International Journal of Analytical Mass Spectrometry and Chromatography, 2013, 1, 81-89
Published Online December 2013 (http://www.scirp.org/journal/ijamsc)
http://dx.doi.org/10.4236/ijamsc.2013.12010
Open Access IJAMSC
Analytical Methods in the Quality Control of Scientific
Publications Part II: The Authors’, Reviewers’, Editors’
Responsibility, and the Publishers’ Authority
Ilia Brondz1,2
1Department of Biosciences, University of Oslo, Oslo, Norway
2R & D Department of Jupiter Ltd., Ski, Norway
Received October 8, 2013; revised November 3, 2013; accepted December 7, 2013
Copyright © 2013 Ilia Brondz. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Publication of scientific documents as research reports and original papers has an important place in displaying the au-
thors’ knowledge, integrity, responsibility, and honesty. The same is true for the reviewers and ed itors. The authority of
a publisher strongly depends on the qualification s of the experts who review the manuscripts, and the recommendations
they provide to th e authors and editors. The hon esty of the authors, review ers, and editors is of the utmost importance.
The author of the paper titled “Analytical Methods in Quality Control of Scientific Publications”, which was published
in the American Journal of Analytical Chemistry, 2012, 3, 443-447 (DOI: 10.4236/ajac.2012.36058) had criticized the
paper published by Dongre et al., “Application of GC-EI-MS for the Identification and Investigation of Positional Iso-
mer in Primaquine, an Antimalarial Drug,” Journal of Pharmaceutical and Biomedical Analysis, 2005, 39, 111-116
(DOI: 10.1016/j.jpba.2005.03.019), for presenting falsifications in this publication. Neither the reviewer nor the Edi-
tor-in-Chief Bezhan Chankvetadze of the Journal of Pharmaceutical and Biomedical Analysis has reacted to accusa-
tions of falsification. If a reviewer and editor are poorly qualified, unprincipled, or even corrupt, as was suggested by
Bob Grant in The Scientist magazine (http://www.the-scientist.com/display/55679/#ixzz0mmsPoMIS), it is not good
enough to consider simply that the publisher/journal has a high ranking and is indexed in PubMed or the Institute for
Scientific Information (ISI). In this editorial, we report a profound misunderstanding or a lack of knowledge by the au-
thors Shixue G., Zhuo yu L., and Wei W ., in their p aper published in ZhongguoYaoye China Pharmaceuticals, Vol. 14,
No. 4, 2005, pp. 36-37 and a similar lack of professionalism by reviewers and editors. The influence and the role of
internationally used pharmacopeias, such as The British Pharmacopoeia, European Pharmacopoeia, The United States
Pharmacopeial Conventio n, and United States Pharmacopeia are shown as the main initiators and dr ivers of these mis -
understandings.
Keywords: Primaquine; Isomers; Enantiomers; TLC; Spurious Publications; Pharmacopeias
1. Historic Perspective of the Problem
Every scientist in chemistry and every chemistry student
know that the water is H2O and all the molecules are of
the same composition and character and have the same
chemical properties. The same ideas can be applied to
methanol, glucose, and millions and millions of distinct
chemical substances. No one refers to water as “water
and related substances”. However, this was not applica-
ble to primaquine as a description by the members of
international pharmacopeia committees. The decision of
pharmacopeia committees concerning primaquine was
that primaquine is “primaquine and related substances”
[1-7]. In this editorial, we report a profound misunder-
standing in paper published by the authors Shixue G.,
Zhuoyu L., and Wei W. [8], who claimed to resolve pri-
maquine enantiomers using TLC without transforming
the enantiomers to diastereomers or to a diastereomeric
transitional state.
