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Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

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Journal of Pharmaceutical and Biomedical Analysis


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Review

Forced degradation and impurity proling: Recent trends in


analytical perspectives
Deepti Jaina , Pawan Kumar Basniwala , b , *
a
b

School of Pharmaceutical Sciences, Rajiv Gandhi Technological University, Bhopal 462 033, Madhya Pradesh, India
LBS College of Pharmacy, Jaipur 302 004, Rajasthan, India

a r t i c l e

i n f o

Article history:
Received 9 May 2013
Received in revised form 28 June 2013
Accepted 7 July 2013
Available online 31 July 2013
Keywords:
Impurity
Forced degradation proling
Analytical perspectives
active pharmaceutical ingredient
Drug products

a b s t r a c t
This review describes an epigrammatic impression of the recent trends in analytical perspectives of degradation and impurities proling of pharmaceuticals including active pharmaceutical ingredient (API) as well
as drug products during 20082012. These recent trends in forced degradation and impurity proling were
discussed on the head of year of publication; columns, matrix (API and dosage forms) and type of elution
in chromatography (isocratic and gradient); therapeutic categories of the drug which were used for analysis. It focuses distinctly on comprehensive update of various analytical methods including hyphenated
techniques for the identication and quantication of thresholds of impurities and degradants in different
pharmaceutical matrices.

c 2013 Elsevier B.V. All rights reserved.

1. Introduction

Abbreviations: 13 C NMR, 13 carbon nuclear magnetic resonance spectroscopy; 1D/


2D NMR, one dimensional/two dimensional nuclear magnetic resonance; 1 H NMR,
proton nuclear magnetic resonance spectroscopy; AAMRT, auto-associative multivariate regression trees; ACN, acetonitrile; APCI-MS, atmospheric-pressure chemicalionization mass spectrometry; API, active pharmaceutical ingredient; BADGE, bisphenol A diglycidyl ether; BEH, bridged ethylene hybrid; C6 H6 , benzene; CAD, charged
aerosol detector; CCD, central composite design; CCl4 , tetrachloromethane; CEAD,
coulometric electrode array detection; CH2 Cl2 , methylene chloride; CH3 COONH4 , ammonium acetate; CHCl2 CH2 Cl, 1,1,2-trichloro ethane; CHCl3 , chloroform; CID, collisioninduced dissociation; CO2 , carbon dioxide; COPD, chronic obstructive pulmonary
disease; DAD/MS, diode array detector-mass spectrometry; DEPT, distortionless enhancement by polarization transfer; EDTA, ethylene diamine tetra acetic acid; ELSD,
evaporative light scattering detector; EMEA, European agency for the evaluation of
medicinal products; ESI/MSn , electronspray ionization multi-stage or tandem mass
spectrometry; ESI-FTICR-MS, electrospray ionization Fourier transform ion cyclotron
resonance mass spectrometry; USFDA, US Food and Drug Administration; FTICR,
Fourier transform ion cyclotron resonance; FT-IR, Fourier transform infrared; GCFID, gas chromatography-ame ionization detector; GCMS, gas chromatography
mass spectrometry; GFC, gel ltration chromatography; GTIs, genotoxic impurities;
H2 O, water; H3 PO4 , phosphoric acid; HCl, hydrochloric acid; HCOOH, formic acid;
HCOONH4 , ammonium formate; HEIP, 1,1,1,3,3,3-hexauoroisopropanol; HILIC, hydrophilic interaction chromatography; HPAE-IPAD, high-performance anion-exchange
chromatography-integrated pulsed amperometric detection; HPLC, high performance
liquid chromatography; HPLC/ESI-MS, high-performance liquid chromatography/
electrospray ionization mass spectrometry; HP-SEC, high-performance size-exclusion
chromatography; HPTLC, high performance thin layer chromatography; ICH, International Conference on Harmonization; IFM, impurity fate mapping; IND, investigational
new drugs; IPA, isoproyl alcohol; K2 HPO4 , dipotassium hydrogen phosphate; KH2 PO4 ,
potassium dihydrogen phosphate; KOH, potassium hydroxide; LC/MS/MS, liquid
chromatographytandem mass spectrometry; ESI-CID-MS/MS, electrospray ionization, collision-induced dissociation and tandem mass spectrometry; LCESI-MSn , liquid chromatographyelectro spray ionization-tandem mass spectrometer; LCESI-QT/

c 2013 Elsevier B.V. All rights reserved.


0731-7085/$ - see front matter 
http://dx.doi.org/10.1016/j.jpba.2013.07.013

A clean bill of health of public is the ultimate motto of pharmaceutical industries. The objective of the pharmaceutical industries
is to protect the public health by enabling the patients to get proper
medicine in proper dose and efcacy at an affordable cost. Thus, safety
and efcacy of pharmaceuticals are two fundamental issues of importance in drug therapy. The safety of a drug is determined by its
pharmacologicaltoxicological prole as well as the adverse effects
caused by the impurities in bulk and dosage forms, i.e., the safety of

MS/MS, liquid chromatographytandem mass spectrometry using electrospray ionization source and Q-trap mass analyzer; LCMS, liquid chromatographymass spectrometry; LiCl, lithium chloride; MDMA, 3,4-methylenedioxy-N-methylamphetamine;
MECC, micellar electrokinetic capillary chromatography; MEKC, micellar electrokinetic
chromatography; MeOH, methanol; MPLC, medium pressure liquid chromatography;
MPTP, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; CE, capillary electrophoresis;
MS, mass spectrometry; Na2 HPO4 , disodium phosphate; Na3 PO4 , sodium phosphate;
NaCl, sodium chloride; NDA, New Drug Application; NH3 , ammonia; NH4 H2 PO4 , ammonium dihydrogen phosphate; NH4 OH, ammonium hydroxide; NOESY, nuclear overhauser effect spectroscopy; NSAIDs, non-steroidal anti-inammatory drugs; OVIs, organic volatile impurities; PCA, principal component analysis; PDA, photodiode array; PDA-MS, photodiode array detector-mass spectrometry; PFPA, pentauoropropionic acid anhydride; Q-TOF, quadrupole-time-of-ight; RI, refractive index; RRF, relative response factor; SDS, sodium dodecyl sulfate; SDS-PAGE, sodium dodecyl sulfate
polyacrylamide gel electrophoresis; SFC, supercritical uid chromatography; SPME,
headspace solid phase microextraction; TEA, triethylamine; TFA, triuoroacetic acid;
Tris, trisaminomethane; UPLC, ultra performance liquid chromatography.
* Corresponding author at: LBS College of Pharmacy, Jaipur 302 004, Rajasthan, India.
Tel.: +91 9414788171.
E-mail addresses: deepti2515@yahoo.com (D. Jain) pawanbasniwal@gmail.com
(P.K. Basniwal).

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D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

a drug product is dependent not only on the toxicological properties


of the active drug substance itself, but on the impurities that it contains. Another side of coin is that the formulation should be stable
throughout shelf life of product with respect to its identity, strength,
purity and quality of drug. Quality of pharmaceuticals has to be monitored from the very beginning, i.e., from raw materials to the end,
i.e., nished product, including marketing surveillance [13].
As per Websters dictionary impurity is something that is impure
or makes something else impure. An impure substance may be dened as a substance of interest mixed or impregnated with an extraneous or usually inferior substance [4,5]. A number of terms have been
commonly used to describe organic impurities, such as starting material, intermediates, penultimate intermediate (nal intermediate),
by-products, transformation products, interaction products related
products and degradation products. The United States Pharmacopoeia
(USP) has different sections for impurities including impurities in
ofcial articles, ordinary impurities and organic volatile impurities.
These are described as foreign substances, toxic impurities, concomitant components, signal impurities, ordinary impurities and organic
volatile impurities (OVIs) [6] (Tables 1 and 2).
ICH guidelines categories impurities as: organic impurities (starting materials, process-related impurities, intermediates and degradation products); inorganic impurities (salts, catalysts, ligands and
heavy metals); other materials (lter aids and charcoal) and residual solvents (organic and inorganic liquids) [2]. ICH guidelines give
simple classication of the impurities while none of these are unable
to describe enantiomeric (chiral) impurities. Chiral impurities have
the identical molecular formula and the same connectivity between
various atoms, and they differ only in three-dimensional arrangement of their atoms in the space. The differences in pharmacological/
toxicological proles have been observed with chiral impurities in
vivo [7].
Therefore, it is quite obvious that the products intended for human consumption must be characterized as completely as possible.
Monitoring and controlling of impurities generally give assurance of
the quality and safety of a drug. Thus, the analytical activities concerning impurities in drugs are among the most important issues in
modern pharmaceutical analysis [8,9]. Analytical monitoring of impurities in new drug substances is a key component of the recent
guideline issued by the International Conference on Harmonization
(ICH) [2].
Forced degradation studies provide data to support identication
of possible degradants; degradation pathways and intrinsic stability
of the drug molecule and validation of stability indicating analytical
procedures. A draft guidance document suggests that results of onetime forced degradation studies should be included in Phase 3 INDs
(Investigational New Drugs). NDA (New Drug Application) registration requires data of forced degradation studies as forced degradation
products, degradation reaction kinetics, structure, mass balance, drug
peak purity, etc. This forced degradation study provides information
about degradation pathways of API, alone and in drug product, any
possible polymorphic or enantiomeric substances and difference between drug related degradation and excipient interferences [24].
Thus, forced degradation and impurity proling is one of the key
for IND as well as NDA registration document. Although different
books [11,12] and review articles [1316] have been published to
summarize the study on impurity and degradation proling, but still
there is no report on recent years which enable to describe the recent
analytical perspectives of impurity and degradation proling. Keeping this view in the mind, present work has been aimed to review the
analytical trends for forced degradation studies and impurity proling
of active pharmaceutical ingredients and pharmaceutical drug product. Articles published on forced degradation studies and impurity
proling during 20082012, were extensively reviewed and different
parameters, such as matrix of analysis, therapeutic category of the
drug, present impurity and degradant, column specication used for

Fig. 1. Year-wise publications for impurity and degradation proling during 2008
2012 .

separation, mobile phase composition used for elution, mode and/or


wavelength of detection and year of publication were accounted to
set the recent trend in analytical perspective.
2. Analytical perspectives
2.1. Yearly trend
For this write-up, publications were extensively reviewed which
were published on impurity, degradation proling and stability indicating assay methods during 20082012; which includes HPLC, capillary electrophoresis, gas/liquid chromatography, thin-layer chromatography, etc. Fig. 1 has shown column graph of year-wise publications for impurity and degradation proling during 20082012,
which reveals that in general such study are increasing year by year.
Unanimously, HPLC and its hyphenated techniques have been
proved as main technique for forced degradation and impurity proling. Year-wise analytical perspectives were discussed as following:
2.1.1. 2008
2.1.1.1. Impurity proling Refractive index (RI) detector as universal detector in analytical HPLC was employed for identication of 12 impurities of clindamycin palmitate hydrochloride,
which were isolated by preparative HPLC and characterized by
LCMS, FT-IR, NMR {1 H, 13 C and distortionless enhancement by
polarization transfer (DEPT)} techniques [28] and same techniques were also used for characterization of oxidation impurity
of clopidogrel as 5-[1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-6,7dihydrothieno[3,2-c]pyridin-5-ium [29]. Econazole nitrate is potent broad-spectrum antifungal used for skin infections. Its two
main impurities were determined 4-chlorobenzyl alcohol and (2,4-dichlorophenyl)-1H-imidazole-1-ethanol in cream formulations
along with two preservatives [33]. HPLC-DAD and HPLCMS were
compared for identication by peak tracking in impurity proling of quinolones, which provides spectral specicity and 2D
chromatographic correlation [38]. Four impurities of montelukast
sodium were identied during process development by LCMS in
the range of 0.050.15% [44]. Normal phase of HPLC and chiral amylase stationary phase were used to determine enantiomers impurity of phenylethanolamine derivative by using n-hexaneethanol
triethylamine (TEA) as mobile phase [47]. HPLC equipped with coulometric electrode array detection (CEAD) was used for determination of pipecuronium bromide and its four impurities, which provides very high sensitivity and selectivity. In coulometric electrode
array system, multiple channels are set at different potentials to
give a two-dimensional analysis (Fig. 2). A peak is identied not
only by retention time but also by dominant channel and peak ratios across the channels (as compared to standard), which is especially useful when evaluating component in a complex mixture

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

13

Table 1
Different terminology used for impurities [10].
Impurity

Description

Starting material
Intermediates

Materials that are used to begin the synthesis of an API


Produced during synthesis of the desired material, especially when they have been isolated and
characterized
Last compound in synthesis chain prior to production of nal compound. Also known as nal
Intermediate
Unplanned compounds produced in the reaction
Relatively nondescript term that relates to theorized and non-theorized products that may be
produced in the reaction, which can include synthetic derivatives of by-products
It considers interactions that could occur between various involved chemicals intentionally or
unintentionally. Two types of interaction products that can be commonly encountered are drug
substanceexcipient interactions and drug substance-container/closure interactions
Similar chemical structures as the API and may exhibit potentially similar biological activity
Produced because of decomposition of the material of interest or active ingredient
Introduced by contamination or adulteration, not as a consequence of synthesis or preparation, are
labeled foreign substances, e.g., pesticides in oral analgesics
Have signicant undesirable biological activity, even as minor components; and they require
individual identication and quantication by specic tests
Bulk pharmaceutical chemicals may contain concomitant components, e.g., antibiotics that are
mixtures and are geometric and optical isomers
Impurities include some process-related impurities or degradation products that provide key
information about process
Impurities in bulk pharmaceutical chemicals that are innocuous by virtue of having no signicant
undesirable biological activity in amounts present are called ordinary impurities
Residual solvents that may be found in drug substance. ICH classication: Class I (to be avoided): C6 H6 ,
CCl4 , 1,2-dichloromethane, 1,1-dichloroethane, and 1,1,1-trichloroethane. Class II (should be limited):
ACN, CHCl3 , CH2 Cl2 , pyridine CHCl2 CH2 Cl, and 1,4-dioxane. Class III: low toxic potential and permitted
daily exposure of 50 mg or more. Class IV: solvents for which adequate toxic data are not available
Starting materials, process-related impurities, intermediates, and degradation products
Salts, catalysts, ligands, heavy metals or other residual metals
Filter aids and charcoal
Organic and inorganic liquids used during production and/or crystallization
Differ only in the arrangement of their atoms in three-dimensional space. The differences in
pharmacological/toxicological proles have been observed with chiral impurities in vivo

Penultimate intermediate
By-products
Transformation products
Interaction products

Related products
Degradation products
Foreign substances
Toxic impurities
Concomitant components
Signal impurities
Ordinary impurities
Organic volatile impurities

Organic impurities
Inorganic impurities
Other materials
Residual solvents
Chiral impurities

Fig. 2. Chromatograms recorded from the mixture containing 1 g ml1 of PIB and
its four impurities on coulometric electrodes at increasing potentials: 300, 400, 500,
600, 700, 800, 850, and 900 mV. (Reuse with the permission of Elsevier Limited, The
Boulevard, Langford Lane, Kidlington, Oxford, OX5 1GB, UK.)

[48]. HPLC method was transferred to develop ultra-performance


liquid chromatography (UPLC) equipped with BEH column for determination of primaquine phosphate along with its related substance within run time of 5 min [50]. Two impurities of tazarotene
were characterized by means of NMR analysis as ethyl 6-((4,4dimethyl-4H-thiochromen-6-yl)ethynyl)nicotinate and 1,4-bis(4,4dimethylthiochroman-6-yl)buta-1,3-diyne, which are by-product of
synthetic process [53].

2.1.1.2. Forced degradation proling HPLC with uorescence detector was employed to study stability of betahistine in different forced
degradation conditions (heat, moisture, acidbase, and ultra-violet
light), where two potential degradation products were identied. The

dansylated products of UV-degraded betahistine were well separated


by thin-layer chromatography [22]. Second order reaction was followed by alkaline forced degradation of bicalutamide, where an acid
and an amine were identied as alkaline degradants [24]. Very interesting, four major degradation products of dexamethasone in its
coated drug-eluting stents and drug-loading solution were identied
which was used for local drug delivery to prevent restenosis [30].
Both + ESI and ESI modes of LCMS were used to characterize three
known and two unknown forced degradation products of glimepiride
formed under different stress conditions. Degradants were formed
due to hydrolysis of sulfonylurea and lactam bridge [39] while lthyroxine was determined in presence of eight degradation impurities
and its dosage form excipients [40]. A degradation product of pridinol
mesylate was identied as the dehydrated and N-oxidation derivatives, which was formed by rst-order kinetics of the acid-catalyzed
degradation of pridinol [49].

2.1.1.3. Impurity and forced degradation proling Mixture of phosphate buffer and acetonitrile were used to separate three processrelated impurities and degradation products (different forced
degradation conditions) of almotriptan malate [18]. In addition
to four known impurities of carvedilol, one unknown degradation product was identied as N-[(2RS)-3-(9H-carbazol-4-yloxy)-2hydroxypropyl]-N-[2-(2-methoxyphenoxy)ethyl]hydroxylamine in
tablet dosage form which was found as exceeded thresholds of
ICH Q3B guidelines [27]. Reversible acetylcholinesterase inhibitor,
donepezil hydrochloride was assayed along with four impurities and
an excipient in oral pharmaceutical formulation, where selectivity of
method was assured from forced degradation of the drug [32]. Degradation pathway for forced degradation behavior of enalapril maleate
was identied in different stress conditions [34] and two degradation
impurities of epirubicin were found in aqueous formulation [35].

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D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

Table 2
Representative chromatographic analytical methods of impurity and forced degradation proling during 20082012.
S.
no.

Name of drug

1.

2.

Methamphetamine
hydrochloride
Almotriptan
malate

Matrix; therapeutic
category

Impurity/degradant

Column/stationary phase

Mobile phase

Detection

API; psychostimulant

29 impurities

Capillary column, 30 m
0.32 mm 1.0 mm

Nitrogen gas

API; antimigraine

3 impurity

C18, 250 mm 4.6 mm,


5 m

Sodium phosphate
buffer (pH 7.6):ACN
(80:20)
ACN:CH3 COOH (25
mM, pH 4.0);
gradient
O-Phosphoric acid
(25 mM, pH 2.5)
and Octane sulfonic
acid (25
mM):n-Propanol
(73:27)
ACN:CH3 COONH4
buffer (pH 4.7; 0.01
M), gradient
ACN: sodium
acetate (0.02 mM,
pH 4.5); gradient

Mass
selective
detector
227 nm

2008 [18]

234 nm

2008 [19]

215 nm

2008 [20]

247 nm

2008 [21]

UV 254 nm;
Fluorescence
336 and 531
nm
PDA-MS
detector
215 nm

2008 [22]

3.

