Analytical Methods in the Quality Control of Scientific Publications Part II: The Authors’, Reviewers’, Editors’ Responsibility, and the Publishers’ Authority

doi:10.4236/ijamsc.2013.12010

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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

Email: ilia.brond[email protected]; ilia[email protected]

Received October 8, 2013; revised November 3, 2013; accepted December 7, 2013

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

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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Figure 1. The contamination of primaquine by quinocide has been publicly known since April 1998.

I. BRONDZ

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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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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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

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.

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I. BRONDZ 89

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[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