2. Primaquine
What meant by the “related substances” in terms of pri-
maquine? How they related? Are the substan ces the deg-
radation products produced during shelf life (storage), or
are they byproducts of primaquine synthesis, remaining

I. BRONDZ 82
unreacted reagents, or something else? The members of
pharmacopeia committees were diffidently silent on this
issue. Primaquine phosphate [1] slowly transforms to
become primaquine diphosphate [9], and later to prima-
quine bis-phosphate. Primaquine has also been qualified
as primaquine and its enantiomer [10]; however, it ap-
pears to have been never straightforwardly and openly
stated that primaquine has been contaminated with sig-
nificant proportions of a toxic substance known as qui-
nocide and should be classified as primaquine and qui-
nocide. Quinocide was found in primaquine as long ago
as 1997 as shown in docu ment Figure 1 and described in
publications [11-14].
Primaquine is a mixture of two enantiomers of prima-
quine and two enantiomers of quinocide. These enanti-
omers are found in raw ware primaquine; the mixture is
optical active and as such is not racemic. This is shown
in Figure 2.
In primaquine, the proportions of contaminants at the
time of discovery of the contaminant quinocide in (1997-
1998) were from 10% in low quality samples to 6.5% in
the highest quality sa mples, but never less than 6%. Fig-
ure 3 is a copy of the original documents for the routine
analysis of commercial raw ware primaquine. This
analysis was reported by an analytical laboratory, Weifa
AS, Oslo, Norway.
In this document, the total contamination level was
recorded at over 8%.
The unexplained definition of “related substances” has
brought to light a lot of speculations. To date, pharma-
copeia committees appear to have resisted recognizing
the presence of contamination of primaquine with the
defined chemical and toxic substance quinocide, which
exceeded accepted norms for a single known contaminant.
An example of the definition given in the United States
Pharmacopeia (USP) [15] is reproduced in Fig u r e 4.
What is the primaquine related compound Aa 8-[(4-
aminopentyl) amino]-6-methoxyquinoline? In what way
or manner is primaquine, which is N-(6-methoxyquino-
lin- 8-y l) p e nt a n e -1,4- di a mi ne r e late d t o 8-[(4- am i nope nt yl )
amino]-6-methoxyquinoline?
How is primaquine related to 8-[(4-aminopentyl)
amino]-6-methoxyquinoline as shown in Figure 5? The
recognition of single and defined contaminant or “speci-
fied unidentified impurity” at this magnitude should lead
to the demand for the requalification of the permitted
amount of contamination in primaquine or acceptance of
the high level of contamination with a single known
contaminant in other drugs. It is not a case with the “re-
lated substance”. Howev er, according to this table from a
USP publication [15] quinocide is present in primaquine
at NMT 2%, despite the fact that approximately 3% of
this substance was present in nearly all raw unprocessed
primaquine used in the pharmaceutical industry before. Is
this reduction because of the changes and use at presence
new synthes i s procedure for prim a quine?
There are general rules for permitted amounts of a sin-
gle known contaminant in pharmaceutical preparations.
If these rules are followed, the pharmaceutical industry
will lose significant income, which this industry receives
by launching improper products (with single contaminant
about 2%) as primaquine with the apparent blessings of
pharmacopeia committees.
Knowledge of the contamination of primaquine with
quinocide has been available since 1997. We had many
problems to overcome before we could break barriers to
present this information in 2003 [11]. The pharmaceuti-
cal industry and pharmacopeia committees put obstacles
in the way of obtaining this information. Globally, the
pharmaceutical industry, pharmaceutical authorities, and
pharmacopeia committees conducted a circus perform-
ance, the circus of “non-recognition the fact of contami-
nation of primaquine with quinocide”. The Chongqing
Institute for Drug Control was no exception to the rule
[8]. At present, other circus performances are taking
place: “the non-information about the toxic abilities of
the mixture of 8-[(4-aminopentyl)amino]-6-methoxyqui-
noline with primaquine.”
3. Isomers and Isomerism
In organic chemistry, there are several million different
compounds, but most of them are composed of very few
elements: C, H, O, N, S, halides, and more rarely, several
metals. A chemical formula presents the substance by
composition of these elements qualitatively an d quantita-
tively, for example: C4H10. The formula, or as it is called,
the empirical formula for this substance can represent
n-butane. However, two different substances with this
empirical formula exist, (normal) n-butane and 2-
methylpropane. In isomers, the elements are commonly
found in the same number in chemical formulae, but are
connected in various different ways. The carbon atoms in
each of these substances are connected to each other in a
different way. The connection of carbon atoms in a
molecule is shown by the structural formula. The struc-
tural formulae of both n-butane an d 2-methylpropan e are
shown in Figure 6.