Alprazolam

Tablets; anxiolytic

20 degradant

C18, 150 mm 4.6 mm,


5 m

4.

Atomoxetine
hydrochloride

API; antidepressants

Phenyl
methylamino-propanol
and mandelic acid

C8, 50 mm 4.6 mm,


3.5 m

5.

Atorvastatin
calcium

Tablets;
anti-hyperlipidemic

An acid degraded impurity

C18 (BEH), 100 mm


2.1 mm, 1.7 m

6.

Betahistine

API and tablet;


vasodilator

9 degradants

C18, 250 mm 4.6 mm,


5 m

7.

API; steroid

2 impurities

8.

Betamethasone
17-valerate
Bicalutamide

9.

Bovine obestatin

API and tablet;


anticancer
API; antibodies

2 degradants and 6
process-related impurities
3 impurities

C18, 250 mm 4.6 mm,


5 m
C18, 250 mm 4.6 mm,
5 m
C18, 250 mm 4.6 mm,
5 m

10.

Budesonide

Tablets; steroid

10 impurities

C18, 125 mm 4.6 mm,


5 m

11.

Canine obestatin

API; antibodies

9 impurities

C18, 250 mm 4.6 mm,


5 m

12.

Carvedilol

Tablets;
antihypertensive

5 impurities

C18, 100 mm 4.6 mm,


5 m

13.

API; antibiotic

12 impurities

C18, 250 mm 4.6 mm,


5 m

14.

Clindamycin
palmitate HCl and
clindamycin
Clopidogrel

API; antiplatelet

5-[1-(2-Chlorophenyl)-2methoxy-2-oxoethyl]-6,7dihydrothieno[3,2-c]
pyridin-5-ium

C8, 250 mm 4.6 mm, 5


m

15.

Dexamethasone

Dexamethasone-coated
eluting stents; steroid

Process impurities and


degradants

C8, 4.6 mm 250 mm, 5


m

16.

API; hepatoprotective

5 degradants

C18, 250 mm 4.6 mm


5 m

17.

Dimethyl-4,4 dimethoxy5,6,5 ,6 dimethylene


dioxy-biphenyl2,2 -dicarboxylate
(DDB)
Donepezil HCl

API and tablet;


anti-Alzheimer

4 impurities of side
reaction and degradation

C18, 250 mm 4.6 mm,


5 m

18.

Econazole nitrate

Cream; antifungal

4-Chlorobenzyl alcohol
and
-(2,4-dichloro-phenyl)
-1H-imidazole-1-ethanol)

C18, 300 mm 3.9 mm,


10 m

ACN:H2 O (60:40)
0.01 M KH2 PO4 (pH
3.0):ACN (50:50)
Eluent A: H2 O (0.1%
formic acid); Eluent
B: ACN (0.1% formic
acid); gradient
ACN:phosphate
buffer (pH 3.2, 28.6
mM) (30:70)
Eluent A: H2 O (0.1%
formic acid); Eluent
B: ACN (0.1% formic
acid); gradient
ACN:phosphate
buffer (pH 2.5; 0.01
M) (40:60)
CH3 COONH4
buffer:MeOH
(15:85)
Eluent A: ACN:
potassium
phosphate buffer
(pH 2.3, 10 mM)
(20:80); Eluent B:
ACN: potassium
phosphate buffer
(pH 2.3; 10 mM)
(80:20); gradient
HCOONH4 (20 mM,
pH 3.8):ACN;
gradient
ACN:H2 O (60:40)

Phosphate buffer (5
mM, pH 3.67):
MeOH; gradient
MeOH: H2 O;
gradient

Year
[Ref.]
2008 [17]

2008 [23]
2008 [24]

196, 230 and


296 nm

2008 [25]

240 nm

2008 [26]

196, 230 and


296 nm

2008 [25]

240 nm

2008 [27]

226 nm;
LC/MS/MS

2008 [28]

220 and 300


nm
LC/MS/MS

2008 [29]

239 nm

2008 [30]

235 nm

2008 [31]

270 nm

2008 [32]

220 nm

2008 [33]

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

15

Table 2
Continued
S.
no.

Name of drug

Matrix; therapeutic
category

Impurity/degradant

Column/stationary phase

Mobile phase

Detection

Year
[Ref.]

19.

Enalapril maleate

API; antihypertensive

5 degradants

C18, 250 mm 4.6 mm,


5 m

210 nm

2008 [34]

20.

Epirubicin HCl

Injection; antibiotic

3 degradation impurities

C18, 250 mm 4.6 mm,


5 m

254 nm

2008 [35]

21.

Fenobrate

Tablets;
anti-hyperlipidemic;

Acid and alkali degraded


impurity of each

C18 (BEH), 100 mm


2.1 mm, 1.7 m

247 nm

2008 [36]

22.

Fluorapacin

2 related substances

2008 [37]

Gatioxacin

10 related substances

TEA (1%, pH
4.3):ACN (87:13)

200500 nm

2008 [38]

24.

Glimepiride

API; antidiabetic

5 degradants

C2, 250 mm 4.6 mm, 5


m
C18, 250 mm 4.6 mm,
5 m; C18, 150 mm 6
mm, 5 m; C18, 250 mm
4.6 mm, 5 m
C8, 150 mm 4.6 mm, 5
m

218 nm

23.

API and injection;


anticancer
API; antibacterial

ACN: phosphate
buffer (pH 3);
gradient
Eluent A: 0.1% TFA
Eluent B: ACN:
MeOH:TFA
(80:20:0.1);
gradient
ACN:CH3 COONH4
buffer (10 mM, pH
4.7); gradient
ACN:H2 O (85:15)

235 nm

2008 [39]

25.

Human obestatin

API; antibodies

4 impurities

C18, 250 mm 4.6 mm,


5 m

196, 230 and


296 nm

2008 [25]

26.

Levothyroxine

API; thyroid hormone

8 impurities

C2, 250 mm 4.6 mm, 5


m

223 nm

2008 [40]

27.

Lopinavir

API; anti-HIV

8 related impurities

210 nm

2008 [41]

API; psychostimulant

29 impurities

GC-FID

2008 [42]

API; antiischemic

6 related impurities

C18, 250 mm 4.6 mm,


5 m
Capillary, 30 m 0.32
mm 1.0 m
Amino, 100 mm 3.2
mm, 3 m; cyano, 100
mm 2.1 mm, 5 m;
silica, 100 mm 2.1
mm, 3 m; sulfobetaine,
100 mm 2.1 mm, 5 m
C18, 100 mm 4.6 mm,
3 m

ACN: CH3 COONH4


(20 mM, pH 3)
(20:80)
Eluent A: H2 O (0.1%
formic acid); Eluent
B: ACN (0.1% formic
acid); gradient
Eluent A: TFA
(0.1%); Eluent B:
ACN; gradient
KH2 PO4 (0.02 M, pH
2.5): ACN; gradient
Nitrogen gas
ACN:HCOONH4 (5
mM, pH 5) (85:15)

Electrospray
interface
detector

2008 [43]

Eluent A: Na2 HPO4


buffer (50 mM, pH
3.7): ACN (4:1);
Eluent A: Na2 HPO4
buffer (50 mM, pH
3.7): ACN (1:4);
gradient
Eluent A: H2 O
(HCOOH 0.1%);
Eluent B: ACN
(HCOOH 0.1%);
gradient
Eluent A: TEA (1%,
pH 2.5):MeOH
(70:30); Eluent B:
phosphate buffer
(pH 2.5):ACN
(85:15); gradient
Eluent A: H2 O
(HCOOH 0.1%);
Eluent B: ACN
(HCOOH 0.1%);
gradient
H2 O:ACN (52:48)

225 nm

2008 [44]

196, 230 and


296 nm

2008 [25]

200500 nm

2008 [45]

196, 230 and


296 nm

2008 [25]

227 nm

2008 [46]

28.
29.

Methamphetamine
Mildronate

30.

Montelukast
sodium

API; antiallergic

4 impurities

31.

Mouse obestatin

API; antibodies

3 impurities

C18, 250 mm 4.6 mm,


5 m

32.

Moxioxacin

API; antibacterial

4 related substances

C18, 250 mm 4.6 mm,


5 m; C18, 150 mm 6
mm, 5 m; C18, 250 mm
4.6 mm, 5 m

33.

Ovine obestatin

API; antibodies

5 impurities

C18, 250 mm 4.6 mm,


5 m

34.

Paclitaxel

API; anticancer

10-Deacetylbaccatin III,
baccatin III, 10-deacet-yl7-xylosyltaxol C,
photo-degradant, taxol C,
ceph-alomannine,
10-deacetyl-7-epitaxol,
7-Epi-taxol

Phenyl, 150 mm 4.6


mm, 3 m

16

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

Table 2
Continued
S.
no.

Impurity/degradant

Column/stationary phase

Mobile phase

Detection

Year
[Ref.]

API; antiasthamatic
Phenylethanolamine
derivatives
Pipecuronium
Powder for injection;
bromide
steroid

11 impurities

ASH, 250 mm 4.6 mm,


5 m

nHexane:gthanol:TEA
(98:2:0.1)

254 nm

2008 [47]

4 impurities

Cyano, 250 mm 4.6


mm, 5 m

37.

Pridinol mesylate

API; muscle relaxant

2 degradant

C18, 250 mm 4.6 mm,


5 m

38.

Primaquine
phosphate
Primaquine
phosphate
Salicylaldehyde
isonicotinoyl
hydrazone

API; antimalarial

2 impurities

API; antimalarial

2 impurities

API; chelating agent

2 -Hydroxy-acetophenone, Isonicotinoyl
hydrazone, 2 -hydroxy
propiophenone
Isonicotinoylhydrazone
9 process impurities

C18 (BEH), 50 mm 2.1


mm, 1.7 m
C18, 250 mm 4.6 mm,
5 m
C18, 250 mm 4.6 mm,
5 m

35.

36.

39.
40.

Name of drug

Matrix; therapeutic
category

C18, 250 mm 4.6 mm,


5 m
Capillary, 30 m 0.25
mm, 0.25 m
C18, 250 mm 4.6 mm,
5 m

41.

Tamsulosin

42.

Tazarotene

Capsule, tablet and API;


antihypertensive
API; anti-Acne

43.

Tenatoprazole

API; peptic ulcer

6 degradants

44.

Levooxacin

API; antibacterial

3 process related
impurities and 1 oxidative
degradant

C18, 250 mm 4.6 mm,


5 m

45.

Aalicylic acid and


betamethasone
dipropionate

Lotion;
anti-inammatory

C8, 150 mm 4.6 mm, 4


m

46.

Anastrozole

Tablet; anti-cancer

Salicylic acid related: 7


betamethasone
dipropio-nate related: 15
potential leachables: 5
5 impurities

47.

Biapenem

API; antibiotic

4 impurities

48.

API; antimalarial

4 process related
impurities

49.

Chloroquine and
hydroxychloroquine
Citalopram

API; antidepressant

1 impurity

50.

Cyclosporin A

51.

Diacerein

Soft gelatin capsules;


Immunomodulator
API; antiarrtheritis

4 degradants and 2 related


compounds
2 related impurities

52.

Eletriptan

API; antimigraine

1 degradants (oxidative)

C18, 150 mm 3.9 mm,


5 m

53.

Fatty alcohol
ethoxylates

Surfactant

6 impurities

C1, 4.6 mm 150 mm

54.

Gentamicin

API; antibiotic

33 related impurities

Hydro-RP, 250 mm
4.6 mm, 5 m

55.

Heparin sodium

API; anticoagulant

6 impurities

AS11-HC, 250 mm 4
mm, 9 m

56.

Ibuprofen

API; analgesic

3-[4-(2ZirChrom-CARB, 150 mm
Methylpropyl)phenyl]propanoic 4.6 mm, 5 m; C18,
acid
150 mm 4.6 mm, 5
m; Zr-PS, 150 mm
4.6 mm, 5 m; C18, 150
mm 3.0 mm, 7 m

2 by-product

C3, 250 mm 4.6 mm, 5


m
C18, 4.6 mm 150 mm,
5 m
C18, 250 mm 4.6 mm,
5 m
C18, 100 mm 30 mm 5
m
C18, 250 mm 4 mm, 5
m
C18, 250 mm 4.6 mm,
5 m

2008 [48]
Tetramethylammonium Electrochemical
hydroxide (4.53 g/L,
detection
pH 6.4):ACN (6:4)
220 nm
MeOH:IPA:potassium
phosphate (50 mM,
pH 6.0) (51:9:40)
TFA (0.01%):ACN
265 nm
(75:25)
TFA (0.01%): ACN
265 nm
(75:25)
Phosphate buffer
LCESI-MS
(10 mM + 2 mM
EDTA, pH 6):MeOH
(40:60)
CH3 COONH4 (10
mM):ACN; gradient
Helium gas

2008 [49]

2008 [50]
2008 [50]
2008 [51]

280 nm

2008 [52]

MS detection

2008 [53]

306 nm

2009 [54]

294 nm

2009 [55]

240 nm

2009 [56]

H2 O:ACN; gradient

215 nm

2009 [57]

CH3 COONH4 (1
mM): ACN; gradient
TFA
(0.06%):ACN:IPA
(87:12:1)
NH3 :H2 O:ACN
(0.1:50:50)
THF:phosphoric
acid (0.05M) (44:56)
Acetic acid
(0.10%):ACN (53:
47)
MeOH:H2 O + TEA
(1%) (30:70) (pH
6.52)
Eluent A:
H2 O:MeOH (80:20);
Eluent B: MeOH;
gradient
Eluent A: MTFA
(50m, pH 2); Eluent
B: MeOH; gradient
Eluent A: H2 O;
Eluent B: NaCl (2.5
M + 20 mM Tris,
pH 3); gradient
ACN:phosphate
buffer (25 mM, pH
2.1) (40:60)

220 nm

2009 [58]

220 nm

2009 [59]

225 nm

2009 [60]

220 nm

2009 [61]

254 nm

2009 [62]

225 nm

2009 [63]

ELSD
detector

2009 [64]

ESI/MSn
detection

2009 [65]

215 nm

2009 [66]

220 and 285


nm

2009 [67]

MeOH:acetate
buffer (10 mM, pH
4.5) (55:45)
Eluent A: NaH2 PO4
(25 mM) + 0.5%
TEA (pH 6); EluentB:
MeOH; gradient
Methanesulfonic
acid:ACN (0.05%);
gradient

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

17

Table 2
Continued
S.
no.

Name of drug

Matrix; therapeutic
category

57.

Icofungipen

API; antifungal

58.

Lamivudine

API; anti-HIV

59.

Lansoprazole

API; peptic ulcer

5 enantiomers and related


impurities

Chiral, 250 mm 4.6


mm

60.

Metformin

Tablet; antidiabetic

Related compound:
1-cyanoguanidine

Nova-Pak silica, 150 mm


3.9 mm, 4 m

61.

Moxioxacin HCl

API; antibacterial

4 synthesis-related
impurities

C18, 50 mm 4.6 mm, 5


m

62.

Nevirapine
analogue

API; anti-HIV

3 impurities

Cyano, 4.6 mm 150


mm, 5m

63.

Nimodipine

Tablet;
antihypertensive
Tablet; steroid

3 impurities

C8, 250 mm 4.6 mm, 5


m
C18, 50 mm 2.1 mm, 5
m
C3, 250 mm 4.6 mm, 5
m
C18, 250 mm 4.6 mm,
5 m

Column/stationary phase

Mobile phase

Detection

(1R,2S)-2-(Cinnamyl
amino) -4-methylene
cyclopentane carboxylic
acid
5 degradants

C18, 1005 AB

ACN:H2 O (25:75)

210 and 254


nm

2009 [68]

C18, 250 mm 4.6 mm,


5 m

Eluent A: MeOH;
Eluent B:
CH3 COONH4 buffer
(10 mM, pH4);
gradient
Methyl-tert-butyl
ether:ethyl
acetate:ethanol
diethylamine
(60:40:5:0.1)
NH4 H2 PO4
buffer:MeOH
(21:79)`
H2 O + TEA
(2%):ACN 90:10 (pH
6.0)
Eluent A: H2 O
(HCOOH 0.1%);
Eluent B: ACN
(HCOOH 0.1%);
gradient
ACN:H2 O
(67.5:32.5)
MeOH:H2 O (53:47)

277 nm

2009 [69]

310 nm

2009 [70]

232 nm

2009 [71]

290 nm

2009 [72]

ESI/MSn
detection

2009 [73]

236 nm

2009 [74]

ESI/MS
detection
254 nm

2009 [75]
2009 [76]

245 nm

2009 [77]

250 nm

2009 [78]

225 nm

2009 [79]

250 nm

2009 [80]

275 nm

2009 [81]

225 nm

2009 [82]

220 nm

2009 [83]

225, 247 and


257 nm
210 nm

2009 [84]
2009 [85]

220 nm

2009 [86]

278 nm

2009 [87]

64.

Norethisterone

65.
66.

Phenazopyridine
HCl
Pridinol mesylate

67.

Puerarin

Injection; vasodilator

9 impurities

68.

Rizatriptan
benzoate

API; antimigraine

Rizatriptan-1,2-dimer and
Rizatriptan-2,2-dimer

69.

Ropinirole HCl

API; anti-Parkinsons

4-[2(Dipropylamino)ethyl]1H-indol-2,3-dione

X-BridgeTM , 3 mm 100
mm, 3.5 m

70.

Salidroside

API; antidepressant

3 impurities

71.

Sertraline

API; antidepressant

9 impurities

72.

Taranabant

API; anti-obesity

6 impurities

C18, 150 mm 4.6 mm,


5 m
C18, 250 mm 4.6 mm,
5 m
C18, 250 mm 4.6 mm,
5 m

73.

Tropicamide

API; ophthalmology

3 impurities

74.

Valsartan

API; antihypertensive

5 impurities

75.

Zarlukast

API; antiasthamatic

5 impurities

C18, 250 mm 4.6 mm,


5 m

76.

Zotarolimus

Coated stents;
immunomodulator

3 degradant

C8, 250 mm 4.6 mm, 5


m

API; analgesic
API, tablet, injection,
Patches;
antihypertensive

Year
[Ref.]

