguaranof the
Sotion oThe imthe ormethoof impthesecisedrecom
chemiconseqwhelmthe im(HPLCthese aferencuncertimpuriis thetitativepharmapplic fointo codose otherap
Thefact th[1114ering (volatilgenicNMRwith ppapers[2325[26,27merabImpurmaceupurity
hree types of impurities listed in the ICH Guidelinesorganic impurities; (2) inorganic impurities; (3) resid-s, (2) and (3) are easy to control. The number of toxicsolvents that may occur in bulk drug substances is
eir toxicity is well characterized and the limits set upe-mentioned guidelines and in the pharmacopoeiashat these cannot contribute to the side effect profile.h the more problematic is the potential contribu-anic impurities to the side effects of bulk drugs.
ity profile of drugs depends on the synthetic route,and purity of the starting materials and reagents,purification and storage conditions: various kindses can originate from differences and changes ofrs. (Note: the author of the present paper criti-fficial classification  of organic impurities anded a modified classification better reflecting the
behind the occurrence of the impurities .) As ae of the uncertainties outlined above, in the over-
majority of cases the pharmacopoeias do not specifyies in the high-performance liquid chromatographicd thin-layer chromatographic (TLC) purity tests;
xpressed as the main component neglecting the dif-their responses. Of course this can be source of
moreover sometimes erroneous results. This is whyrofiling, i.e. analytical activities the aim of whichction, identification/structure elucidation and quan-ermination of impurities are key issue in moderntical analysis. This creates the basis for the successfulof the principles outlined in the FDA/ICH documentstrolling the limits of individual impurities takingeration the toxicity of the impurity and the dailydrug thus greatly contributing to the safety of drug
ortance of impurity profiling is well reflected by thethe recent years four books , book chapters
special issue in Trends in Analytical Chemistry cov-neral aspects, (b) degradation-related impurities, (c)
purities, (d) TLC aspects, (e) genotoxic and carcino-rities, (f) HPLC aspects and (g) the role of off-line, another one in Advanced Drug Delivery Reviewss on various analytical aspects , several reviewling with general , HPLC , HPLCMSpillary electrophoresis (CE) and related techniquesd CE-MS , chiral CE  aspects and innu-dinary papers have been published on this subject.rofiling is a hot topic, indeed, in contemporary phar-analysis!
S. Gorog / Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 247253 249
2. The safety issue and the pharmacopoeias
2.1. Historical overview
Pharmacopoeias are traditionally considered to be the safe-guards and guarantee for the quality of drugs. As shown inTable 1, the principal national pharmacopoeias (and in addi-tion that of the authors country) were first published at varioustimes in the 19th century. Due to the globalisation of the phar-maceutical market, the pharmacopoeias of the countries in theEuropean Union are now under the umbrella of the EuropeanPharmacopoeia (Ph. Eur.) , moreover further harmonisa-tion of these standards has been in progress since 1990 amongPh. Eur., the United States Pharmacopoeia (USP)  and theJapanese Pharmacopoeia (JP)  in the framework of the Inter-national Conference on Harmonisation (ICH).
Table 1 the mission of pharmacopoeias is . . .to maintain andimprove health. . .by disseminating authoritative standards. . .formedicines.pharmacopcan be consetting thesto) reflect tthe currentopment incontributeously increthe era of c
If we coing, e.g. UUSP 30 (20
The strumore or
constant As alrea
tion are band chrodards.