Different compounds that have the same empirical,
molecular formula are “empirical formula isomers”. Two
empirical formula isomers can also be the constitutional
isomers. Primaquine and quinocide are shown in Figure
7. They are also empirical formula and constitutional
isomers at the same time.
Constitutional isomers are isomers that differ in the
order in which their atoms are connected, and are also
known as “structural isomers”. The formal definition of
constitutional isomers is “compounds that have the same
molecular formula and different connectivity”.
Because carbon atoms have a valence of four, they can
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I. BRONDZ
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83
Figure 1. The contamination of primaquine by quinocide has been publicly known since April 1998.

I. BRONDZ 84
Figure 2. A solution of raw ware primaquine use d in indus-
try. Primaquine is optically active and not racemic. The CD
analysis demonstrated this [14].
be connected to four other different atoms. Valences can
be visually placed at the corners of a tetrahedron; such
constructions are symmetric if all corners of the tetrahe-
dron are occupied by atoms of the same type and can be
superimposed or asymmetric if the four corners are oc-
cupied by different atoms and cannot be superimposed,
as shown in Figure 8. This is also true if the atoms are
changed to functional groups or other substituents. The
carbon in molecules in Figure 8 is known as an asym-
metric or chiral carbon. Solutions of molecules contain-
ing a chiral carbon in their structure have the property of
being able to rotate the plane of polarized light. Two
molecules with different spatial locations of different
atoms around carbon are stereoisomers. Enantiomers are
two stereoisomers that are related to each other by a
mirror reflection: they are mirror images of each other,
which are non-superimposable. Two enantiomers are
shown in Figure 8.
Enantiomers in Figure 8, by contrast with isomers in
Figure 7, have the same physicochemical properties such
as melting point, boiling point, and solubility, with the
exception of rotating a plane of polarized light in oppo-
site directions. If, when in solution, all molecules of the
enantiomer rotate the plane of polarized light in a clock-
wise direction they are described as the (+)-enantiomer.
If, when in solution all molecules of the enantiomer ro-
tate the plane of polarized light in a counterclockwise
direction they are described as the (–)-enantiomer. The
angle of the rotation of a plane of polarized light by each
molecule of an enantiomer pair has the same magnitude,
but different direction. The enantiomers crystalize as
right or left crystals depending on the sign of the enan-
tiomer. Enantiomer molecules of different signs of rota-
tion have different reactivity toward enzymes and bio-
logical systems.
4. Diastereomers
There are a number of other isomers; however, it is of
interest here to understand that diastereomers are isomers
with two chiral carbons in their molecules as shown in
Figure 9.
Two diastereomers respectively, have different phys-
icochemical properties such as melting point, boiling
point, and solubility. They are also can be optically ac-
tive; a solution of diastereomers can rotate a plane of
polarized light.
5. Mixture of Enantiomers
In nature, because of stereospecific synthesis involving
enzymes, as a rule all molecules that are formed by pri-
mary synthesis have a common stereochemistry. In biol-
ogy, adopted nomenclature for the chiral carbons is levo
(L-) and dextro (D-). All naturally occurring amino acids
in proteins belong to the L-stereo chemical series. It is
possible to find amino acids with D-chirality; however,
this is because of secondary metabolic transformation.
“Enantiomer” is the modern term for “optical isomer.” In
industrial synthesis, stereospecific synthesis is seldom
used. It is usual to use nonstereospecific synthesis.
Therefore, industrial synthesis usually results in a mix-
ture of enantiomers. A solution of 50% (+)-enantiomers
and 50% of (–)-enantiomers does not rotate plane polar-
ized light. The solution is called optically inactive or
racemic, or a simple “racemate”. A solution in which one
of the enantiomer presented in excess, but not to the ex-
clusion of the other, is called “enantioenriched”.