Impurity/degradant

19-Norandrostenedione
3-Phenyl-5-phenylazopyridine-2,6-diamine
3-Piperidino-propiophenone, hydrochloride,
1-(3,3-diphenylprop-2-en1-yl)piperidine

C18, 250 mm 4.6 mm,


5 m
C8, 250 mm 4.6 mm, 5
m

C18, 150 mm 4.6 mm,


5 m
C18, 250 mm 4.6 mm,
5 m

H2 O:ACN (25:75)
Potassium
phosphate buffer
(50 mM, pH
6.4):MeOH:2propanol
(20:69:11)
Formic acid (0.1%):
MeOH; gradient
Ammonium
dihydrogen
ortho-phosphate
(20 mM) + 2 ml
TEA (pH 2): ACN;
gradient
ACN:sodium
heptane sulfonate
(5 mM) (21.6:78.4)
(pH 2)
MeOH:H2 O (13:87)
TFA (0.4%):ACN
(80:20)
H3 PO4 in H2 O
(0.1%):ACN;
gradient
MeOH:H2 O (30:70)
Elunent A:
CH3 COONH4 (10
mM, pH 3.0) Eluent
B: H2 O:ACN (1:4);
gradient
Eluent A: phosphate
buffer + 1-decane
sulfonic acid
sodium (pH 4):
MeOH (85:15);
Eluent B:
ACN:MeOH:H2 O
(85:10:5)
CH3 COONH4 (10
mM, pH 3.8): ACN;
gradient

18

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

Table 2
Continued
S.
no.

Name of drug

Matrix; therapeutic
category

Impurity/degradant

Column/stationary phase

Mobile phase

Detection

Year
[Ref.]

API; antiplatelet

2 impurities

C18, 250 mm 20 mm,


5 m

MeOH:H2 O (55:45)

210 nm

2010 [88]

78.

10-O-(N,Ndimethyl
aminoethyl)-ginkgolide B methane
sulfonate
Acetazolamide

API; diuretics

1 degradant and 4
process-related impurities

C18, 250 mm 4.6 mm,


5 m

254 nm

2010 [89]

79.

Acetylspiramycin

API; antibiotics

C18, 250 mm 4.6 mm,


5 m

232 nm

2010 [90]

80.

Albuterol sulfate
and ipratropium
bromide

Nasal solution;
anti-asthamatic

17 impurities
(process-related,
degradant and starting
materials)
Albuterol sulfate related:
8; Ipratropium bromide
related: 5

Eluent A: NaH2 PO4


(0.02M, pH
3.0):ACN (950:50);
Eluent B: H2 O:ACN
(150:850); gradient
ACN:CH3 COONH4
(0.1 M, pH 7.2)
(50:50)

210 nm

2010 [91]

81.

Alizapride

API; antiemetic

2 degradants

C18, 150 mm 4.6 mm,


5 m

225 nm

2010 [92]

82.

Atorvastatin
calcium

API;
anti-hyperlipidemic

4 impurities

C18, 150 mm 4.6 mm,


3.5 m

246 nm

2010 [93]

83.

Barnidipine

API; antihypertensive

4 degradants

C18, 250 mm 4.6 mm,


5 m

250 nm

2010 [94]

84.

Clopidogrel
bisulfate

API and tablet;


antiplatelet

5 impurities

Chiral, 250 mm 4.6


mm, 5 m

240 nm

2010 [96]

85.

CU201(antitumor
peptidic dimer)

API; anticancer

11 forced degradants and 3


impurities

C8, 150 mm 4.6 mm, 3


m

266 nm

2010 [97]

86.

Desloratadine

Tablet; antiallergic

5 impurities and forced


degradants

C18 (BEH), 50 mm 2.1


mm, 1.7 m

280 nm

2010 [98]

87.

Duloxetine HCl

API; antidepressant

3 related impurities

C18, 250 mm 4.6 mm,


5 m

230 nm

2010 [99]

88.

Enalapril maleate

API; antihypertensive

Several degradation
impurities

RP-S, 250 mm 4.6 mm,


5 m

215 nm

2010
[100]

89.

Eprosartan

API; antihypertensive

Impurity: dibenzoic acid

C2, 250 mm 4.6 mm


mm, 5 m

234 nm

2010
[101]

90.

Escitalopram

API; antidepressant

3 process-related
impurities

C18, 150 mm 4.6 mm,


3 m

240 nm

2010
[102]

91.

Ezetimibe

Process-related impurity

Felbamate

C18, 250 mm 4.6 mm,


5 m
C18 (BEH), 100 mm
2.1 mm, 1.7 m

232 nm

92.

API;
anti-hyperlipidemic
API and tablets;
antiepileptic

2010
[103]
2010
[104]

77.

3-Hydroxy-2-phenylpropyl carbamate and


2-Phenyl-propane-1,3-diol

C8, 250 mm 4.6 mm, 5


m

Eluent A: KH2 PO4


+
Heptane-1-sulfonic
acid sodium salt in
H2 O (pH 4); Eluent
B: ACN; gradient
Eluent A:
CH3 COONa buffer
(20 mM, pH 4);
Eluent B: MeOH;
gradient
Eluent A: HCOONH4
(pH 4, 10 mM):ACN
(60:40); Eluent B:
ACN; gradient
ACN:phosphate
buffer (pH 7)
(75:25)
nHexane:ethanol:diethyl
amine (95:5:0.05)
Eluent A: H2 O (0.1%
formic acid); Eluent
B: ACN (0.1% Formic
acid), gradient
Eluent A:
KH2 PO4 buffer (10
mM, pH
2.5):MeOH:ACN
(80:15:5); Eluent B:
buffer:THF: ACN
(30:5:70)
Eluent A: KH2 PO4
(10 mM + 0.2%
TEA, pH 2.5); Eluent
B: ACN:MeOH
(20:80); gradient
Eluent A: phosphate
buffer (20 mM, pH
6.8): ACN (95:5);
Eluent B: phosphate
buffer (20 mM, pH
6.8):ACN (34:66);
gradient
Eluent A: TEA buffer
(pH 3); Eluent B:
ACN; gradient
HCOONH4 (1.5
g/1000 ml
H2 O):ACN; gradient
H2 O:ACN; gradient
KH2 PO4 buffer (pH
3.5):MeOH (68:32)

210 nm

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

19

Table 2
Continued
S.
no.

Name of drug

Matrix; therapeutic
category

Impurity/degradant

Column/stationary phase

Mobile phase

Detection

93.

Fentanyl

API; analgesic

16 impurities

C18, 150 mm 3.0 mm,


5 m

215 nm

2010
[105]

94.

Filgrastim

API; hematopoietic
stimulator

5 impurities

C8, 250 mm 4.6 mm, 5


m

215 nm

2010
[106]

95.

GW876008
(corticotropinrelease factor 1
antagonist)

API; antidepressant

4 impurities

C8, 150 mm 4.6 mm,


3.5 m

220 nm

2010
[107]

96.

l-Aspartic acid
and l-alanine

API; food supplement

C3, 150 mm 4.6 mm, 5


m

CAD
detection

2010
[108]

97.

Omeprazole

API and tablets; peptic


ulcer

Succinic acid, citric acid,


malic acid, maleic acid,
fumaric acid, glycine,
glutamic acid
9 impurities

Eluent A: phosphate
buffer (pH 2);
Eluent B: Eluent
A:ACN (1:1);
gradient
Eluent A: TFA (0.1%)
in ACN:H2 O;
(10:90); Eluent B:
TFA (0.1%) in
ACN:H2 O (80:20);
gradient
Eluent A: H2 O:TFA
(100:0.05); Eluent
B: MeOH:ACN: TFA
(50:50: 0.05);
gradient
MeOH:H2 O (50:50)

299 nm

2010
[109]

98.

Orlistat

Capsules; anti-obesity

18 impurities

C18, 4.6 mm 150 mm,


5 m

210 nm

2010
[110]

99.

Oxytocin

API; uterine stimulant


(hormone)

Acetic acid, carbamido


oxytocin, -dimer,
acetyl-oxytocin, -dimer
and ve impurities

C18, 250 mm 4.0 mm,


5 m

220 nm

2010
[111]

100.

Pentoxifylline

API; antidiabetic

3 degradants

C18, 250 mm 4.6 mm,


5 m

274 nm

2010
[112]

101.

Piracetam

4 impurities

Pregabalin

C18, 250 mm 4.6 mm,


10 m
C8, 250 mm 4.0 mm, 5
m

205 nm

102.

API; neurovascular
enhancer
API and tablet;
antipsychotic

2010
[113]
2010
[114]

103.

Rabeprazole
sodium

API; peptic ulcer

Methylthio impurity of
rabeprazole

C8, 150 mm 4.6 mm, 5


m

104.

Raltegravir

API; anti-HIV

5 impurities

105.

API; anti-HIV

9 impurities

106.

RG7128 (HCV
polymerase
inhibitor)
Rifaximin

C18, 250 mm 4.6 mm,


5 m
C18, 100 mm 19 mm,
5 m

API; antibiotic

1 impurity

107.

Ritonavir

API; anti-HIV

21 degradants

108.

Sertraline

API; antidepressant

3 non-chiral related
impurities

109.

Valsartan

API; antihypertensive

7 degradants

C18 (BEH), 100 mm


2.1 mm, 1.7 m

110.

Vestipitant

API; antiemetic

3 biphenyl impurities

C18, 150 mm 4.6 mm,


5 m

111.

Abacavir

API; anti-HIV

8 degradants

112.

ALB 109564

API; anticancer

4 impurities

C18, 250 mm 4.6 mm,


5 m
C18, 250 mm 10 mm,
5 m

Methyl tertbutylether:ethyl
acetate:
ethanol:diethylamine
(60:40:5:0.1)
ACN + H3 PO4
(0.005%):H2 O +
H3 PO4 (0.005%)
(86:14)
Eluent A:
ACN:KH2 PO4 (pH
4.4):H2 O
(15:15:70); Eluent
B: ACN:KH2 PO4 (pH
4.4):H2 O (70:
15:15)
Formic acid
(0.05%):ACN;
gradient
TEA:ACN (85:15)
(pH 6.5)
MeOH:acetate
buffer (10 mM, pH
5.0) (15:85)
Eluent A: phosphate
buffer (pH 7.6):ACN
(98:2) Eluent B:
ACN; gradient
H2 O:ACN:TFA
(0.02%); gradient
Formate buffer (10
mM, pH 3.5):ACN;
gradient
ACN:MeOH:H2 O
(36:32:32)
H2 O:MeOH:ACN
(40:20:40)
Phosphate buffer
(10 mM, pH
2.8):MeOH (63:37)
Eluent A: acetic acid
buffer (1%): ACN
(90:10); Eluent B:
acetic acid buffer
(1%): ACN (10:90);
gradient
TFA (0.1%) in D2 O:
TFA (0.1%) in ACN,
gradient
H2 O:ACN (90:10)
Eluent A: H2 O (0.1%
TFA) Eluent B: ACN
(0.1% TFA)

215 nm

2 impurities

Chiral, 250 mm 4.6


mm, 10 m

C18, 150 mm 19 mm,


5 m
C18, 250 mm 4.6 mm,
5 m
C18, 150 mm 4.6 mm,
5 m

345 and 450


nm

Year
[Ref.]

284 nm

2010
[115]

240 and 304


nm
276 nm

2010
[116]
2010
[117]

276 nm

2010
[118]
2010
[119]
2010
[120]

210 nm
220 nm

225 nm

2010
[121]

254 nm

2010
[122]

220 nm

2011
[123]
2011
[124]

20

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

Table 2
Continued
S.
no.

Name of drug

Matrix; therapeutic
category

Impurity/degradant

Column/stationary phase

Mobile phase

Detection

113.

Anastrozole

API; anticancer

3 degradant

Artemisinin

API; antimalarial

115.

Atazanavir sulfate

API; anti-HIV

Artemisitene,
9-epi-artimisinin
13 process impurities and
degradants

116.

Auraptene

API; immunomodulator

5 impurities

HCOONH4 (10
mM):ACN (60:40)
ACN:H2 O (60:40) +
0.1% formic acid
Eluent A: H2 O:0.025
M CH3 COONH4 ;
Eluent B: ACN;
gradient
H2 O:ACN; gradient

215 nm

114.

C3, 100 mm 4.6 mm, 3


m
C18, 150 mm 2.1 mm,
5 m
C8, 150 mm 4.6 mm, 3
m

117.

Boron
phenylalanine

API; anticancer

4 impurities

118.

Candesartan
cilexetil
Carbamazepine

API; antibiotics

Process related impurity

API; antiepileptic

7 impurities

120.

Casopitant
mesylate

API; antidepressant and


antiemetic

De-uorinated casopitant
mesylate analogue

121.

Ciclesonide

4 degradants

C18, 250 mm 4.6 mm,


10 m

122.

Colistin
(Polymyxin E)

API and metered dose


inhalers;
antiasthamatic
API; antibiotic

35 impurities

C18, 250 mm 4.6


mm, 5 m

123.

Entacapone

API; anti-Parkinsons

4 forced degradants

C18, 250 mm 4.6 mm,


5 m; C3, 250 mm 4.6
mm, 5 m

124.

Etimicin sulfate

API; antibiotic

6 impurities

C18, 150 mm 4.6 mm,


5 m

125.

Ezetimibe

API;
anti-hyperlipidemic

5 degradation and
process-related impurities

C18, 150 mm 4.6 mm,


5 m

126.

Febuxostat

API; anti-gout

4 impurities

C18, 150 mm 4.6 mm,


5 m

127.

Fesoterodine

API; antispasmodic

5 degradants

C18, 100 mm 4.6 mm,


5 m

128.

API; antidiabetic

4 related impurities

C18, 250 mm 4.6 mm,


5 m

129.

G004
(hypo-glycaemic
agent)
Gentamicin

API; antibiotic

5 impurities

C18, 50 mm 4.6 mm,


1.8 m

130.

Lactic acid

11 impurities

131.

Larotaxel

Sugarcane juice;
humectants
API; anticancer

132.

Lincomycin and
spectinomycin

C18, 250 mm 4.6 mm,


5 m
C18, 250 mm 4.6 mm,
5 m
C18, 50 mm 4.6 mm,
1.8 m

119.

API; antibiotic

5 Related impurities
Lincomycin related
impurities: 4 and
spectino-mycin related
impurities: 5

C18, 150 mm 4.6 mm,


5 m
C18, 150 mm 4.6 mm,
5 m

Cyano, 250 mm 4.6


mm, 5 m
Cyano, 250 mm 4.6
mm, 5 m
C18, 150 mm 4.6 mm,
3.5 m

DAD/MS
250 nm

324 nm

Year
[Ref.]
2011
[125]
2011
[126]
2011
[127]

2011
[128]
2011
[129]

Eluent A:TFA:H2 O:
MeOH (0.1:85:15);
Eluent B: MeOH;
gradient
TFA (pH 3):ACN;
gradient
THF:CH3 OH:H2 O
(3:12:85)
Eluent A: H2 O +
0.2% NH4 OH; Eluent
B: ACN + 0.2%
NH4 OH; gradient
Ethanol:H2 O
(70:30)

230, 256 and


270 nm

242 nm

2011
[133]

ACN:sodium sulfate
(4.46 mM, pH 2.3)
(20:80) + 10%
phosphoric acid;
gradient
Potassium
phosphate buffer
(30 mM, pH
2.75):MeOH (50:50)
Eluent A: H2 O:NH3
(25%):CH3 COOH
(96:3.6:0.4); Eluent
B: MeOH; gradient
Eluent A: TFA
(0.05%):MeOH
(49:51); Eluent B:
ACN:Eluent A (3:1);
gradeint
Eluent A:
CH3 COONH4 (10 m
M, pH 3.5); Eluent
B: ACN; gradient

215 nm

2011
[134]

310 nm

2011
[135]

ELSD

2011
[136]

210 and 235


nm

2011
[137]

315 nm

2011
[138]

210 nm
230 nm
LC/MS/MS

208 nm
ACN:MeOH:CH3 COONH4
(30 mM, pH 3.8)
(30:15:55)
Acetic acid (0.1%) +
233 nm
TEA (0.1%):MeOH
(20:80)
Eluent A: TFA (0.1%
ESI/MSn
detection
pH 2.5); Eluent B:
TFA (0.1% pH 2.5 +
TEA Eluent C: ACN;
gradient
NH4 H2 PO4 (20 mM,
210 nm
pH 2.2)
230 nm
H2 O:ACN; gradient
TFA (0.05%, pH
3.0):ACN (90:10)

ESI/MSn
detection

2011
[130]
2011
[131]
2011
[132]

2011
[139]

2011
[140]
2011
[141]

2011
[142]
2011
[143]
2011
[141]

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

21

Table 2
Continued
S.
no.

Name of drug

Matrix; therapeutic
category

Impurity/degradant

Column/stationary phase

Mobile phase

Detection

133.

Lornoxicam

API; analgesic

Degradants

C18, 250 mm 4.6 mm,


5 m

MS detector

2011
[144]

134.

Memantine

Tablets; anticancer

Maillard reaction
impurities

Hydro RP, 100 mm 3


mm, 2.5 m

CAD
detection

2011
[145]

135.

Meprobamate

API; antipsychotic

C18, 250 mm 4.6 mm,


5 m

200 nm

2011
[146]

136.

Mometasone
furoate
Mometasone
furoate

API; steroid

Carbamic acid-2carbamoyloxymethyl-2methyl-pent-3-enyl
ester
8 impurities

KH2 PO4 buffer (10


mM, pH 3.3):MeOH;
gradient
Heptauoro buturic
acid (0.6%):ACN:
isopropyl
alcohol:H2 O;
gradient
H2 O:ACN (8:2)

H2 O:ACN; gradient

245 nm

API; steroid

8 impurities

Carbon dioxide (SFC


grade)

245 nm

2011
[147]
2011
[147]

138.

Naproxen

API; analgesic

2011
[148]

Olanzapine

API and drug product;


antipsychotics

220 nm

2011
[149]

140.

Olanzapine

API and tablet;


antipsychotics

8 degradants

C18 (BEH), 100 mm


2.1 mm, 1.7 m

250 nm

2011
[150]

141.

Olaquindox

API; anti-amoebic

12 degradants

200400 nm

142.

Palonosetron HCl

API; antiemetic

9 degradants

C18, 150 mm 2 mm, 5


m
Nap, 250 mm 4.6
mm, 5 m

2011
[151]
2011
[152]

143.

Perindopril
tert-butylamine

API; antihypertensive

4 impurities

C4, 4.6 mm 250 mm, 5


m

144.

Phosphorothioate
oligonucleotides

API; diagnostic agent

5 synthesis impurities

C18 (BEH), 1 mm 150


mm, 3.5 m

145.

Polymyxin B

API; antibiotic

38 impurities

C18, 250 mm 4.6 mm,


5 m

146.