The greaof imme
Table 1Principal phar
i.e. in the field of impurity-related tests. In 1960 HPLC didnot yet exist and TLC was at its beginnings. For this reasonimpurityof ignitiity of thcarbonizpoint, etterize theand hencdrugs. Thas beenopmentmajoritychromatcharacte
The pictis notsion of
Dedefi: Toent ollowion a
puritthodgroul wiethoespey ared cote hof prod of
y thd inn th
thazi. . . It has to be added to this quotation that theoeias are not only disseminating the standards butsidered to be flagships of the drug quality issue bye standards. These standards should (or at least oughthe state-of-the-art of the possibilities represented bystate of analytical chemistry. The tremendous devel-analytical instrumentation enables drug analysts toat a higher level and more effectively to the continu-asing demands as regards the safety of drugs than inlassical analysis.mpare the changes within half a century by compar-SP 16, published in 1960 with the currently official07), some conclusions can be drawn:
cture of the monographs for bulk drug materials isless the same: description, identication, physicals, impurity-related tests, assay.dy mentioned, classical colour tests for the identica-eing step-by-step replaced by infrared spectroscopy
matographic retention matching with reference stan-
test development is observable in the field which isnse importance from the point of view of drug safety,
ia First volume Present volume
1820 United States Pharmacopeia (USP)30, 2007
19641971 European Pharmacopoeia 5, 2007gdom 1864 British Pharmacopoeia (BP) 2007
1837 Pharmacopee Francaise 10, 20051872 Deutsches Arzneibuch (DAB) 10,
Nachtrag 8, 20051892 Farmacopea Italiana XI, 2002,
Suppl. 1, 20051871 Pharmacopoeia Hungarica VIII,
200320061874 Japanese Pharmacopoeia XIV,
2001, Suppl. 2006
late 19 w(the lathese atial imthe metionalare stiltion m70%, rtometroutdatillustracase o
methotion bybase bmethobetwee16 istal vioblue [0.1 Mmetricprome-related tests were restricted to tests such as residueon, loss on drying, completeness, colour and clar-e solution, chloride, sulphate, heavy metals, easilyable substances, range and sharpness of the meltingc. It is needless to say that these tests did not charac-
purity of the drug material at a sufficiently high levele only very moderately contributed to the safety ofhe development in this field in the last few decades
very rapid and substantial. Thanks to the devel-in chromatographic technology, the overwhelmingof monographs in modern pharmacopoeias contain
ographic (usually HPLC or TLC) tests suitable for therisation of the impurity profile of the drug material.ure as regards the development of assay methodsas clear as with the impurities. The discus-this will be the subject of Section 2.2 in this
methods for bulk drug materials inoeias
nitionnition of assay in ICH documents  is as follows:provide an exact result which allows an accurate
f the content or potency of the analyte in a sample.ing sections will show how the requirements in thisre fulfilled in the current pharmacopoeias.
-selective methodsng the state-of-the-art of analytical chemistry in theand early 1960s, the principal methods in USP 16titration and ultraviolet-visible spectrophotometrybeing often based on colour reactions). Althoughon-selective methods, i.e. the majority of the poten-ies are likely to contain the same moieties on whichs are based as the drug itself: acidic or basic func-ps and chromophores, respectively, these methodsdely used in the pharmacopoeias. The share of titra-ds in the current USP and Ph. Eur. is about 40 andctively, while the same figures for UV spectropho-e about 10% in both pharmacopoeias; the role oflorimetric methods has decreased substantially. Tow minimal the changes have been in these fields, themethazine hydrochloride is mentioned. The assaythis classical drug material in USP 16 was titra-tous perchloric acid after the liberation of the freee classical mercury(II) acetate method . TheUSP 30 [28a] is the same the only differencese two texts being that the same indicator in USPd methylrosaniline chloride and in USP 30 crys-
nd the solutions should be titrated to green  orcolour. Ph. Eur. titrates the protonated base with
um hydroxide in ethanolic medium using potentio-point detection [29a]. Fig. 1 shows the formulae ofne hydrochloride with its named impurities in Ph.
250 S. Gorog / Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 247253
Fig. 1. The formulae of promethazine hydrochloride and its named impurities in Ph. Eur. 5 [27a].
Eur. [29a]. It is evident that with the exception of phenoth-iazine all impurities are titrated together with promethazine,i.e. the methods are not selective and the assay results are notaccurate.
A similar example is levonorgestrel. Its assay in USP 30is based on UV spectrophotometric measurement of the , -unsaturated 3-oxo moiety at 241 nm [30b] while in Ph. Eur. 5the indirect titrimetric determination of the ethinyl group (after
Fig. 2. The fogroup.rmulae of levonorgestrel, its named impurities in Ph. Eur. 5 [27b] and some other impurities . Key: UV-active moiety; - - - - ethinyl
S. Gorog / Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 247253 251
reaction with silver nitrate) is prescribed [29b]. Fig. 2 shows theformulae of levonorgestrel together with its named impurities inPh. Eur. 5 [the majoritabsorbing asame appli
The gendescribed a
The assaterize thno (or veof drugs
These manalysinof drugs
In an eapaper assay methwhen neceprinciple knand metabodation studreference s
of titrimetrthem by seof cases Hin 1980 [4in generalin the histmethod (toorganic imdrug formuimprovingbulk drugand 15% ipositive.