However, the (+)/(–) system has no fixed relationship
with the (R)/(S) system. Optical activity is easy to meas-
ure, but advanced equipment is needed to decide whether
a molecule has an R or S configuration. Pharmacopeia
committees broadly and heavily misuse this point.
6. Enantiomer Resolution (Chiral
Resolution)
Several different techniques are used to separate sub-
stances. One of the techniques is chromatography. The
separation of enantiomers by chromatography is called
“resolution of enantiomers” or “chiral resolution”, or
simply “resolution”. The chromatography technique is
mainly based on the physicochemical properties of mo-
lecules.
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I. BRONDZ 85
Figure 3. The document from routine laboratory analysis at Weifa AS, Oslo, Norway shows more than 8% contamination
with quinocide. The primaquine content in the raw ware is less than 92%.
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I. BRONDZ 86
Figure 4. There are USP qualitative and quantitative de-
scriptions of the composition of primaquine. Abbreviation
NMT is general notices and requirements in US Pharma-
copeial Convention standing for “not more than”.
Figure 5. (a) Primaquine; (b) Quinocide 8-[(4-aminopentyl)
amino]-6-methoxyquinoline.
Figure 6. The structural formulae of both n-butane and 2-
methylpropane.
Isomers that have distinct differences in melting po int,
boiling point, or solubility can be separated by chroma-
tographic methods. However, enantiomers have the same
physicochemical properties and cannot be separated by
traditional chromatography. Nevertheless, chromatogra-
Figure 7. The two constitutional isomers: primaquine and
quinocide.
Figure 8. Enantiomers are two stereoisomers that are re-
lated to each other by a mirror reflection.
Figure 9. Two diastereomers.
phic separation or so-called resolution can be performed
by chromatography for enantiomers. Chromatography
resolution of enantiomers is based on the fact that di-
astereomers have different physicochemical properties
such as melting point, boiling point, or solubility. Three
main approaches are used. 1) A synthetic reaction of a
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I. BRONDZ 87
mixture of a pair of enantiomers with an optically active
isomer. The demands of the reaction are that the products
become diastereomers and that diastereomers can be de-
composed to the initial enantiomers and an additional
product (optically active substance). 2) The enantiomers
and an optically active substance in solution (mobile
phase) compose a transitional diastereomeric state and
this transitional state is easy decomposed into initial re-
agents. The specific substance in the mobile phase,
which is called a “chiral selector”, is an optically active
substance. 3) The use of an “enantio-/chiral support” or
“enantio-/chiral stationary phase”; which, under chroma-
tographic conditions, forms a transitional diastereomeric
state with enantiomers. The transitional diastereomeric
state is in mass balance with the reactants. The reactants
(enantiomer stationary phase/enantiomers in solution) will
be composed and decomposed during the chroma-
tographic process. In all of these approaches, the trans-
formation of a mixture of a pair of enantiomers to the
mixture of diastereomers is needed for resolution. An
enantiomer mixture without these processes cannot be
resolved.
7. Is It “A New Method to Resolve
Enantiomers on TLC” without
Transforming the Enantiomers to
Diastereomers or to a Diastereomeric
Transitional State?
The publication by Shixue et al. [8], (the part of text
presented in Figure 10) describes a groundbreaking dis-
covery, which can be summarized as separation of sub-
(a)
(b)
Figure 10. (a) The text described resolution of enantiomers without selectors on non-chiral phase is the part of text from
original journal; (b) The text below is text from Web SciFinde r Scholar.
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I. BRONDZ 88
stances related to primaquine and its enantiomer that was
achieved by using TLC and HPLC with mobile phases,
without selectors, and on a silica based support/statio nary
phase (achiral phase). Most interesting in this discovery
was the authentication of a spot as an enantiomer to pri-
maquine. The spot was separated from primaquine and
was above the primaquine spot on the TLC plate. The
spot was presented as an authentic enantiomer of prima-
quine.