Streptomycin
sulfate
Sulindac

API; antibiotic

21 impurities

API; analgesic

E-sulindac, sulde and


sulfone form

YMCPack Pro, 250 mm


4.6 mm; 3 m
C18, 53 mm 7 mm, 1.5
m

API; billiary cirrhosis

5 related impurities

API; antihypertensive

2 photodegradant

CH3 COONa (40 mM,


pH 4.7):MeOH
(60:40)
EDTA disodium salt
dihydrate (50 mM,
pH 3):ACN (6:4)
Eluent A: NaH2 PO4
(20 mM) buffer (pH
6.8): ACN: MeOH
(5:2:3) Eluent B:
H2 O: ACN (1:9)
HCOOH (0.1%):
ACN; gradient
Eluent A: Phosphate
buffer (20 mM + 2
ml TEA, pH 2.5);
Eluent B: phosphate
buffer: ACN (50:50);
gradient
Butyl acetate
(0.24%) + ethyl
acetate (0.30%) +
SDS (2%) +
n-butanol (7.75%)
+ dihydrogen
phosphate (20 mM,
pH 3.7)
Eluent A: TEA (16
mM) + HFIP (400
mM, pH 7.0) in H2 O;
Eluent B: TEA (16
mM) + HFIP (400
mM) in MeOH;
gradient
ACN:sodium sulfate
(4.46 g/l, pH 2.3)
(20:80) + 10%
phosphoric acid
PFPA (20 mM):
acetone (99:1)
ACN: phosphate
buffer (pH 2, 10
mM); gradient
Acetic acid: MeOH
(0.1%) (30:70)
ACN: KH2 PO4 (20
mM, pH 3) (40:60)

254 nm

139.

2-(6-Methoxynaphthalen-2-yl)acrylic
acid
8 impurities

137.

147.

148.
149.

Ursodeoxycholic
acid
Valsartan

C18, 250 mm 4.6 mm


mm, 5 m
C18, 250 mm 4.6 mm,
5 m; 2-ethyl-pyridine:
250 mm 4.6 mm, 5
m;Cyano: 250 mm
4.6 mm, 5 m
C18, 100 mm 4.6 mm,
5 m
C8, 250 mm 4.0 mm, 4
m

C18, 150 mm 4.6 mm,


5 m
Cyano, 250 mm 4.6
mm, 5 m

210 nm

Year
[Ref.]

215 nm

2011
[153]

LCMS/MS

2011
[154]

215 nm

2011
[134]

CAD/MS
Detection
340 nm

2011
[155]
2011
[156]

RI detection

2011
[157]
2011
[158]

226 nm

22

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

Table 2
Continued
S.
no.

Name of drug

Matrix; therapeutic
category

Impurity/degradant

Column/stationary phase

Mobile phase

Detection

150.

Zarlukast

API; antiasthamatic

8 impurities

C18, 250 mm 4.6 mm,


5 m

220 nm

2011
[159]

151.

Rapamycin

API; immunomodulator

9 degradant

Diol-120-NP, 250 mm
4.6 mm, 5 m

278, 248, 230


and 210 nm

2012
[160]

152.

4-Methyl
thioamphetamine

API; psychostimulant

22 impurities

Capillary, 30 m 0.25
mm, 0.25 m

Eluent A: phosphate
buffer + 1-decane
sulfonic acid
sodium (pH 4):
MeOH (85:15);
Eluent B:
ACN:MeOH:H2 O
(85:10:5); gradient
Hexanes:2propanol;
gradient
Helium

2012
[161]

153.

Halobetasol
propionate
Artemisinin

API; steroids

Acetamide and
arylsulfonate
Extract residue impurities

C18, 100 mm 2.10


mm, 2.6 m
C18, 250 mm 4.6 mm,
5 m

ACN:H2 O; gradient

Eluent A: phosphate
buffer (pH 5.4);
Eluent B: ACN:THF
(90:10); gradient
Eluent A: KH2 PO4
(15
mM):ACN:MeOH
(8:1:1) Eluent B:
ACN; gradient
ACN:H2 O (60:40) +
0.1% formic acid
NH4 H2 PO4 (1.2%,
pH 4.5):ACN (80:20)

Mass
selective
detector
230, 220 and
205 nm
192, 200,
205, 210 and
215 nm
220 nm

220 nm

2012
[165]

318 nm

2012
[166]
2012
[167]
2012
[168]

154.

Artemisia annua
extracts; antimalarial

155.

Atorvastatin
calcium

API;
anti-hyperlipidemic

7 impurities

C18, 250 mm 4.6 mm,


3.5 m

156.

Azelnidipine

Solution;
anti-hypertensive

4 degradants

C18, 100 mm 4.6 mm,


3 m

157.

Benzopyridooxathiazepine
Bupropion
hydrochloride
Caffeine

API; anticancer

10 degradants

API and tablets;


Anti-depressant
API; stimulant

Alkaline degradates,
3-chlorobenzoic acid
4 impurities

C18, 150 mm 2.1 mm,


3 m
C18, 4.6 mm 150 mm,
5 m
C18, 150 mm 4.6 mm,
5 m, 29 columns;
Others, 150 mm 4.6
mm mm, 5 m, 6
columns
C18, 250 mm 4.6 mm;
5 m
C18, 200 mm 4.6 mm,
5 m
C8, 250 mm 4.6 mm, 5
m

158.
159.

160.

Cefditoren pivoxil

161.

Clocortolone
pivalate
Cloperastine
fendizoate

162.

API and tablet;


Antibiotic
API; steroid

1 degradants
3 impurities

API; cough relaxant

Methyl p-toluene
sulfonate and 2-chloro
ethyl p-toluene sulfonate

163.

Deferasirox

API; Antidote of Iron

2-[3,5-Bis(2-hydroxyphenyl)-[1,2,4]-triazol-1yl]-benzoic
acid

C8, 250 mm 4.6 mm, 5


m

164.

Desvenlafaxine

API and tablet;


Antidepressant

1 degradants (acid)

C18, 250 mm 4.6 mm,


5 m

165.

Diltiazem HCl

6 related substances

166.

Dipyridamole

API and tablet;


Anti-hypertensive
API; antiplatelet

2 impurities

C18, 150 mm 4.6 mm,


5.0 m
C2, 150 mm 4.6 mm, 5
m

167.

Eslicarbazepine
acetate

API; antiepileptic

15 impurities

C8, 250 mm 4.6 mm, 5


m

ACN:H2 O:MeOH
(50:30:20)

210 nm
275 nm

THF:ACN:CH3 COONH4
(pH 4.5) (40:50:10)

ACN:H2 O (50:50)

218 nm

ACN:H2 O (70:30)

254 nm

Phosphate buffer
(10 mM, pH
3.0):MeOH with
10% ACN (45:55)
Eluent A:H2 O:TFA
(100:0.05); Eluent
A: ACN:MeOH:TFA
(50:50:0.05)
gradient
TEA (0.2%)
+ CH3 COONH4 (50
mM, pH 6.5):MeOH
(40:60)
TEA (0.2%):ACN;
gradient
Eluent A: KH2 PO4
buffer (10 mM, pH
7.0):MeOH (50:50);
Eluent B:
MeOH:KH2 PO4 (10
mM) buffer; (95:5);
gradeint
Eluent A: KH2 PO4
(10 mM, pH 5): ACN
(95:5); Eluent B:
ACN:H2 O (80:20);
gradient

227 nm

Year
[Ref.]

2012
[162]
2012
[163]
2012
[164]

2012
[169]
2012
[170]
2012
[171]

LCESI-QT/
MS/MS

2012
[172]

228 nm

2012
[173]

240 nm

2012
[174]
2012
[175]

295 nm

215 nm

2012
[176]

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

23

Table 2
Continued
S.
no.

Name of drug

Matrix; therapeutic
category

Impurity/degradant

Column/stationary phase

Mobile phase

Detection

Eluent A: glycine
buffer (40 mM, pH
9); Eluent B:
ACN:H2 O (90:10);
gradient
Eluent A: H2 O:NH3
(25%):CH3 COOH
(96:3.6:0.2); Eluent
B: MeOH; gradient
Eluent A: 1-octane
sulfonic acid
sodium (10 mM) +
CH3 COONH4 (10
mM) + 0.1% TEA
(pH 4):MeOH
(95:5); Eluent B:
MeOH; gradient
Eluent A: H2 O (0.1%
formic acid); Eluent
B: ACN (0.1% formic
acid); gradient
Eluent A: NH4 H2 PO4
(20 mM) +
1-heptane sulfonic
acid sodium salt
buffer (1%) (pH
2.6):ACN:MeOH
(95:4:1); Eluent
B:ACN NH4 H2 PO4
(20 mM) +
1-heptane sulfonic
acid sodium salt
buffer (1.0%) (pH
9.5) (6:4); gradient
Eluent A:
CH3 COONH4 (50
mM, pH 9.5); Eluent
B: ACN:MeOH
(40:60); gradient
Eluent A: H2 O (0.1%
formic acid); Eluent
B: ACN (0.1% formic
acid); gradient
Eluent A: NH4 OH
(100 mM): H2 O
(1:9); Eluent B:
NH4 OH (100 mM):
ACN (1:9); gradient
CH3 COONH4 (20
mM, pH 4.5):ACN
(60:40)
Eluent A: formic
acid buffer (100
mM, pH 3.5):H2 O
(1:9); Eluent B:
formic acid buffer
(100 mM, pH
3.5):ACN (1:9);
gradient
ACN:ethanol:nbutyl amine:TFA
(96:4:0.10:0.16)
MeOH:H2 O (80:20)

305 nm

2012
[177]

ESI/MSn
detection

2012
[178]

240 and 282


nm

2012
[179]

190400 nm

2012
[180]

222 nm

2012
[181]

237 nm

2012
[182]

ESI/MSn
detection

2012
[183]

ESI/MSn
detection

2012
[183]

ESI/MSn
detection

2012
[183]

ESI/MSn
detection

2012
[183]

254 nm

2012
[184]

296 nm

2012
[185]
2012
[186]

168.

Esomeprazole
magnesium

Tablets, pepetic ulcer

7 impurities

C18 (BEH), 50 mm 2.1


mm, 1.7 m

169.

Etimicin sulfate

API; antibiotic

26 impurities

C18, 250 mm 4.6 mm,


5 m

170.

Fampridine

API; agent multiple


sclerosis

Isoniacin, niacin,
Isonico-tinamide,
3-aminopyridine, 2-amino
pyridine,
famp-ridine-N-oxide,
3-hydr-oxy-4-amino
pyridine

C18, 250 mm 4.6 mm,


5 m

171.

Glucocorticoids

API; steroid

4-Dimethyl aminopyridine

C18, 50 mm 2 mm, 3
m

172.

Guaifenesin,
terbutaline sulfate
and ambroxol HCl

Cough syrup; cough


relaxant

13 related substances

C18, 250 mm 4.6 mm,


5 m

173.

Imatinib mesylate

Capsules; anticancer

8 impurities

C18 (BEH), 50 mm 2.1


mm, 1.7 m

174.

l-Alanyl-lglutamine

API; food supplement

5 impurities

C18, 150 mm 3 mm, 3


m

175.

l-Alanyl-lglutamine

Infusion solution; food


supplement

9 impurities

Polysulfoethyl A, 150
mm 4.6 mm, 5 m

176.

l-Alanyl-lglutamine

Infusion solution; food


supplement

7 impurities

QN-AX, 150 mm 4
mm, 5 m

177.

l-Alanyl-lglutamine

Infusion solution; food


supplement

7 impurities

QN-AX, 150 mm 4
mm 5 m

178.

Linezolid

API; antibiotic

6 impurities

Chiral, 250 mm 4.6


mm, 5 m

179.

Luliconazole

API and cream;


antifungal
API; psychostimulant

6 degradants

C18, 250 mm 4.6 mm,


5 m
Capillary, 30 m 0.32
mm 1.0 m

180.
Methamphetamine

20 impurities

Helium gas

Mass
selective
detector

Year
[Ref.]

24

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

Table 2
Continued
S.
no.

Name of drug

Matrix; therapeutic
category

Impurity/degradant

Column/stationary phase

Mobile phase

Detection

181.

Moxonidine

Tablet; antihpertensive

5 impurities

C18, 250 mm 4.6 mm,


5 m

255 nm

2012
[187]

182.

Nevirapine

API; anti-HIV

2 impurities

ABZ, 150 mm 4.6 mm,


5 m

220 nm

2012
[188]

183.

Niacinamide

API; vitamin

C18, 250 mm 4.6 mm,


5 m

254 nm

2012
[189]

184.

API; antihypertensive

185.

Nonpeptide
(angiotensin AT1
receptor
antagonist)
Pantoprazole

Niacin, isonicotinamide,
picolinamide,
3-cyano-pyridine,
niacinamide N-oxide
4 impurities

MeOH:potassium
phosphate buffer
(50 mM), (15:85)
(pH 3.5)
Ammonium
phosphate buffer
(50 mM, pH
4.5):ACN (7:3)
CH3 COONH4 (20
mM, pH 5):ACN
(97:3)

API; peptic ulcer

186.

Plazomicin

API; antibiotic

187.

Praziquantel

188.

Rivastigmine
tartrate

API andTablet;
Anthelmintic
API; anti-Alzheimer

11 impurities

189.

Ropinirole

API; anti-Parkinsons

5 degradants

Silica gel 60F-254

190.

Nanoemulsion;
antiprotozoal
API; antioxidant

2 degradants

C18, 150 mm 4 mm, 5


m
C18, 250 mm 4.6 mm,
5 m

192.

SCD: chalcone
derivative
Sodium
tanshinone IIA
sulfonate
Telmisartan

API; antihypertensive

193.

Thiocolchicoside

API; muscle relaxant

Methyl
4 ,4 -dibromometh-yl
biphenyl-2-carboxylate
6 degradants

194.

Trandolapril

API; antihypertensive

16 degradants

C18 (BEH), 138 mm


2.1 mm, 1.7 m

195.

Wogonin

API; anxiolytic

2 degradants

C18, 250 mm 4.6 mm,


5 m

196.

Zolmitriptan

API; antimigraine

6 impurities

Phenyl, 100 mm 3
mm, 2.7 m

197.

Bortezomib

API; anticancer

3 impurities

C18, 250 mm 4.6 mm,


5 m

191.

2-Chloromethyl-3,4dimethoxy pyridine
HCl
3 impurities
2 impurities

8 impurities

2.1.2. 2009
2.1.2.1. Impurity proling Both techniques of LCMS, ion trap mass
spectrometry and time of ight mass spectrometry were used
for characterization of impurities in chloroquine and hydroxychloroquine bulk drug samples [59]. 1-(1,1-Bis(4-uorophenyl)1,3-dihydroisobenzofuran-5-yl)-4-(dimethylamino) butan-1-one hydrobromide as an impurity of citalopram was isolated by semipreparative HPLC and structure was established by using Q-TOF
mass analyzer, NMR and IR spectroscopy. Overlaid FT-IR spectra

Year
[Ref.]

C18, 250 mm 4.6 mm,


5 m

Phosphoric acid (pH


3.5):ACN (51:49)

210 nm

2012
[190]

C18, 50 mm 4.6 mm, 3


m

CH3 COONH4 (10


mM):ACN (79:21)

210 nm

2012
[191]

C18, 4.6 mm 150 mm,


3.5 m
Silica, 4.0 mm 125
mm, 100/5 m
C18, 250 mm 4.6 mm,
5 m

NH4 OH (25
mM):ACN; gradient
ACN:CH3 COONH4
(25 mM) (40:60)
Eluent A: KH2 PO4
(10 mM, pH
7.6):ACN (90:10);
Eluent B:
ACN:MeOH (60:40);
gradient
Toluene:ethyl
acetate:NH3 (6 M)
(5:6:0.5)
MeOH:H2 O (70:30)
(pH 5,TFA)
CH3 COONH4
(0.2%):MeOH
(35:65)
KH2 PO4 +
sodium-1-pentane
sulfonate (pH 3)
Ammonium
formate buffer (10
mM; pH 3):ACN;
gradient
Ammonium
hydrogen carbonate
(10 mM, pH
8.14):ACN (68:32)
MeOH:CH3 COONH4
buffer (5 mM)
(75:25)
KH2 PO4 (20 mM) +
sodium 1-hexan
sulfonate (5 mM, pH
2):ACN; gradient
Eluent A:
HCOOH:ACN:H2 O
(1:300:700); Eluent
B: HCOOH:ACN:H2 O
(800:200:1);
gradient

210 nm

2012
[192]
2012
[193]
2012
[194]

C18, 125 mm 4.6 mm,


5 m
C18, 250 mm 4.6 mm,
5 m

210 nm
210 nm

250 and 254


nm

2012
[195]

330 nm

2012
[196]
2012
[197]

271 nm

230 nm

2012
[198]

MS/MS
Detection

2012
[199]

190 and 500


nm

2012
[200]

275 nm

2012
[201]

220 nm

2012
[202]

270 nm

2012
[203]

has shown (Fig. 3) that structure of impurity and drug related


to each other with difference of peak at 1681 cm1 and 2229
cm1 from
C O and
C N, respectively [60]. Principally, cyclosporin A is used as immunosuppressive agent for prophylaxis
against allograft rejection after organ transplantation. Impurities of

this agent in Neoral capsules and its generic versions were determined [61]. Two monoacylated diacerein impurities of diacerein with
same molecular weight (MW = 326) but different position of acetyl

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

Fig. 3. Overlaid FT-IR spectra of (a) citalopram and (b) citalopram impurity-II. (Reuse
with the permission of Elsevier Limited, The Boulevard, Langford Lane, Kidlington,
Oxford OX5 1GB, UK.)

group was conrmed by NMR spectroscopy, which were characterized as 5-acetoxy-4-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2carboxylic acid (1.14%) and 4-acetoxy-5-hydroxy-9,10-dioxo-9,10dihydroanthracene-2-carboxylic acid (1.24%) [62]. Polyethylene glycol (PEG) present as impurity in fatty alcohol ethoxylates (FAEs) which
are used as surfactants. Gradient elution favor the separation of PEG
and FAEs as these have dramatic difference in hydrophobicity of
PEG and FAEs, while evaporative light scattering detection (ELSD)
is not compactable with gradient elution, so both isocratic and gradient elution were used to study the same [64]. Atmospheric pressure chemical ionization (APCI) of mass spectroscopy was applied for
identication of gentamicin impurities, where no suppression in ionization was observed at high TFA concentration [65]. Over sulfated
chondroitin sulfate (OSCS) and dermatan sulfate were estimated in
heparin API by using a polymer-based strong anion exchange (SAX)
column with gradient elution form, which were present due to over
sulfating and incomplete purication, respectively [66]. As zirconiabased stationary phase coated with graphitized carbon offers wide
pH and temperatures range for separation, was applied to analyze 3[4-(2-methylpropyl)phenyl]propanoic acid as an impurity of ibuprofen [67]. Salidroside is phenolic glycoside of genus Rhodiola, used for
treatment of cardiovascular and cerebrovascular diseases. The biosynthetic pathways for impurities icariside D2, 4-hydroxyphenacyl-dglucopyranoside and picein were proposed [81]. Column packed with
dimethyl beta-cyclodextrin used as chiral stationary phases, was used
to determine related enantiomeric impurities of sertraline as it minimizes chiral hydrogen bonding and establishes weak dipole effect for
high selectivity of separation [82]. Off-line HPLCFT-IR coupling was
used for identication of tropicamide along with its major impurity
(apotropicamide) in raw material [84].