It is evididated HPLassays. Hodecreases icision, the
in characterising the quality of bulk drug materials: the authorof the present paper proposed HPLC method also to be omitted
thwhcal idrugfor th1%on e
arlies. Itcisiople aal brsubjmati(randomhe qu
discontrielectds and nomenpro
ittedals (e asshennec
ts to27b] and some other impurities . As it is seen,y of the impurities contain UV-active groups stronglyt 241 nm and/or ethinyl group(s). This means that the
es to this case as was described for promethazine.eral conclusions that can be drawn from the factsbove are as follows:
ric and spectrophotometric methods are non-: although these are rapid, inexpensive and precise, their accuracy is low.ethods do not meet the criteria of ICH described in2.2.1.y values obtained by these methods do not charac-
e quality of the bulk drug substance and hence are ofry limited) value from the point of view of the safety.ethods could easily be left out from the protocol ofg bulk drug materials without endangering the safety.
rlier publication it was proposed by the author of thisthat non-selective (and as shown later also selective)ods for bulk drug materials be replaced by making ssary calculations of the basis of the mass balanceown mainly from drug distribution, pharmacokineticlic investigations. It is often used also in drug degra-ies, e.g. [41,42] and for characterizing the quality oftandards :
redient content = (100 impurities)% inorganic impurities organic impurities
volatile impurities)%. (1)
ctive methods (HPLC)possibility to solve the problem of the non-selectivity
ic and spectrophotometric assay methods is to replacelective methods, i.e. in the overwhelming majorityPLC. Since its first appearance in a pharmacopoeia4] the speed of the propagation of this methodand at the pharmacopoeia level is unprecedentedory of pharmaceutical analysis. This is the maingether with TLC) for the determination of relatedpurities and the stability indicating assay method forlations. This greatly contributes to the possibility ofdrug safety. As for HPLC as an assay method formaterials (with a share of about 50% in USP n Ph. Eur. ) the picture is far from clear and
ent that a well-designed, carefully optimised and val-C method has sufficient selectivity to furnish accuratewever, the limited precision of this method greatlyts value as a quality attribute. Due to this limited pre-HPLC assay is not suitable to play an important role
from thwhen nThe arcited ption thand -eand a sconser
of theis woranalytiof the
Asof 0.5basedwith esystemthe preof sam
A reon thisa syste0.61%of freeraise tqualityresultsdescribbetterthe sammagnifalse oof speassay c
Asis to cpoor smethomethorequirelowingcenturproposbe ommateribalanclisted wbe still
In tenergythe aimanalysalytical protocol of bulk drug materials replacing it sary with the mass balance concept (Eq. (1)) .entation for this is described in more detail in the. In addition to the precision issue here we only men-PLC assay is very time consuming, labour-intensivesive. Column conditioning, system suitability tests,ient number of replicates take according to the moste calculation, about half a working day in the coursey of a drug material. It is at least questionable if itile to spend so much time, energy and money on annvestigation that adds very little if any to the safety.e question of the precision, the authors value of RSDfor a typical HPLC assay on bulk drug materials wasstimation only  but this was in good agreementr [45,46] and subsequent [47,48] results on similarhas to be noted that another study  showed thatn can greatly be improved by using higher weightsnd standard.eakthrough in this field was the publication of a paperect quite recently by Hofer et al. . In the course ofc study with 21 drug substances an average RSD ofge 0.291.0%) was found by them with 898 degreesfor the analysis. In the title of this paper the authorsestion Is HPLC assay for drug substance a usefultrol attribute? They demonstrate with experimentalmodel calculations that in agreement with the viewsn Ref.  the mass balance approach is a muchity control attribute: the assay results are essentiallyut the standard deviations are less by one order ofThis also means that in such a way the number of-specification results originating from the closenesstion limits and the standard deviation of the HPLCe greatly reduced.
ussed in Section 1, the main aim of drug analysisbute to the improvement of drug safety. Due to theivity of the titrimetric and spectrophotometric assayd the insufficient precision of the selective HPLC
ne of these methods can be considered to fulfil thist. Although it is evident that realization of the fol-posal would require the breakthrough of the walls oftraditions in pharmaceutical analysis, the author still
n agreement with Hofer et al. ) assay methods tofrom the protocol of the quality control of bulk drugsmall molecules) by replacing them with the massay. (Note: both in Refs.  and  some cases areassay methods in the classical sense of the word can
essary).ase of the acceptance of this principle much time,cost could be spared. It is, however, by no means
this paper to propose to decrease the efforts of drugcontrol the quality of drugs. In contrast, it is our aim to
252 S. Gorog / Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 247253
improve the quality of drugs. However, the author is convincedthat the spared time, energy and money could be used much moreeffectivelythe more o
Williambalance memethods) fence StandimpuritiesThe impurithat the imcomponentthis princip
Some taas follows.ber of unknaim of conwith potentPh. Eur. toties is usefualways the0 and 15. Othe pharmadrug materpossible sycated struclisting of thspace to thown drug m
It is espPh. Eur. anportion ofa specifictheir determmethod orties (terminHPLC (orsis of the istandard foresponse facertain imprity.