Without a doubt, the results of this outstanding dis-
covery were directly inspired by publication of informa-
tion in pharmacopoeias [6,7,9] and in the other out-
standing scientific publications of authoritative power.
How could a simple pharmaceutical analyst stand against
the “Bibles of Pharmacy?” The qualifications of the lead-
ing scientists in the Chongqing Institute of Drug Control
Committee, Chongqing, 400015, China who recognized
and allowed publication of these results are not clear.
However, of most interest is in the absence of reactions
from the reviewers and editor of China Pharmaceuticals.
How could this paper be published in a serious journal?
My personal opinion is that members of pharmaco-
poeia committees have guarded the pharmaceutical in-
dustry by concealing knowledge about the presence of
other substance such as quinocide as a contaminant in
primaquine by presenting the contaminant as related sub-
stance or as enantiomer.
An interesting approach was taken in the USP [16] in
which description of related substances or (S) and (R)
enantiomers is omitted. Who would protest against the
definition that primaquine is a (+/–)-8-[(4-amino-1-me-
thylbutyl)amino]-6-methoxyquinoline with an empirical
formula C15H21N3O as it defined in [16]. The analysis of
primaquine was published [11-14,17-21] and as a tech-
nical note in 2006 in [17], and discussion is in progress
[14,18-21].
8. Conclusions
1) Plagiarism, falsification [22], and corruption by
some authors, journal editors, and reviewer s , a r e the most
important plague of scientific and professional publica-
tion [23].
2) This defect is present in all classes of publications
including the highly indexed and those with high reputa-
tions.
3) A harder line should be taken against plagiarism.
4) The identity of reviewers should be known.
5) The introduction of academic editors for the review
of papers is needed.
6) The exclusion of Editors-in-Chief found to have
concealed falsified papers should be taken as an action
by all publishers.
7) The exclusion of Editors-in-Chief guilty of corrup-
tion should be taken as an action by all publishers.
REFERENCES
[1] “British Pharmacopoeia,” Vol. I, HMSO, London, 1988,
p. 462.
[2] “British Pharmacopoeia,” 1988, HMSO, London, 1990, p.
1252 (Addendum).
[3] “British Pharmacopoeia,” Vol. I, HMSO, London, 1993,
p. 541.
[4] “British Pharmacopoeia,” 1993, HMSO, London, 1997, p.
2015 (Addendum).
[5] “European Pharmacopoeia,” 3rd Edition, Council of Euro p e,
Strasbourg, 1997, p. 1385.
[6] “British Pharmacopoeia,” Vol. I, HMSO, London, 2000,
p. 1285.
[7] “European Pharmacopoeia,” 3rd Edition, Council of Euro p e,
Strasbourg, 2001, p. 1323.
[8] S. X. Gong, Z. Y. Lei and W. Wu, “薄层色谱法检查磷
酸伯氨喹的有关物质及对映异构体的研究(Study on
the Test for Related Substances of Primaquine Phosphate
by TLC and Its Enantiomers),” ZhongguoYaoye (China
Pharmaceuticals), Vol. 14, No. 4, 2005, pp. 36-37. (in
Chinese)
[9] “European Pharmacopoeia,” 5th Edition, Main Volume
5.0, 2005 with Supplements 5.1 a nd 5.2, Co uncil of Eu rope,
Strasbourg, 2004, p. 2308.
[10] “British Pharmacopoeia,” 14th Edition, Her Majesty’s
Stationary Office, London on Behalf of MHRA, London,
2009, Vol. I & II.
[11] I. Brondz, D. Mantzeilas, U. Klein, M. N. Lebedeva, F.S.
Mikhailitsyn, G. D. Souleimanov and D. Ekeberg, “The
Main Contaminant of the Anti-Malarial Drug Primaquine
Is Its Positional Isomer,” The 3rd International Sympo-
sium on Separation in BioSciences SBS 20 03: A 100 Years
of Chromatography, Moscow, 13-18 May 2003, Abstract
p. 57, 165.