2.1.2.2. Forced degradation proling Forced degradation of tenatoprazole (novel proton pump inhibitor) was carried out to establish intrinsic stability, and found susceptible in acidic, oxidative and
photolytic condition [54], while with levooxacin only oxidative
degradant was identied [55]. As beta-lactam antibiotics are sensitive towards acidic/alkaline degradation, in this sequence, impurities in biapenem aqueous solution were identied as two dimmers
and three hydrolytic degradants and the degradation pathway was
also discussed [58]. Forced degradation study of zotarolimus and zotarolimus coated stents has revealed that coated stunt should protect
from moisture and heat, as these produce different type of degradants
[87].

2.1.2.3. Impurity and forced degradation proling Anti-inammatory


lotion containing betamethasone dipropionate and salicylic acid was

25

analyzed by stability-indicating HPLC method, where 27 analytes


were determined including salicylic acid and betamethasone dipropionate related compounds [56]. As per ICH guidelines, anastrozole,
its potential impurities and degradation products were determined in
tablet dosage form, which consists 1% of API as anastrozole [57]. Mechanistic explanation for origin of degradation products of lamivudine
and identication of degradation products among list of impurities
in the WHO monograph were reported [69]. A stability-indicating
liquid chromatographic method was applied for analysis of metformin hydrochloride and 1-cyanoguanidine in tablet by using isocratic elution as per USP requirements for new methods for assay
determination [71]. Formation of impurity of nevirapine analogue
HIV-non-nucleoside reverse transcription inhibitor was established
as by-product of side reaction, which was conrmed by a series of
photo- and oxidative stress studies [73]. Impurities were identied
and elucidated in taranabant (anti-obesity agent) prepared by cyanuric chloride-mediated coupling reaction (end-game synthesis) and
forced degradation revealed that impurities were unstable compared
to drug [83]. Five related impurities of valsartan (antihypertensive
drug) and ve impurities including two regioisomers of zarlukast
were identied, characterized, synthesized and their synthetic pathways and fragmentation pathways were discussed [85,86].
2.1.3. 2010
2.1.3.1. Impurity
proling 10-O-(N,N-dimethylaminoethyl)ginkgolide B methanesulfonate is derivative of ginkgolide B,
obtained from Ginkgo biloba and used as platelet-activating factor antagonist. Two related impurities were characterized as
10-O-(N,N-dimethylaminoethyl)-11,12-seco-ginkgolide
B
and
10-O-(N,N-dimethylaminoethyl)-11,12,2,15-diseco-3,14-dehydroginkgolide B [88]. Complexity of acetylspiramycin was revealed by
LC/MSn investigation, where 31 unknown and 17 known impurities
were identied. These impurities were raised due to starting materials and synthetic process [90]. Number of related impurities in
albuterol sulfate and ipratropium bromide was determined in nasal
solution [91]. Ion trap and Q-TOF mass analyzer were employed
to determine mass of unknown impurities of ecitalopram which
is used as antidepressant. Spectral data of 1 H and 13 C NMR were
used to elucidate the structure of impurities which was conrmed
by synthesis [102]. 2-(4-Hydroxybenzyl)-N,5-bis(4-uorophenyl)5-hydroxypentanamide was identied as process-related impurity
in ezetimibe by LC/MS/MS and NMR, where 2D-NOESY NMR techniques was used to assign chemical shift [103]. Impurity containing
samples of lgrastim (recombinant human granulocytecolony
stimulating factor) were analyzed by liquid chromatography assays
and chromatographic data were correlated with biological activity
of lgrastim [106]. Corona charged aerosol detector (CAD) coupled
with ion-pair high-performance liquid chromatography was used
for quality control of l-aspartic acid, where CAD was found much
more sensitive compared to evaporative light scattering detector
[108]. Proton-pump inhibitor omeprazole and its potential organic
chiral impurities were analyzed by normal phase chromatography
using methyl tert-butylether:ethyl acetate:ethanol:diethylamine
(60:40:5:0.1) on Chiralpak IA chiral stationary phase [109]. Postcolumn derivatization with o-phtaldialdehyde/2-mercaptoethanol
was used for uorescence detection of pregabalin and its impurities,
where buffer capacity reagent should be high enough to maintain
pH and it was also applied to its tablet formulation [114]. Methylthio
impurity as process related new impurity in rabeprazole sodium was
characterized along with other ve impurities (rabeprazole-N-oxide,
rabeprazole sulfone, rabeprazole sulde, methoxy rabeprazole and
mercapto-1H-benzimidazole) [115]. Impurities originated during
building of methyloxadiazoyl portion of raltegravir and presence of
desuoro analog due to raw material were characterized by LCMS
incorporating a quadrupole time of ight mass spectrometer [116].
Nine impurities in diester prodrug of cytidine analog at low level

26

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

(0.050.10%) were identied and puried by heart-cut and recycle


chromatographic techniques [117]. Combined application of liquid
chromatography, NMR and high resolution NMR was employed for
characterization of mutagenic impurities in vestipitant. Starting
material for the synthesis was identied as root cause of impurities
[122].

2.1.3.2. Forced degradation proling Hydrolytic forced degradation


product of acetazolamide, carbonic anhydrase inhibitor was formed,
while it was found to be stable towards heat and light [89]. Alizapride
carboxylic acid and alizapride N-oxide were two degradants of forced
degradation of alizapride (potent anti-emetic), were investigated in
API as well as its pharmaceutical formulations [92]. New calcium
channel blocker, barnidipine was exposed to natural and stressing
light irradiation and HPLC and spectrophotometry were used to determine pyridine derivative as the main photodegradation products
[94]. Raman et al. have resolved duloxetine hydrochloride and its positional isomer raised from forced degradation [99]. Forced degradation
of enalapril maleate in presence of magnesium monoperoxyphthalate
and investigated by HPLC and UPLCMS methods. First order kinetics
was followed by autocatalytic degradation of the drug, where hydrolysis of ethylic ester and intermolecular cyclization were observed
[100]. Fentanyl was found to be susceptible towards acid and oxidative conditions during forced degradation but degradants were found
to be no-toxic [105]. Forced degradation pathways of ritonavir under
hydrolysis, oxidation, thermal and photolysis conditions were investigated. Carbamate and urea linkages present in ritonavir, so it was
found more prone to hydrolysis [119].

2.1.3.3. Impurity and forced degradation proling Clopidogrel purity


was determined in bulk samples and pharmaceutical dosage forms
in presence of its impurities and forced degradation products respectively [96], while BEH technology equipped with C18-UPLC column
was employed to determine purity of desloratadine within 8 min of
run time [98]. Degradation prole of pentoxifylline has revealed a
prominent oxidative degradant as gem-dihydroperoxide [112] and
four impurities of piracetam were determined in tablet dosage form
[113]. Non-chiral related impurities of sertraline were determined by
HPLC [120], while valsartan was determined by UPLC in presence of
its degradants and impurities in APIs and its dosage forms [121].
2.1.4. 2011
2.1.4.1. Impurity proling Artemisinin is isolated from Artemisia
annua L. and used for production of other anti-malarial as artemisinin
derivatives. Two impurities artemisitene and 9-epi-artemisinin
were identied in artemisinin API [126]. Five unknown impurities
of atazanavir sulfate were characterized using spectral data and
establish mechanistic pathway [127]. Process-related substances
of citrus auraptene (chemopreventive agent) were also identied as umbelliferone, (E)-6,7-dihydroxy-3,7-dimethyl-2-octeneumbelliferone, (E)-6,7-epoxy-3,7-dimethyl-2-octene-umbelliferone
and 4-methylauraptene [128]. 2-Ethoxy-1-[[2 -(1-ethyl-1H-tetrazol5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic
acid
ethyl ester as a process related impurity in candesartan cilexetil was characterized and quantied at trace-level of <0.2%,
which was further conrmed by its synthesis [130]. In similar
fashion tetrabenzo[b,f,b f ]azepino[4 ,5 :4,5] thieno[2,3-d]azepine3,9-dicarboxamide as unknown impurity of antiepileptic drug
carbamazepine was characterized [131]. Carryover impurity from
intermediate stage and raw materials of febuxostat was explored by
LCMS Q-TOF instrument, which is indicated for hyperuricemia and
gout [138]. Precolumn or postcolumn derivatization of aminoglycosides is essential to enable either UV or uorescence detection, so LC/
MS/MS method was employed to determine gentamicin, lincomycin,

Fig. 4. Schematic diagram showing Maillard reaction between lactose and memantine. (Reuse with the permission of Elsevier Limited, The Boulevard, Langford Lane,
Kidlington, Oxford OX5 1GB, UK.)

and spectinomycin in the presence of their impurities in pharmaceutical formulation [141]. Carboxylic acid impurities as pyruvic,
oxalic, formic, succinic, itaconic, aconitic, acrylic, citric, propionic and
fumaric acids were quantify in lactic acid prepared from fermentation of sugarcane juice and compared to commercial samples while
acetic, malic and butyric acids were not observed in any of sample
[142]. Four Maillard reaction (reaction between amino compounds
and reducing sugar, Fig. 4) impurities without chromophore were
determined as memantine-lactose, memantinedimethylamino
glycine, memantinegalactose and memantineglucose adducts
by HPLC using charged aerosol detection. Heptauorobuturic acid
was introduced in mobile phase to improve resolution and peak
shapes of the impurities [145]. No mutagenic potential of 2-(6methoxynaphthalen-2-yl) acrylic acid as unknown polar impurity of
naproxen was found by Ames test (biological assay method) using
Salmonella typhimurium [148]. MELC offers UV detection near 200
nm, proteins solubilization in complex matrices and fast analysis
time. Impurities in streptomycin sulfate was determined by reversed
phase ion-pair HPLC method using charged aerosol detection at the
level of 4.6% and 16.0%, which offers straightforward quantication
of all impurities [155]. Refractive index detection technique was used
to determine impurities of ursodeoxycholic acid which is used for
treatment of gallstones, billiary cirrhosis, viral hepatitis and cystic
brsosis [157].

2.1.4.2. Forced degradation proling Boron neutron capture therapy


is a two stage cancer treatment, where one of lead drug candidates is boron phenylalanine, which is used in large dose. Boron
phenylalanine was found to be more prone to alkali, oxidative and
acidic degradation, where mannitol-mediated degradation to phenylalanine has been observed in lyophilized samples of mannitol-drug
[129]. Desisobutyryl-ciclesonide was identied as hydrolytic degradation product of inhaled corticosteroids ciclesonide, which was due
to presence of ester linkage, while stable in oxidation, thermal and

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

photolysis conditions [133]. Intrinsic stability of fesoterodine was established according to ICH guidelines by forced degradation [139]
and 1-(4-(2-(2-bromobenzenesulfonamino)ethyl)phenylsuphonyl)3-(trans-4-methyl cyclohexyl) urea was characterized as impurity
of G004, a sulfonylurea derivative potential hypoglycaemic agent
[140]. Major forced degradation product of lornoxicam was formed
due to amide hydrolysis and oxygen addition across the enolic double bond [144]. Anti-HIV drugs, abacavir sulfate and atazanavir sulfate and anti-cancer drug anastrozole were studied to understand
the forced degradation behavior under different stressed conditions
[147,149]. Olanzapine and its degradation products were determined
in API and pharmaceutical dosage forms [150], while its oxidative
degradation impurities were characterized as hydroxymethylidene
thione and acetoxymethylidene thione [149]. Different forced degraded samples of olaquindox were studied by HPLC combined with
hybrid ion trap/time-of-ight mass spectrometry and especially its
degradation products were correlated with its phototoxicity and
photoallergic reaction [151]. Two photo-degraded products of valsartan were characterized as: N-[2 -(1H-tetrazol-5-yl)-biphenyl-4ylmethyl]-N-isobutylpentanamide formed by decarboxylation and N(diazirino[1,3-f] phenanthridin-4-ylmethyl)-N-isobutylpentanamide
resulted from additional loss of nitrogen from tetrazole followed by
cyclization [158].

2.1.4.3. Impurity and forced degradation proling Forced degradation


and impurity proling of etimicin sulfate, new aminoglycoside antibiotic with lower toxicity has revealed that starting material, synthetic byproducts and degradation products were main source of
the impurities [136]. Structure of degradation product and (R,R,S)
stereoisomer of ezetimibe were elucidated by different spectroscopy
along other impurities and particle size and shape of ezetimibe crystals, while stereochemical purity of ezetimibe was determined by
HPLC [137]. 7,8-Cyclopropyl baccatin III, 10-deacetyl larotaxel, 10deacetyl-7,8-cyclopropyl baccatin III and 2 ,13-bissidechain larotaxel
were identied as process related impurities and major degradation
products of semisynthetic taxoid larotaxel [143]. Forced degradation
studies of tranquilizer and skeletal muscle relaxant meprobamate
was carried out to evaluate the nature of impurity. Carbamic acid-2carbamoyloxymethyl-2-methyl-pent-3-enyl ester was characterized
as process related impurity, which must be controlled to less than
0.05% as per ICH/FDA/EMEA regulatory guidelines due to daily dose
of meprobamte is >2 g/day [146]. Cosmosil nap column containing
naphthalethyl stationary phase has been employed to achieve better
resolution than conventional column, in between palonosetron hydrochloride, degradation products and its isomeric impurities, which
has strong and hydrophobic interactions [152].
2.1.5. 2012
2.1.5.1. Impurity proling Pharmaceutical impurities may act as
genotoxins, which impose genetic mutation in DNA and may trigger cancer (carcinogen). Acetamide and arylsulfonate are commonly
detected potential genotoxic impurities (GTIs) in APIs. Molecularly
imprinted polymers were synthesized and used as scavenger resins
for removal of acetamide and arylsulfonates from API and halobetasol
propionate was used as a model API in rebinding test [162]. Due to
regulatory requirements, GTIs analysis is becoming topic of interest
in analytical chemistry. In this context, GTIs (alkyl halides and aromatics) and related structurally alerting compounds were analyzed
by using polymeric ionic liquids as selective solid-phase microextraction sorbent coatings [205]. Caffeine and its related impurities
were used to study 35 columns to classify as per their selectivity
[168]. Three impurities of synthetic corticosteroid, clocortolone pivalate were characterized process impurities [170]. Alkyl halide (2chloroethanol) and sulfonate esters (methyl p-toluenesulfonate and

27

2-chloroethyl p-toluenesulfonate) as genotoxic impurities in cloperastine fendizoate were determined by two different chromatographic methods, GCMS and HPLC-DAD, respectively, due to different physical and chemical properties of these impurities. Fendizoate was removed by strong anion-exchange (SAX)-SPE before GCMS analysis, as a step of sample purication [171]. Although, six impurities were reported in deferasirox, but a new impurity was characterized as 2-[3,5-bis(2-hydroxy-phenyl)-[1,2,4]-triazol-1-yl]-benzoic
acid, which can be minimized by controlling the concentration of
2-hydrazino-benzoic acid in 4-hydrazinobenzoic acid [172]. Cross
examination by liquidliquid extraction and solid-phase microextraction [186] and common synthetic impurities identication [161]
were reported for impurity proling in methamphetamine and 4methylthioamphetamine, respectively. Chloromethyl-3,4-dimethoxy
pyridine hydrochloride, is generally used as counter-ions to form salt
or protecting group appears as genotoxic impurity in APIs. Ammonium acetate was used to improve detection sensitivity of this genotoxic impurity by LC/MS/MS technique, where it increases ionization
[191]. High pH mobile phase (pH > 11) with XBridge C18 column was
employed for analysis of aminoglycoside plazomicin and its impurities, which allows higher loadings of drug and its impurities. Thus,
higher pH of mobile phase compensates lower UV absorption of the
drug [192]. Methyl 4 ,4 -dibromo methyl biphenyl-2-carboxylate was
identied as principle synthetic route impurity in telmisartan based
on spectral data deriving from 2D-NMR and MS [198]. Zolmitriptandimer was characterized as impurity in zolmitriptan by means of LC
MS and NMR studies which was identied as by-product of its last
step Fischer indole synthesis [202]. When a uid has temperature
and pressure are higher than corresponding critical values, known
as supercritical uid [206] and it is used in supercritical uid chromatography (SFC) for impurity proling of pharmaceutical products.
The elution prole in SFC is generally orthogonal to RPLC data, which
were very useful in assessing purity of APIs. SFC method is more
complex than RPLC due to difcult to understand solute (complex
molecule)-stationary phase interactions [207].

2.1.5.2. Forced degradation proling Due to autoxidation, epoxides


and ketones were formed through free radical-mediated reactions
involving alkene and alcohol sites of rapamycin, which were identied by forced degradation studies [160]. 2,2 -Azobisisobutyronitrile
as a radical initiator was used to understand mechanistic oxidative degradation pathway of azelnidipine in solution, which may
be helpful to stabilize its dosage form [165]. Forced degradation
behavior of 1-(4-methoxyphenylethyl)-11H-benzo[f]-1,2-dihydropyrido[3,2,c][1,2,5]oxathiazepine 5,5 dioxide, new potent anticancer
agent was in different stress conditions, where degradation products were elucidated by means of ESI-orbitrap-MS [166]. Stabilityindicating LC methods were reported to determine cefditoren pivoxil
and synthetic chalcone derivative, respectively, in presence of
degradants formed due to forced degradation [196]. To establish inherent chemical stability of thiocolchicoside, a glycoside of Colchicum
autumnale, forced degradation study was performed, where degradation pathways for hydrolytic and oxidative conditions were elucidated [199]. First order kinetic was followed by trandolapril hydrolysis in acidic and neutral conditions and this degradation prole was
investigated by two techniques UPLC-DAD and UPLCMS/MS [200].