Using rocertainlyof (relateneous us
but alsochromatful compthe unwapure enation andor tetraapresently
to the residue of ignition thus causing systematic error in usingthe mass balance principle for the assay.
Gorong. Ae Foo99), w
ki (Ess, SaToddceutic377. Zho
alysisS. GoS.W.C. Caem. 2K. Fe
em. 2by concentrating on impurities than by carrying outr less obsolete and useless assay tests.s et al.  described the possible pitfalls of the massthod which they recommended (together with otheror the characterisation of the quality of USP Refer-ard materials: In many cases the chromatographicare unknown, or standards of them are not available.ties are then determined by the very risky assumptionpurities have the same response factors as the main. Of course the same applies to the application ofle to ordinary bulk drug materials also.sks and possibilities to surmount these difficulties areIt is an important task to decrease the relative num-owns within the total number of impurities with thetrolling and minimizing the presence of impuritiesially undesirable biological activity. The tendency oflist at the end of the monographs possible impuri-l especially if the list is comprehensive which is not
case: the number of named impurities varies betweenf course full coverage of all possible impurities on
copoeia level is possible only in the case of classicalials with low molecular weight and limited number ofnthetic pathways. For larger molecules with compli-tures and several possible synthesis methods only thee most characteristic impurities is possible leaving
e individual drug companies to fill the gap in theirater files.
ecially important and desirable that the tendency ofd USP to increase within named impurities the pro-specified impurities, i.e. individual impurities withacceptance criterion and with specific methods for
ination is continued. The latter can be an individualthe application of the method for ordinary impuri-ology of USP) using suitable response factors in theTLC densitometric) tests. In both cases the synthe-mpurity is necessary. This can be used as referencer developing the specific method or calculating thector, thus avoiding the over- or underestimation ofurities and also enables the qualification of the impu-
h these goals the following developments in thegy of drug impurity profiling seem to be desirable:
utinely dual (multiple) purity tests. HPLC is and willremain the principal method for the determination
d) organic impurities in drugs. However, the simulta-e of other chromatographic techniques, mainly TLChitherto only scarcely used methods, such as ion
ography, CE and related techniques may afford use-lementary information on impurities, among themnted enantiomer in chiral drugs administered as the
ntiomer. These methods could be useful for the detec-quantitation of ionic species such as ammonium,
lkyl-ammonium salts that are not detectable by theused HPLC or TLC methods and do not contribute
Impof Hgentionin UusedthelemdetemodlemTheselehighthosquaimptheHPLroutmat
 S. Gu
 S. S.
Els S. A
200 S. H
(b)(c)Ch(d)Chg the general applicability, sensitivity and selectivitydetection by more widely using the MSdetector. Theapplicability is an important issue, since the detec-especially the quantitation of UV-inactive impuritiesctive drugs is very problematic using the generally-detectors and this also causes problems in applyingbalance principle for the assay. Although this prob-be solved also by using evaporative light scattering
s , the use of MS detector in the total ion currentems to be necessary even routinely (even if prob-y occur also here with poorly ionisable compounds).lability of relatively inexpensive HPLC-MSD (mass-detector) instruments creates the basis for this. Thesitivity of the MS detector is especially useful inses when the analytical task is the detection andtive measurement of ultra-trace impurities (e.g. signales, genotoxic impurities, etc.). The high selectivity of
spectrometer as a HPLC detector is very useful inV peak purity studies and in detecting rapidly andchanges in the impurity profile of a given bulk drug
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Drug safety, drug quality, drug analysisIntroductionAims and scope of drug analysisDrug safetyDrug qualityDrug purity
The safety issue and the pharmacopoeiasHistorical overviewAssay methods for bulk drug materials in pharmacopoeiasDefinitionNon-selective methodsSelective methods (HPLC)