[12] I. Brondz, D. Mantzilas, U. Klein, D. Ekeberg, E. Hvattum,
M. N. Lebedeva, F. S. Mikhailitsyn, G. D. Souleimanov
and J. Røe, “Nature of the Main Contaminant in the Anti-
malaria Drug Primaquine Di-Phosphate: A Qualitative
Isomer Analysis,” Chromatography B: Biomedical Sci-
ences and Applications, Vol. 800, No. 1-2, 2004, pp. 211-
223. http://dx.doi.org/10.1016/j.jchromb.2003.09.042
[13] I. Brondz, U. Klein, D. Ekeberg, D. Mantzilas, E. Hvat-
tum, H. Schultz and F. S. Mikhailitsyn “Nature of the
Main Contaminant in the Anti-Malaria Drug Primaquine
Di-Phosphate: GC-MS Analysis,” Asian Journal of Chem-
istry, Vol. 17, No. 3, 2005, pp. 1678-1688.
[14] I. Brondz, “Historical Overview of Chromatography and
Related Techniques in Analysis of Antimalarial Drug
Primaquine,” I. Brondz, Ed., Nova Science Publishers,
Inc., New York, 2011.
[15] “The United States Pharmacopeial Convention, Revision
Bulletin,” 2012.
http://www.usp.org/sites/default/files/usp_pdf/EN/USPN
F/primaquine_phosphate-m69050.pdf
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I. BRONDZ 89
[16] USP 34/NF 29, Ed., “United States Pharmacopeia. The
National Formulary,” The United States Pharmacopoeial
Convention Inc., Rockville, Vol. 3, 2011, p. 4011.
[17] I. Brondz, U. Klein, D. Ekeberg, D. Mantzilas, E. Hvat-
tum, H. Schultz and F. S. Mikhailitsyn, “Nature of the
Main Contaminant in the Antimalarial Drug Primaquine
Diphosphate: GC-MS Analysis,” International Symposium
Analytical Forum 2004, Warsaw, 4-8 July 2004, Abstract
p. 119.
[18] I. Brondz and U. Klein, “Separation of the Positional
Isomer Quinocide from the Anti-Malarial Drug Prima-
quine Using a Discovery® HS F5 HPLC Column,” The
Reporter, Vol. 23, No. 4, 2005, p. 1.
[19] I. Brondz, D. Ekeberg, L. Karaliova, I. Jennings, J. A.
Hustad and R. Svendsen, “Separation of the Positional
Isomer Quinocide fro m the Anti-Malaria Drug Primaq uine
Using a Discovery® HS-F5 HPLC Column,” Trends in
Chromatography, Vol. 1, 2005, pp. 78-81.
[20] I. Brondz, U. Klein, L. Karaliova, V. Vlachos, P. Oakley,
R. Leideborg and F. Mikhalitsyn, “Nature of the Main
Contaminant in the Drug Primaquine Di-Phosphate:
Comparison of HPLC and SFC Methods,” 29th Interna-
tional Symposium on High Performance Liquid Phase
Separations and Related Techniques, Stockholm, 26-30
June 2005, Abstract p. 12: 43.
[21] I. Brondz and U. Klein, “Separation of the Positional
Isomer Quinocide from the Anti-Malarial Drug Prima-
quine Using a Discovery® HS F5 HPLC Column,” The
Reporter, Vol. 19, 2006, p. 3.
[22] V. G. Dongre, P. P. Karmuse, M. M. Nimbalkar, D. Singh
and A. Kumar, “Application of GC-EI-MS for the Identi-
fication and Investigation of Positional Isomer in Prima-
quine, an Antimalarial Drug,” Journal of Pharmaceutical
and Biomedical Analysis, Vol. 39, No. 1-2, 2005, pp.
111-116. http://dx.doi.org/10.1016/j.jpba.2005.03.019
[23] I. Brondz, “Analytical Methods in Quality Control of
Scientific Publications,” American Journal of Analytical
Chemistry, Vol. 3, No. 6, 2012, pp. 443-447.
http://dx.doi.org/10.4236/ajac.2012.36058
Open Access IJAMSC