2.1.5.3. Impurity and forced degradation proling HPLC and spectrophotometric methods were applied to determine bupropion hydrochloride, its alkaline degradates and 3-chlorobenzoic acid as impurity [167]. Preparative HPLC, LCMS/MS, UPLC-TOF-MS, NMR and
FT-IR spectroscopy were employed to study forced degradation of

28

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

dipyridamole product and two additional impurities were also characterized [175]. Total 15 impurities and eslicarbazepine were determined by stability indicating RP-HPLCUV method and characterized by LC/ESI-IT/MS/MSn . Acridine-9-carboxylic acid was identied as degraded impurity, while (10S)-10-hydroxy-10,11-dihydro5H-dibenzo[b,f]azepine-5-carbox-amide was found as both degraded
as well as process impurity and remaining all were process related
impurities [176]. 26 impurities were detected in commercial samples of etimicin sulfate, a semi-synthetic aminoglycoside antibiotic
with less chronic nephro- and ototoxicity, by liquid chromatography ion-trap mass spectrometry by using C18 column with an alkaline aqueous mobile phase. The source of impurities were identied as starting material for synthesis and its residual impurities, intermediates, synthetic by-products and degradation products [178].
Seven potential impurities (isoniacin, niacin, isonicotinamide, 3aminopyridine, 2-aminopyridine, fampridine n-oxide and 3-hydroxy4-aminopyridine) of fampridine were determined by using C18 stationary phase in gradient mode and ultraviolet dual wavelength detection technique. Fampridine is used to improve walking in patients
with multiple sclerosis and its major oxidative degradation product was also determined as fampridine n-oxide [179]. About 24 analytes including guaifenesin, terbutaline sulfate, ambroxol HCl, their
related compounds and degradation product were determined by
stability-indicating LC method [181]. In similar way, niacinamide and
potential impurities (niacinamide n-oxide, isonicotinic acid, niacin,
isonicotinamide, picolinamide, 3-cyanopyridine) were also analyzed
where niacinamide n-oxide was identied as oxidative degradation
product [189]. In addition to six known impurities, three impurities
were identied as rivastigmine N-oxide, rivastigmine p-isomer and
rivastigmine o-isomer. Rivastigmine N-oxide was also identied as
oxidative degradant of the drug [194]. Sodium tanshinone IIA sulfonate is used in China for treating cardiovascular disease is isolated
from roots of Salvia miltiorrhiza. Starting material, synthetic byproducts and degradation were identied as main sources the impurities
[197]. Process related impurity (6-chloro-5,7-dihydroxy-8-methoxy2-phenyl-4H-chromen-4-one) and degradation product of alkaline
condition (5,7-dihydroxy-6-methoxy-2-phenyl-4H-chromen-4-one)
of synthetic wogonin crude drug were characterized by HPLCQ-TOF
MS/MS technique [201].

2.2. Quality by design (QbD) and design of experimental (DoE)


concepts in impurity and degradation proling
Response surface design by means of central composite design
(CCD) was employed to forced degradation prole of eletriptan hydrobromide by HPLC, where only oxidative degradant was observed
[63]. Response surface methodology of statistical analysis was applied to optimize chromatographic parameters for determination of
nimodipine and its impurities in tablets [74]. Different paracetamol
formulations were analyzed in relation to their synthetic pathways,
which differ in starting materials, solvents, reagents, catalysts and
intermediates. It was assumed that drug may have different impurity prole, which were analyzed with principal component analysis
(PCA), hierarchical clustering and auto-associative multivariate regression trees (AAMRT) by using chromatographic data [204]. Two
process-related impurities, 3-piperidinopropiophenone hydrochloride (intermediate) and 1-(3,3-diphenylprop-2-en-1-yl)piperidine
(by-product) were determined in pridinol mesylate, where mobile
phase composition (pH and organic component) were optimized by
an experimental design (Design Expert v. 7) [77]. Chemometrical approach was applied to study ropinirole and its impuritys chromatographic behavior [78].
Impurity fate mapping (IFM) approach (Fig. 5) was applied for investigation and control of impurities in the manufacturing process
of pazopanib hydrochloride, which requires an aggressive chemical

Fig. 5. General outline of the impurity fate mapping framework. (Reuse with the permission of Elsevier Limited, The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB,
UK.)

and analytical search for potential impurities in the starting materials, intermediates and drug substance, and experimental studies to
track their fate through the manufacturing process in order to understand the process capability for rejecting such impurities. Comprehensive IFM provide elements of control strategies for impurities [95]. The regression coefcient plots of resolution between peak
pairs were included in the experimental design to optimize separation of oxytocin and its related substances [117]. Multiobjective
optimization technique was employed to optimize microemulsion
liquid chromatographic (MELC) method through Derringers desirability function for separation of perindopril tert-butylamine and its
four impurities, where central composite design was used to study
different factors responsible for the separation [153].
Analysis time for sulindac and its related impurities (E-sulindac,
sulindac sulfone and sulindac sulde) was reduced using Platinum
C18 Rocket column (53 mm 7 mm, 1.5 m particle size) and experimental design, which was processed by software R version 2.7.2.
Four factors were taken into consideration for optimization of the
method, which were: duration of initial isocratic step, percentage
of organic modier at beginning of gradient, percentage of organic
modier at end of gradient and gradient time. Fig. 6 shows the probability surfaces in different directions of the space around the optimal solution (for each graph, two factors were xed at their optimal
values) [156]. Experimental design as tool was applied for analysis
of genotoxic impurity 4-dimethylaminopyridine in glucocorticoids,
where quadratic model, central composite face was employed to optimize the method [180]. Full factorial design and surface response
curve were used to study forced degradation proling of luliconazole
[185]. For optimization of LC method, which was used for analysis
of moxonidine and its impurities in tablet, both central composite
design technique and response surface method were applied by using variable factors as buffer pH value, column temperature, methanol
content [187]. Response surface methodologies, such as Box-Behnken
and Central Composite Design (Fig. 7) were used to optimize compositional parameters and evaluate interaction effects for validation of
stability-indicating HPTLC method which was applied to degradation
kinetic proling of ropinirole [195].
As above we have discussed trends in analytical perspective on impurity and forced degradation proling of pharmaceuticals including
different techniques used in impurity proling, experimental design,
different conditions of analysis (mobile phase, column, types of elution and detection wavelength) and therapeutic category of API. Statistical tools have been applied to analyze above various parameters
of impurity and forced degradation proling and these parameters

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

29

Fig. 8. Different columns used for impurity and forced degradation proling during
20082012.

Fig. 6. Surface of probability to reach S > 0. The design space is surrounded by black
lines for an expected probability to have well-separated peaks is 0.9. Factors optimal
values are placed between parentheses. (Reuse with the permission of Elsevier Limited,
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK.)

combination of hydrophilic stationary phases and hydrophobic mobile phases and generally effective for separation of low-molecular
weight polar compounds. Different columns (cyano, amino, silica and
sulfobetaine) with variation in pore size, particle size and dimension
were used for the study [43].
Chiral chromatography is a tool for analytical determination of
enantiomeric purity as well as isolation of pure enantiomers. In
this context, enantioselective and chemoselective HPLC method was
employed to determine (R)-( + )- and (S)-()-lansoprazole enantiomers and its reported impurities using Chiralpak IA with mixture of mobile phase consisting of methyl-tert-butyl ether:ethyl acetate:ethanol:diethylamine [70]. BEH (bridged ethylene hybrid) C18
column one of the newer technology in column chemistry, where
surface hybrid groups reduce surface silanol concentration, internal
bridging groups provide high interconnectivity and internal hybrid
groups provide hydrophobicity. These characteristics of BEH column
enables strength of column (withstand higher pressure), great peak
shape, wider pH range and shorten run time. Ultra performance liquid chromatography (UPLC) equipped with BEH column was used
for determination of atorvastatin, fenobrate and their impurities in
tablets, which offers high optimum velocities and low minimum plate
heights for well-retained compounds with very small run time [21].

2.4. Matrix: API and dosage forms


Fig. 7. Response surface plot showing effect of different ratios of toluene (X1), ethyl
acetate (X2) and ammonia solution (X3) on retardation factor (Y). (Reuse with the
permission of Elsevier Limited, The Boulevard, Langford Lane, Kidlington, Oxford OX5
1GB, UK.)

are going to be discuss in following.


2.3. Column
Column is heart of the chromatography which can be selected depending upon their pore size, surface area, carbon load, particle size,
length, chemistry of column. The degree of retention of a neutral hydrophobic analyte on a wholly alkyl phase (C18 or C8) can be inferred
from the carbon load value. Maximum C18 and C8 columns were
used, 62% and 9%, respectively, for impurity and forced degradation
proling (Fig. 8). Amino, C2, C3, phenyl and cyano columns were used
to some extent. Off the track from conventional RP-HPLC, hydrophilic
interaction chromatography (HILIC) was employed for simultaneous
determination of mildronate and its six impurities, which is based on

Maximum work on active pharmaceutical ingredient (API) for impurity and degradation proling, which was totalled to 73% during
20082012 (Fig. 9). Maximum of 14% of total work was on tablet
doasge form and followed by capsules, creams and injections. Although, other dosage forms were also subjected to perform this study,
such as coated eluting stents [30,87], powder for injection [48], lotion
[56], soft gelatin capsules [61], patches [77], nasal solution [91], plant
extracts [163], syrup [181], and nanoemulsion [196].

2.5. Elution: isocratic and gradient


Both, gradient and isocratic elutions were used for determination of impurities as by-products, intermediates, starting materials,
degradants, isomer impurity, etc. by using different columns as we
have discussed in above section. The isocratic mode (53%) of elution
was much more adopted than gradient elution (47%, Fig. 10) but both
are very close to each other. Thus, both elution mode have been used
during last ve years for impurity and degradation proling.

30

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

3. Conclusion
The present review describes comprehensive update on recent
trends in analytical perspectives of degradation and impurities proling of pharmaceuticals including active pharmaceutical ingredient
(API) as well as drug products during 20082012, which may serve
and ample view to all the interest group.
Acknowledgements

Fig. 9. Different matrix used for impurity and forced degradation proling during
20082012.

One of the authors, Pawan Kumar Basniwal, earnestly indebted


to Science and Engineering Research Board (SERB), DST, New Delhi,
India, for the nancial support for this research work under Fast Track
Scheme for Young Scientists.
References

Fig. 10. Types of elution performed in LC analysis for impurity and forced degradation
proling during 20082012.

Fig. 11. Drug categories of different matrix used for impurity and forced degradation
proling during 20082012.

2.6.Therapeutic categories
Although, most of all therapeutic categories have been taken
into consideration for impurity and forced degradation proling, but
drug candidate belongs to chemotherapeutic category were maximum used for this study as 18% (Fig. 11) and followed by drugs acting on cardiovascular system (16%), central nervous system (15%),
immunomodulator (6%), GIT (6%), antineoplastics (6%), psychopharmacological agents (4%), etc. Recently, ten impurities of antihyperlipidemic drug (simvastatin) were summarized by Basniwal and
Jain [208].

[1] D. Roy, Implementation of revised schedule M and SSI, The Indian Pharmacist.
(2003) 811.
[2] ICH. Impurities in new drug substances Q3A (R2), in: International Conference
on Harmonization. Geneva, Switzerland, IFPMA, 2006.
[3] J.G. Hardman, L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Gilman, Good
and Gilmans The Pharmaceutical Basics of Therapeutics,ninth ed., New York,
McGraw-Hill, 1999, pp. 363.
[4] S. Gorog, Identication and Determination of Impurities in Drugs, Amsterdam,
Elsevier Science, 2000, 748.
[5] S. Ahuja, Impurities Evaluation of Pharmaceuticals, New York, Marcel Dekker
Inc., 1998, 42.
[6] The United State Pharmacopeia USP 24. The National Formulary NF 19, 2000,
Twinbrook Parkway, Rockville, MD, United State Pharmacopeial Convention,
Inc. 12601, 1998, pp. 18761878, 20852.
[7] J.M. Daniels, E.R. Nestmann, A. Kerr, Development of stereoisomeric (chiral)
drugs: a brief review of scientic and regulatory considerations, Drug Information Journal. 31 (1997) 639646.
[8] S. Husain, R. Nageswara Rao, Monitoring of process impurities in drugs, in: Z.
Deyl, I. Miksik, F. Tagliaro, E. Tesarova (Eds.), Advanced Chromatographic and
Electromigration Methods in Biosciences. Amsterdam, Elsevier Science, 1998,
pp. 834888.
[9] R. Nageswara Rao, V. Nagaraju, An overview of the recent trends in development of HPLC methods for determination of impurities in drugs, Journal of
Pharmaceutical and Biomedical Analysis. 33 (2003) 335377.
[10] K.M. Alsante, A. Ando, R. Brown, J. Ensing, T.D. Hatajik, W. Kong, et al., The role
of degradant proling in active pharmaceutical ingredients and drug products,
Advanced Drug Delivery Reviews. 59 (2007) 2937.
[11] S. Ahuja, K.M. Alsante, Handbook of Isolation and Characterization of Impurities
in Pharmaceuticals, Amsterdam, Elsevier, 2003.
[12] R.J. Smith, M.L. Webb, Analysis of Drug Impurities, Oxford, Blackwell, 2007.
og,
The importance and the challenges of impurity proling in modern
[13] S. Gor
pharmaceutical analysis, Trends in Analytical Chemistry. 25 (2006) 755757.
og,
Recent advances in the impurity proling of drugs, Current
[14] D. Bartos, S. Gor
Pharmaceutical Analysis. 4 (2008) 215230.
[15] S.W. Baertschi, Analytical methodologies for discovering and proling
degradation-related impurities, Trends in Analytical Chemistry. 25 (2006),
758567.
[16] D.Q. Liu, L. Wu, M. Sun, P.A. MacGregor, On-line H/D exchange LCMS strategy
for structural elucidation of pharmaceutical impurities, Journal of Pharmaceutical and Biomedical Analysis. 44 (2007) 320329.
[17] J.X. Zhang, D.M. Zhang, X.G. Han, Identication of impurities and statistical classication of methamphetamine hydrochloride drugs seized in China, Forensic
Science International. 182 (2008) 1319.
[18] A.P. Kumar, V.R.L. Ganesh, D.V.S. Rao, C. Anil, B.V. Rao, V.S. Hariharakrishnan, et al., A validated reversed phase HPLC method for the determination of
process-related impurities in almotriptan malate API, Journal of Pharmaceutical and Biomedical Analysis. 46 (2008) 792798.
[19] A.L. Huidobroa, P. Pruimb, P. Schoenmakersb, C. Barbas, Ultra rapid liquid
chromatography as second dimension in a comprehensive two-dimensional
method for the screening of pharmaceutical samples in stability and stress
studies, Journal of Chromatography A. 1190 (2008) 182190.
[20] P.F. Gavin, B.A. Olsen, A quality by design approach to impurity method development for atomoxetine hydrochloride (LY139603), Journal of Pharmaceutical
and Biomedical Analysis. 46 (2008) 431441.
[21] A.A. Kadav, D.N. Vora, Stability indicating UPLC method for simultaneous determination of atorvastatin, fenobrate and their degradation products in tablets,
Journal of Pharmaceutical and Biomedical Analysis. 48 (2008) 120126.
[22] A. Khedr, M. Sheha, Stress degradation studies on betahistine and development
of a validated stability-indicating assay method, Journal of Chromatography B.
869 (2008) 111117.
[23] M. Li, M. Lin, A. Rustum, Application of LCMSn in conjunction with
mechanism-based stress studies in the elucidation of drug impurity structure: rapid identication of a process impurity in betamethasone 17-valerate

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

drug substance, Journal of Pharmaceutical and Biomedical Analysis. 48 (2008)


14511456.
R.N. Rao, A.N. Raju, R. Narsimha, Isolation and characterization of process related impurities and degradation products of bicalutamide and development
of RP-HPLC method for impurity prole study, Journal of Pharmaceutical and
Biomedical Analysis. 46 (2008) 505519.
B.D. Spiegeleer, V. Vergote, A. Pezeshki, K. Peremans, C. Burvenich, Impurity proling quality control testing of synthetic peptides using liquid
chromatography-photodiode array-uorescence and liquid chromatographyelectrospray ionization-mass spectrometry: the obestatin case, Analytical Biochemistry. 376 (2008) 229234.
P. Ferraboschi, V. Bertacche, I. Maccone, E. Pini, L. Ragonesi, A. Venturini, et al.,
Estimation and characterization of budesonide tablets impurities, Journal of
Pharmaceutical and Biomedical Analysis. 47 (2008) 636640.
O. Galanopoulou, S. Rozou, E.A. Vyza, HPLC analysis, isolation and identication
of a new degradation product in carvedilol tablets, Journal of Pharmaceutical
and Biomedical Analysis. 48 (2008) 7077.
C. Bharathia, P. Jayaram, J.S. Raj, M.S. Kumar, V. Bhargavi, V.K. Handa, et al., Identication, isolation and characterization of impurities of clindamycin palmitate
hydrochloride, Journal of Pharmaceutical and Biomedical Analysis. 48 (2008)
12111218.
A. Mohan, M. Hariharan, E. Vikraman, G. Subbaiah, B.R. Venkataraman, D. Saravanan, Identication and characterization of a principal oxidation impurity in
clopidogrel drug substance and drug product, Journal of Pharmaceutical and
Biomedical Analysis. 47 (2008) 183189.
Q. Chen, D. Zielinski, J. Chen, A. Koski, D. Werst, S. Nowak, A validated, stabilityindicating HPLC method for the determination of dexamethasone related substances on dexamethasone-coated drug-eluting stents, Journal of Pharmaceutical and Biomedical Analysis. 48 (2008) 732738.
G.M. Hadad, Validated stability-indicating HPLC method for the determination of dimethyl-4,4 -dimethoxy-5,6,5 ,6 -dimethylene dioxybiphenyl-2,2 dicarboxylate, Journal of Pharmaceutical and Biomedical Analysis. 47 (2008)
695703.
S. Kafkal, S. Matthaiou, P. Alexaki, M. Abatzis, A. Bartzeliotis, M. Katsiabani, New
gradient high-performance liquid chromatography method for determination
of donepezil hydrochloride assay and impurities content in oral pharmaceutical formulation, Journal of Chromatography A. 1189 (2008) 392397.

A.A.G. Galdos, P.L. Garca, M.S.A. Prado, M.I.R.M. Santoro, E.R.M.K.


Hackmann,
Simultaneous determination of econazole nitrate, main impurities and preservatives in cream formulation by high performance liquid chromatography,
Talanta. 77 (2008) 673678.
S.P. Bhardwaj, S. Singh, Study of forced degradation behavior of enalapril
maleate by LC and LCMS and development of a validated stability-indicating
assay method, Journal of Pharmaceutical and Biomedical Analysis. 46 (2008)
113120.
D. Kumar, R.S. Tomar, S.K. Deolia, R. Srivastava, M. Metra, S. Tyagi, Isolation
and characterization of degradation impurities in epirubicin hydrochloride
injection, Journal of Chromatography B. 869 (2008) 4553.
K.V.R. Prasad, R.I. Ristic, D.B. Sheen, J.N. Sherwood, Crystallization of paracetamol from solution in the presence and absence of impurity, International
Journal of Pharmaceutics. 215 (2001) 2944.
Y. Bao, X. Mo, X. Xu, Y. He, X. Xu, H. An, Stability studies of anticancer agent
bis(4-uorobenzyl)trisulde and synthesis of related substances, Journal of
Pharmaceutical and Biomedical Analysis. 48 (2008) 664671.
W. Li, C. Hu, Spectral correlation of high-performance liquid chromatographydiode array detection data from two independent chromatographic runs Peak
tracking in pharmaceutical impurity proling, Journal of Chromatography A.
1190 (2008) 141149.
G. Bansal, M. Singh, K.C. Jindal, S. Singh, LCUVPDA and LCMS studies to
characterize degradation products of glimepiride, Journal of Pharmaceutical
and Biomedical Analysis. 48 (2008) 788795.
R.B. Shah, A. Bryant, J. Collier, M.J. Habib, M.A. Khan, Stability indicating validated HPLC method for quantication of levothyroxine with eight degradation
peaks in the presence of excipients, International Journal of Pharmaceutics.
360 (2008) 7782.
S.R. Chitturi, C. Bharathia, A.V.R. Reddy, K.C. Reddy, H.K. Sharma, V.K. Handa,
et al., Impurity prole study of lopinavir and validation of HPLC method for
the determination of related substances in lopinavir drug substance, Journal
of Pharmaceutical and Biomedical Analysis. 48 (2008) 14301440.
J.X. Zhang, D.M. Zhang, X.G. Han, Identication of impurities and statistical classication of methamphetamine hydrochloride drugs seized in China, Forensic
Science International. 182 (2008) 1319.
J. Hmelnickis, O. Pugovics, H. Kazoka, A. Viksna, I. Susinskis, K. Kokums, Application of hydrophilic interaction chromatography for simultaneous separation of six impurities of mildronate substance, Journal of Pharmaceutical and
Biomedical Analysis. 48 (2008) 649656.
M. Saravanan, K.S. Kumari, P.P. Reddy, M.N. Naidu, J.M. Babu, A.K. Srivastava,
et al., Identication, synthesis, isolation and spectral characterization of potential impurities of montelukast sodium, Journal of Pharmaceutical and Biomedical Analysis. 48 (2008) 708715.
K.K. Rajic, D. Novovic, V. Marinkovic, D. Agbaba, First-order UV-derivative spectrophotometry in the analysis of omeprazole and pantoprazole sodium salt and
corresponding impurities, Journal of Pharmaceutical and Biomedical Analysis.
32 (2003) 10191027.
P. Sun, X. Wang, L. Alquier, C.A. Maryanoff, Determination of relative response

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

31

factors of impurities in paclitaxel with high performance liquid chromatography equipped with ultraviolet and charged aerosol detectors, Journal of Chromatography A. 1177 (2008) 8791.
J. Yang, J. Guan, L. Pan, K. Jiang, M. Cheng, F. Li, Enantioseparation and impurity
determination of the enantiomers of novel phenylethanolamine derivatives
by high performance liquid chromatography on amylase stationary phase,
Analytica Chimica Acta. 610 (2008) 263267.
A. Bazewicz, Z. Fijaek, K. Samsel, Determination of pipecuronium bromide
and its impurities in pharmaceutical preparation by high-performance liquid
chromatography with coulometric electrode array detection, Journal of Chromatography A. 1201 (2008) 191195.
R.M. Bianchini, P.M. Castellano, T.S. Kaufman, Validated stability-indicating
HPLC method for the determination of pridinol mesylate. Kinetics study of
its degradation in acid medium, Journal of Pharmaceutical and Biomedical
Analysis. 48 (2008) 11511160.
V.G. Dongre, P.P. Karmuse, P.P. Rao, A. Kumar, Development and validation of
UPLC method for determination of primaquine phosphate and its impurities,
Journal of Pharmaceutical and Biomedical Analysis. 46 (2008) 236242.
P. Kovarkova, K. Vavrova, K. Tomalova, M. Schongut, K. Hruskova, P. Haskova,
et al., HPLC-DAD and MS/MS analysis of novel drug candidates from the group
of aromatic hydrazones revealing the presence of geometric isomers, Journal
of Pharmaceutical and Biomedical Analysis. 48 (2008) 295302.
R.N. Rao, M.V.N.K. Talluri, A.N. Raju, D.D. Shinde, G.S. Ramanjaneyulu, Development of a validated RP-LC/ESI-MSMS method for separation, identication and determination of related substances of tamsulosin in bulk drugs and
formulations, Journal of Pharmaceutical and Biomedical Analysis. 46 (2008)
94103.
E. Brenna, S. Frigoli, G. Fronza, C. Fuganti, S. Serra, Impurities of tazarotene: isolation and structural characterization, Journal of Pharmaceutical and Biomedical Analysis. 46 (2008) 574576.
M. Mahadika, V. Bhusaria, M. Kulkarnib, S. Dhaneshwar, LCUV and LCMS
evaluation of stress degradation behaviour of tenatoprazole, Journal of Pharmaceutical and Biomedical Analysis. 50 (2009) 787793.
M.L. Devi, K.B. Chandrasekhar, A validated stability-indicating RP-HPLC
method for levooxacin in the presence of degradation products, its process
related impurities and identication of oxidative degradant, Journal of Pharmaceutical and Biomedical Analysis. 50 (2009) 710717.
M. Shou, W.A. Galinada, Y.C. Wei, Q. Tang, R.J. Markovich, A.M. Rustum, Development and validation of a stability-indicating HPLC method for simultaneous
determination of salicylic acid, betamethasone dipropionate and their related

[57]

[58]

[59]

[60]

[61]

compounds in Diprosalic Lotion , Journal of Pharmaceutical and Biomedical


Analysis. 50 (2009) 356361.
Y.R. Reddy, S.R. Nandana, D.V. Bharathi, B. Nagarajua, S.S. Reddy, L.K. Ravindranath, et al., LC and LCMS/MS study of forced decomposition behavior
of anastrozole and establishment of validated stability-indicating analytical
method for impurities estimation in low dose anastrozole tablets, Journal of
Pharmaceutical and Biomedical Analysis. 50 (2009) 397404.
M. Xia, T.J. Hang, F. Zhang, X.M. Li, X.Y. Xu, The stability of biapenem and structural identication of impurities in aqueous solution, Journal of Pharmaceutical
and Biomedical Analysis. 49 (2009) 937944.
V.G. Dongre, P.D. Ghugare, P. Karmuse, D. Singh, A. Jadhav, A. Kumar, Identication and characterization of process related impurities in chloroquine and
hydroxychloroquine by LC/IT/MS, LC/TOF/MS and NMR, Journal of Pharmaceutical and Biomedical Analysis. 49 (2009) 873879.
B. Raman, B.A. Sharma, P.D. Ghugare, P.P. Karmuse, A. Kumar, Semi-preparative
isolation and structural elucidation of an impurity in citalopram by LC/MS/MS,
Journal of Pharmaceutical and Biomedical Analysis. 50 (2009) 377383.
F.N. Bonifacio, M. Giocanti, J.P. Reynier, B. Lacarelle, A. Nicolay, Development
and validation of HPLC method for the determination of cyclosporin A and its

[62]

[63]

[64]

[65]

[66]

[67]

[68]

capsules and its generic versions, Journal of Pharmaimpurities in Neoral


ceutical and Biomedical Analysis. 49 (2009) 540546.
C. Ashok, M. Golak, D. Adwait, V. Krishna, A. Himani, P. Umesh, et al., Isolation
and structural elucidation of two impurities from a diacerein bulk drug, Journal
of Pharmaceutical and Biomedical Analysis. 49 (2009) 525528.
B. Jocic, M. Zecevic, L. Zivanovic, A. Protic, M. Jadranin, V. Vajs, Study of forced
degradation behavior of eletriptan hydrobromide by LC and LCMS and development of stability-indicating method, Journal of Pharmaceutical and Biomedical Analysis. 50 (2009) 622629.
D. Lee, S. Rumbelow, S.K.R. Williams, Identication and quantitation of trace
impurities in fatty alcohol ethoxylates using HPLC and MALDI-TOF mass spectrometry, Analytica Chimica Acta. 654 (2009) 5963.
R. Grahek, L.Z. Kralj, Identication of gentamicin impurities by liquid chromatography tandem mass spectrometry, Journal of Pharmaceutical and
Biomedical Analysis. 50 (2009) 10371043.
M.L. Trehy, J.C. Reepmeyer, R.E. Kolinski, B.J. Westenberger, L.F. Buhse, Analysis
of heparin sodium by SAX/HPLC for contaminants and impurities, Journal of
Pharmaceutical and Biomedical Analysis. 49 (2009) 670673.
P. Kalafut, R. Kucer, J. Klimes, J. Sochor, An innovative approach to the analysis
of 3-[4-(2-methylpropyl)phenyl]propanoic acid as an impurity of ibuprofen
on a carbon-coated zirconia stationary phase, Journal of Pharmaceutical and
Biomedical Analysis. 49 (2009) 11501156.
P. Novaka, P. Tepes, M. Ilijas, I. Fistric, I. Bratos, A. Avdagic, et al., LCNMR and
LCMS identication of an impurity in a novel antifungal drug icofungipen,
Journal of Pharmaceutical and Biomedical Analysis. 50 (2009) 6872.

32

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
[69] G. Bedse, V. Kumar, S. Singh, Study of forced decomposition behavior of lamivudine using LC, LCMS/TOF and MSn, Journal of Pharmaceutical and Biomedical
Analysis. 49 (2009) 5563.
[70] R. Cirilli, R. Ferretti, B. Gallinella, L. Turchetto, L. Zanitti, F.L. Torre, Development and validation of an enantioselective and chemoselective HPLC method
using a Chiralpak IA column to simultaneously quantify (R)-( + )- and (S)-()lansoprazole enantiomers and related impurities, Journal of Pharmaceutical
and Biomedical Analysis. 50 (2009) 914.
[71] F.A. Rimawi, Development and validation of an analytical method for metformin hydrochloride and its related compound (1-cyanoguanidine) in tablet
formulations by HPLC-UV, Talanta. 79 (2009) 13681371.
[72] P. Djurdjevic, A. Ciric, A. Djurdjevic, M.J. Stankov, Optimization of separation
and determination of moxioxacin and its related substances by RP-HPLC,
Journal of Pharmaceutical and Biomedical Analysis. 50 (2009) 117126.
[73] F. Qiu, S. Pennino, C.A. Busacca, D.L. Norwood, Identication of a process impurity formed during synthesis of a nevirapine analogue HIV NNRT inhibitor
using LC/MS and forced degradation studies, Journal of Pharmaceutical and
Biomedical Analysis. 49 (2009) 733738.
[74] P. Barmpalexis, F.I. Kanaze, E. Georgarakis, Developing and optimizing a validated isocratic reversed-phase high-performance liquid chromatography separation of nimodipine and impurities in tablets using experimental design
methodology, Journal of Pharmaceutical and Biomedical Analysis. 49 (2009)
11921202.
[75] C.J. Walker, D.A. Cowan, V.H.T. James, J.C.Y. Lau, A.T. Kicman, Doping in sport2. Quantication of the impurity 19-norandrostenedione in pharmaceutical
preparations of norethisterone, Steroids. 74 (2009) 335340.
[76] R.N. Rao, P.K. Maurya, A.N. Raju, Isolation and characterization of a potential
process related impurity of phenazopyridine HCl by preparative HPLC followed
by MSMS and 2D-NMR spectroscopy, Journal of Pharmaceutical and Biomedical Analysis. 49 (2009) 12871291.
[77] R.M. Bianchini, P.M. Castellano, T.S. Kaufman, Development and validation of
an HPLC method for the determination of process-related impurities in pridinol
mesylate, employing experimental designs, Analytica Chimica Acta. 654 (2009)
141147.
[78] H. Zhanga, X. Yang, Proling and quantication of isoavone-C-glycosides impurities in puerarin injection by liquid chromatography coupled to ESI-ion
trap mass spectrometry, Journal of Pharmaceutical and Biomedical Analysis.
49 (2009) 843847.
[79] T.J.S. Raj, C. Bharathi, M.S. Kumar, J. Prabahar, P.N. Kumar, H.K. Sharma, et al.,
Identication, isolation and characterization of process-related impurities in
rizatriptan benzoate, Journal of Pharmaceutical and Biomedical Analysis. 49
(2009) 156162.
[80] B.J. Stojanovic, A. Malenovic, D. Ivanovic, T. Rakic, M. Medenica, Chemometrical
evaluation of ropinirole and its impuritys chromatographic behavior, Journal
of Chromatography A. 1216 (2009) 12631269.
[81] Y. Peng, J. Luo, Q. Lu, X. Chen, Y. Xie, L. Chen, et al., HPLC analysis, semipreparative HPLC preparation and identication of three impurities in salidroside bulk drug, Journal of Pharmaceutical and Biomedical Analysis. 49 (2009)
828832.
[82] R.N. Rao, M.V.N.K. Talluri, P.K. Maurya, Separation of stereoisomers of sertraline and its related enantiomeric impurities on a dimethylated -cyclodextrin
stationary phase by HPLC, Journal of Pharmaceutical and Biomedical Analysis.
50 (2009) 281286.
[83] Y.W. Chen, Y. Liu, T. Novak, L. Frey, K. Campos, A. Klapars, et al., Identication
and structural elucidation of process impurities generated in the end-game
synthesis of taranabant (MK-0364) via cyanuric chloride, Journal of Pharmaceutical and Biomedical Analysis. 49 (2009) 702710.
[84] Z. Stefanowicza, J. Stefanowicz, K. Mulas, Determination of tropicamide and its
major impurity in raw material by the HPLC-DAD analysis and identication of
this impurity using the off-line HPLCFT-IR coupling, Journal of Pharmaceutical
and Biomedical Analysis. 49 (2009) 214220.
[85] A. Sampath, A.R. Reddy, B. Yakambaram, A. Thirupathi, M. Prabhakar, P.P.
Reddy, et al., Identication and characterization of potential impurities of valsartan, AT1 receptor antagonist, Journal of Pharmaceutical and Biomedical
Analysis. 50 (2009) 405412.
[86] G. Goverdhan, A.R. Reddy, K. Srinivas, V. Himabindu, G.M. Reddy, Identication,
characterization and synthesis of impurities of zarlukast, Journal of Pharmaceutical and Biomedical Analysis. 49 (2009) 895900.
[87] Q. Chen, D. Zielinski, J. Chen, S. Nowak, C.C. Zhou, Structural identication
and characterization of potential degradants of zotarolimus on zotarolimuscoated drug-eluting stents, Journal of Pharmaceutical and Biomedical Analysis.
50 (2009) 778786.
[88] W. Liu, P. Li, F. Feng, L. Mao, Isolation and structure characterization of related
impurities in 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate
(XQ-1H) bulk drug and quantitation by a validated RP-LC, Journal of Pharmaceutical and Biomedical Analysis. 52 (2010) 603608.
[89] P. Srinivasu, D.V.S. Rao, R.V.K. Vegesna, K.S. Babu, A validated stabilityindicating LC method for acetazolamide in the presence of degradation products and its process-related impurities, Journal of Pharmaceutical and Biomedical Analysis. 52 (2010) 142148.
[90] M. Wanga, M. Pendela, C. Hu, S. Jin, J. Hoogmartens, A.V. Schepdael, et al., Impurity proling of acetylspiramycin by liquid chromatographyion trap mass
spectrometry, Journal of Chromatography A. 1217 (2010) 65316544.
[91] G.B. Kasawar, M. Farooqui, Development and validation of a stability indicating
RP-HPLC method for the simultaneous determination of related substances of

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

[101]

[102]

[103]

[104]

[105]

[106]

[107]

[108]

[109]

[110]

[111]

[112]

[113]

[114]

albuterol sulfate and ipratropium bromide in nasal solution, Journal of Pharmaceutical and Biomedical Analysis. 52 (2010) 1929.
I. Tamaro, S. Aprile, G.B. Giovenzana, G. Grosa, Development and validation of
a stability-indicating HPLC-UV method for the determination of alizapride and
its degradation products, Journal of Pharmaceutical and Biomedical Analysis.
51 (2010) 10241031.
A. Mornar, M. Damic, B. Nigovic, Separation, characterization, and quantication of atorvastatin and related impurities by liquid chromatography
electrospray ionization mass spectrometry, Analytical Letters. 43 (2010) 2859
2871.
G. Ioele, F. Oliverio, I Andreu, M.D. Luca, M.A. Miranda, G. Ragno, Different
photodegradation behavior of barnidipine under natural and forced irradiation,
Journal of Photochemistry and Photobiology A: Chemistry. 215 (2010) 205
213.
Y. Li, D.Q. Liu, S. Yang, R. Sudini, M.A. McGuire, D.S. Bhanushali, et al., Analytical
control of process impurities in pazopanib hydrochloride by impurity fate
mapping, Journal of Pharmaceutical and Biomedical Analysis. 52 (2010) 493
507.
D.D. Rao, L. Kalyanaraman, S.S. Sait, P.V. Rao, A validated stability-indicating
normal phase LC method for clopidogrel bisulfate and its impurities in bulk
drug and pharmaceutical dosage form, Journal of Pharmaceutical and Biomedical Analysis. 52 (2010) 160165.
J. Wanga, V. Krishnamoorthi, E. Wang, C. Yang, D. Baptista, X. Wu, et al., LC/MS
characterization of impurities and degradation products of a potent antitumor
peptidic dimer, CU201, Journal of Pharmaceutical and Biomedical Analysis. 51
(2010) 824833.
D.D. Rao, N.V. Satyanarayana, A.M. Reddy, S.S. Sait, D. Chakolea, K. Mukkanti, A
validated stability-indicating UPLC method for desloratadine and its impurities
in pharmaceutical dosage forms, Journal of Pharmaceutical and Biomedical
Analysis. 51 (2010) 736742.
N.V.V.S.S. Raman, K.A. Harikrishna, A.V.S.S. Prasad, K.R. Reddy, K. Ramakrishna,
Determination of duloxetine hydrochloride in the presence of process and
degradation impurities by a validated stability-indicating RP-LC method, Journal of Pharmaceutical and Biomedical Analysis. 51 (2010) 994997.
R. Toporisic, A. Mlakar, J. Hvala, I. Prislan, L.Z. Kralj, Identication of new impurities of enalapril maleate on oxidation in the presence of magnesium monoperoxyphthalate, Journal of Pharmaceutical and Biomedical Analysis. 52 (2010)
294299.
C. Sun, J. Wu, D. Wang, Y. Pan, Characterization of a novel impurity in bulk drug
eprosartan by ESI/MSn and NMR, Journal of Pharmaceutical and Biomedical
Analysis. 51 (2010) 778783.
B. Raman, B.A. Sharma, P.D. Ghugare, S. Nandavadekar, D. Singh, P.K. Karmuse,
et al., Structural elucidation of process-related impurities in escitalopram by
LC/ESI-MS and NMR, Journal of Pharmaceutical and Biomedical Analysis. 53
(2010) 895901.
B. Raman, B.A. Sharma, R. Butala, P.D. Ghugare, A. Kumar, Structural elucidation
of a process-related impurity in ezetimibe by LC/MS/MS and NMR, Journal of
Pharmaceutical and Biomedical Analysis. 52 (2010) 7378.
S.K. Shetty, K.V. Surendranath, R.K. Kaja, J. Satish, J. Jogul, U. Manitripathi,
Development and validation of a stability-indicating UHPLC method for assay
of felbamate and related substances, Acta Chromatographica. 22 (2010) 161
172.
A. Garg, D.W. Solas, L.H. Takahashi, J.V. Cassella, Forced degradation of fentanyl:
identication and analysis of impurities and degradants, Journal of Pharmaceutical and Biomedical Analysis. 53 (2010) 325334.
A. Skrlin, E.K. Krnic, D. Gosak, B. Prester, V. Mrsa, M. Vuletic, et al., Correlation of liquid chromatographic and biological assay for potency assessment
of lgrastim and related impurities, Journal of Pharmaceutical and Biomedical
Analysis. 53 (2010) 262268.
S. Provera, L. Rovatti, L. Turco, S. Mozzo, A. Spezzaferri, S. Bacchi, et al., A
multi-technique approach using LCNMR, LCMS, semi-preparative HPLC, HR
NMR and HRMS for the isolation and characterization of low-level unknown
impurities in GW876008, a novel corticotrophin-release factor 1 antagonist,
Journal of Pharmaceutical and Biomedical Analysis. 53 (2010) 517525.
U. Holzgrabe, C.J. Nap, S. Almeling, Control of impurities in l-aspartic acid and
l-alanine by high-performance liquid chromatography coupled with a corona
charged aerosol detector, Journal of Chromatography A. 1217 (2010) 294301.
L. Zanitti, R. Ferretti, B. Gallinella, F.L. Torre, M.L. Sanna, A. Mosca, et al., Direct
HPLC enantioseparation of omeprazole and its chiral impurities: application to
the determination of enantiomeric purity of esomeprazole magnesium trihydrate, Journal of Pharmaceutical and Biomedical Analysis. 52 (2010) 665671.
A. Schneider, L.A. Wessjohan, Comparison of impurity proles of orlistat pharmaceutical products using HPLC tandem mass spectrometry, Journal of Pharmaceutical and Biomedical Analysis. 53 (2010) 767772.
D. Ashena, E.V. Hemelrijck, S. Chopra, J. Hoogmartens, E. Adams, Liquid chromatographic analysis of oxytocin and its related substances, Journal of Pharmaceutical and Biomedical Analysis. 51 (2010) 2429.
M.K. Mone, K.B. Chandrasekhar, Degradation studies of pentoxifylline: isolation and characterization of a novel gem-dihydroperoxide derivative as major oxidative degradation product, Journal of Pharmaceutical and Biomedical
Analysis. 53 (2010) 335342.
M.S. Araynel, N. Sultana, F.A. Siddiqui, A.Z. Mirza, F. Qureshi, M.H. Zuberi, Simultaneous determination of piracetam and its four impurities by RP-HPLC
with UV detection, Journal of Chromatographic Science. 48 (2010) 589595.
M. Dousa, P. Gibala, K. Lemr, Liquid chromatographic separation of pregabalin and its possible impurities with uorescence detection after postcolumn

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

[115]

[116]

[117]

[118]

[119]

[120]

[121]

[122]

[123]

[124]

[125]

[126]

[127]

[128]

[129]

[130]

[131]

[132]

[133]

[134]

[135]

[136]

[137]

[138]

derivatization with O-phtaldialdehyde, Journal of Pharmaceutical and Biomedical Analysis. 53 (2010) 717722.
P.S. Rao, U.K. Ray, P.B. Gupta, D.V.N.S. Rao, A. Islam, P. Rajput, et al., Identication, isolation and characterization of new impurity in rabeprazole sodium,
Journal of Pharmaceutical and Biomedical Analysis. 52 (2010) 620624.
T.J. Novaka, N. Grinberg, B. Hartman, S. Marcinko, L.D. Michele, B. Mao, LCMS
using a hybrid quadrupole time of ight mass spectrometer for impurity identication during process chemical development of a novel integrase inhibitor,
Journal of Pharmaceutical and Biomedical Analysis. 51 (2010) 7883.
J. Chow, Y. Liu, K. Comstock, M. Brandl, F. Lin, F. Li, et al., Isolation and identication of ester impurities in RG7128, an HCV polymerase inhibitor, Journal of
Pharmaceutical and Biomedical Analysis. 53 (2010) 710716.
R. Stradia, D. Nava, M. Nebuloni, B. Pastura, E. Pini, Structural elucidation of
the rifaximin Ph. Eur. impurity H, Journal of Pharmaceutical and Biomedical
Analysis. 51 (2010) 858865.
R.N. Rao, B. Ramachandra, R.M. Vali, S.S. Raju, LCMS/MS studies of ritonavir
and its forced degradation products, Journal of Pharmaceutical and Biomedical
Analysis. 53 (2010) 833842.
A. Ferrarini, A.L. Huidobro, F. Pellati, C. Barbas, Development and validation of
a HPLC method for the determination of sertraline and three non-chiral related
impurities, Journal of Pharmaceutical and Biomedical Analysis. 53 (2010) 122
129.
C. Krishnaiah, A.R. Reddy, R. Kumar, K. Mukkanti, Stability-indicating UPLC
method for determination of valsartan and their degradation products in active pharmaceutical ingredient and pharmaceutical dosage forms, Journal of
Pharmaceutical and Biomedical Analysis. 53 (2010) 483489.
S. Provera, L. Martini, G. Guercio, L. Turco, L. Costa, C. Marchioro, Application
of LC-NMR and HR-NMR to the characterization of biphenyl impurities in the
synthetic route development for vestipitant, a novel NK1 antagonist, Journal
of Pharmaceutical and Biomedical Analysis. 53 (2010) 389395.
R.N. Rao, R.M. Vali, B. Ramachandra, S.S. Raju, Separation and characterization
of forced degradation products of abacavir sulphate by LCMS/MS, Journal of
Pharmaceutical and Biomedical Analysis. 54 (2011) 279285.
D.J. Milanowskia, J. Keilmana, C. Guob, U. Mocek, Isolation and identication
of ve impurities of ALB 109564(a) drug substance, Journal of Pharmaceutical
and Biomedical Analysis. 55 (2011) 366372.
C. Sitaram, R. Rupakula, B.N. Reddy, Determination and characterization of
degradation products of anastrozole by LCMS/MS and NMR spectroscopy,
Journal of Pharmaceutical and Biomedical Analysis. 56 (2011) 962968.
R.W. Stringham, M. Pennell, W. Cabric, G. Carzanac, F. Giorgic, S. Lalli, et al.,
Identication of impurities in artemisinin, their behavior in high performance
liquid chromatography and implications for the quality of derived anti-malarial
drugs, Journal of Chromatography A. 1218 (2011) 68386842.
S.R. Chitturi, Y.S. Somannavara, B.G. Peruria, S.N.H.K. Sharma, S. Reddy B., V.K.
Handa, et al., Gradient RP-HPLC method for the determination of potential
impurities in atazanavir sulfate, Journal of Pharmaceutical and Biomedical
Analysis. 55 (2011) 3147.
Y.G. Li, H.F. Chen, M.Z. Tu, P.Z. Zhang, X.Y. Wang, Identication, synthesis and
quantication of process-related impurities in auraptene, Journal of Pharmaceutical and Biomedical Analysis. 56 (2011) 191199.
L. Dick, N. Dooley, M.A. Elliott, S.J. Ford, M.R. Gordon, G.W. Halbert, et al.,
Boron phenylalanine and related impurities: HPLC analysis, stability prole
and degradation pathways, Journal of Pharmaceutical and Biomedical Analysis.
56 (2011) 633636.
B. Raman, B.A. Sharma, G. Mahale, D. Singh, A. Kumar, Investigation and structural elucidation of a process related impurity in candesartan cilexetil by LC/
ESI-ITMS and NMR, Journal of Pharmaceutical and Biomedical Analysis. 56
(2011) 256263.
S. Thomas, C.S. Mathela, A. Agarwal, S.K. Paul, Identication and structural
elucidation of an unknown impurity in carbamazepine active pharmaceutical
ingredient by liquid chromatographytandem mass spectrometry and semipreparative chromatographic isolation, Journal of Pharmaceutical and Biomedical Analysis. 56 (2011) 423428.
` A. Nicoletti, L. Martini, et al.,
L. Turcoa, S. Provera, O. Curcuruto, E. Bernabe,
Detection, identication and quantication of a new de-uorinated impurity
in casopitant mesylate drug substance during late phase development: an
analytical challenge involving a multidisciplinary approach, Journal of Pharmaceutical and Biomedical Analysis. 54 (2011) 6773.
E.F. Elkady, M.A. Fouad, Forced degradation study to develop and validate
stability-indicating RP-LC method for the determination of ciclesonide in bulk
drug and metered dose inhalers, Talanta. 87 (2011) 222229.
L.V. Bossche, A.V. Schepdael, S. Chopra, J. Hoogmartens, E. Adams, Identication
of impurities in polymyxin B and colistin bulk sample using liquid chromatography coupled to mass spectrometry, Talanta. 83 (2011) 15211529.
N. Soukhova, Z. Kassymbek, S. Bradby, A.M. Esker, P. White, S. Wahab, Development of characterization methods for entacapone in a pharmaceutical bulk,
Journal of Pharmaceutical and Biomedical Analysis. 54 (2011) 860865.
H. Wang, Z. Zhang, F. Xiong, L. Wu, P. Li, W. Ye, Isolation and structure characterization of related impurities in etimicin sulfate by LC/ESI-MSn and NMR,
Journal of Pharmaceutical and Biomedical Analysis. 55 (2011) 902907.
K. Filip, K. Bankowski, K. Sidoryk, J. Zagrodzka, M. aszcz, K. Trzcinska, et al.,
Physicochemical characterization of ezetimibe and its impurities, Journal of
Molecular Structure. 991 (2011) 162170.
M.H. Kadivar, P.K. Sinha, D. Kushwah, P. Jana, H. Sharma, A. Bapodra, Study
of impurity carryover and impurity prole in febuxostat drug substance by
LCMS/MS technique, Journal of Pharmaceutical and Biomedical Analysis. 56

33

(2011) 749757.
[139] M.S. Sangoi, V. Todeschini, M. Steppe, Fesoterodine stress degradation behavior
by liquid chromatography coupled to ultraviolet detection and electrospray
ionization mass spectrometry, Talanta. 84 (2011) 10681079.
[140] W. Liua, A. Zhou, F. Feng, H. Zhang, J. Zhou, W. Huang, Qualitative and quantitative studies on impurities in G004, a potential hypoglycaemic agent, using
liquid chromatography, nuclear magnetic resonance and mass spectrometry,
Journal of Pharmaceutical and Biomedical Analysis. 56 (2011) 627632.
N. Radulovic, Development and validation of liquid
[141] K.V. Prcetic, R. Cservenak,
chromatography tandem mass spectrometry methods for the determination
of gentamicin, lincomycin, and spectinomycin in the presence of their impurities in pharmaceutical formulations, Journal of Pharmaceutical and Biomedical
Analysis. 56 (2011) 736742.
[142] M.S. Qureshi, S.S. Bhongale, A.K. Thorave, Determination of organic acid impurities in lactic acid obtained by fermentation of sugarcane juice, Journal of
Chromatography A. 1218 (2011) 71477157.
[143] X. Che, L. Shen, H. Xu, K. Liu, Isolation and characterization of process-related
impurities and degradation products in larotaxel, Journal of Pharmaceutical
and Biomedical Analysis. 55 (2011) 11901196.
[144] D.T. Modhave, T. Handa, R.P. Shah, S. Singh, Stress degradation studies on
lornoxicam using LC, LCMS/TOF and LCMSn, Journal of Pharmaceutical and
Biomedical Analysis. 56 (2011) 538545.
[145] L. Rystov, R. Chadwick, K. Krock, T. Wang, Simultaneous determination of Maillard reaction impurities in memantine tablets using HPLC with charged aerosol
detector, Journal of Pharmaceutical and Biomedical Analysis. 56 (2011) 887
894.
[146] K. Karthikeyan, G.T. Arularasu, V. Muralia, K.C. Pillai, Identication, isolation,
characterization and response factor determination of process-related impurity in meprobamate drug substance, Journal of Pharmaceutical and Biomedical
Analysis. 54 (2011) 208212.
[147] Z. Wang, H. Zhang, O. Liu, B. Donovan, Development of an orthogonal method
for mometasone furoate impurity analysis using supercritical uid chromatography, Journal of Chromatography A. 1218 (2011) 23112319.
[148] M.Y. Iqbal, K.M.V.N. Rao, G. Sridhar, P.P. Raju, G.R. Deshpande, J.M. Babu, Characterization and relative response factor determination of process related impurity in naproxen by nuclear magnetic resonance spectroscopy, Journal of
Pharmaceutical and Biomedical Analysis. 56 (2011) 484490.
[149] P.S. Rao, U.K. Ray, S.G. Hiriyanna, S.V. Rao, H.K. Sharma, V.K. Handa, et al.,
Identication of oxidative degradation impurities of olanzapine drug substance
as well as drug product, Journal of Pharmaceutical and Biomedical Analysis. 56
(2011) 413418.
[150] C. Krishnaiah, M.V. Murthy, R. Kumar, K. Mukkanti, Development of a stabilityindicating UPLC method for determining olanzapine and its associated degradation products present in active pharmaceutical ingredients and pharmaceutical dosage forms, Journal of Pharmaceutical and Biomedical Analysis. 54
(2011) 667673.
[151] Z.Y. Liu, H.H. Zhang, X.J. Chen, X.N. Zhou, L. Wan, Z.L. Sun, Structural elucidation
of degradation products of olaquindox under stressed conditions by accurate
mass measurements using electrospray ionization hybrid ion trap/time-ofight mass spectrometry, International Journal of Mass Spectrometry. 303
(2011) 9096.
[152] M.V. Murthy, K. Srinivas, R. Kumar, K. Mukkanti, Development and validation
of a stability-indicating LC method for determining palonosetron hydrochloride, its related compounds and degradation products using naphthalethyl stationary phase, Journal of Pharmaceutical and Biomedical Analysis. 56 (2011)
429435.
Y. Dotsikas, M. Mas kovic,
B.J. Stojanovic,
D. Ivanovic,
M.
[153] A. Malenovic,
Medenica, Desirability-based optimization and its sensitivity analysis for the
perindopril and its impurities analysis in a microemulsion LC system, Microchemical Journal. 99 (2011) 454460.
[154] I. Nikcevica, T.K. Wyrzykiewiczb, P.A. Limbach, Detecting low-level synthesis impurities in modied phosphorothioate oligonucleotides using liquid
chromatographyhigh resolution mass spectrometry, International Journal of
Mass Spectrometry. 304 (2011) 98104.
[155] U. Holzgrabe, C.J. Nap, N. Kunz, S. Almeling, Identication and control of impurities in streptomycin sulfate by high-performance liquid chromatography
coupled with mass detection and corona charged-aerosol detection, Journal of
Pharmaceutical and Biomedical Analysis. 56 (2011) 271279.
[156] F. Krier, M. Brion, B. Debrus, P. Lebrun, A. Driesen, E. Ziemons, et al., Optimisation and validation of a fast HPLC method for the quantication of sulindac
and its related impurities, Journal of Pharmaceutical and Biomedical Analysis.
54 (2011) 694700.
[157] A. Peepliwal, C.G. Bonde, K.G. Bothara, A validated RP-HPLC method for quantitative determination of related impurities of ursodeoxycholic acid (API) by
refractive index detection, Journal of Pharmaceutical and Biomedical Analysis.
54 (2011) 845849.
[158] R.M. Bianchini, P.M. Castellano, T.S. Kaufman, Characterization of two new
potential impurities of valsartan obtained under photodegradation stress condition, Journal of Pharmaceutical and Biomedical Analysis. 56 (2011) 1622.
[159] G. Goverdhan, A.R. Reddy, V. Himabindu, G.M. Reddy, Synthesis
and characterization of critical process related impurities of an
asthma drug-zarlukast, Journal of Saudi Chemical Society.
(2011).
http://dx.doi.org/10.1016/j.jscs.2011.06.002.
[160] A.R. Oylera, B.E. Segmuller, Y. Sun, A. Polshyna, R. Dunphy, B.L. Armstrong,
et al., Forced degradation studies of rapamycin: identication of autoxidation

34

[161]

[162]

[163]

[164]

[165]

[166]

[167]

[168]

[169]

[170]

[171]

[172]

[173]

[174]

[175]

[176]

[177]

[178]

[179]

[180]

[181]

[182]

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
products, Journal of Pharmaceutical and Biomedical Analysis. 59 (2012) 194
200.
D. Bachut, J. Szawkao, Z. Czarnocki, Identication of common impurities
present in the synthetic routes leading to 4-methylthioamphetamine (4-MTA).
Part II: reductive amination and nitropropene route, Forensic Science International. 217 (2012) 6070.

G. Szekely,
E. Fritz, J. Bandarra, W. Heggie, B. Sellergren, Removal of potentially genotoxic acetamide and arylsulfonate impurities from crude drugs by
molecular imprinting, Journal of Chromatography A. 1240 (2012) 5258.
J.L. Pilkingtona, C. Prestonb, R.L. Gomes, The impact of impurities in various
crude A. annua extracts on the analysis of artemisinin by liquid chromatographic methods, Journal of Pharmaceutical and Biomedical Analysis. 70 (2012)
136142.
L.K. Gupta, Spectroscopic characterization and quantitative determination of
atorvastatin calcium impurities by novel HPLC method, Spectrochimica Acta
Part A: Molecular and Biomolecular Spectroscopy. 97 (2012) 495501.
E. Ueyama, F. Takahashi, J. Ohashi, T. Konse, N. Kishi, K. Kano, Mechanistic
study on degradation of azelnidipine solution under radical initiator-based
oxidative conditions, Journal of Pharmaceutical and Biomedical Analysis. 61
(2012) 277283.

M. Lecoeur, V. Verones,
C. Vaccher, J.P. Bonte, N. Lebegue, J.F. Goossens, Structural elucidation of degradation products of a benzopyridooxathiazepine under stress conditions using electrospray orbitrap mass spectrometry study of
degradation kinetic, European Journal of Pharmaceutical Sciences. 45 (2012)
559569.
S.S. Abbas, M.R. Elghobashy, R.F. Shokry, L.I. Bebawy, Stability indicating HPLC
and spectrophotometric methods for the determination of bupropion hydrochloride in the presence of its alkaline degradates and related impurity,
Bulletin of Faculty of Pharmacy,Cairo University. 50 (2012) 4959.
J. Szulfer, A. Plenis, T. Baczek, Application of a column classication method
in a selectivity study involving caffeine and its related impurities, Talanta. 99
(2012) 492501.
M.M. Annapurnan, S.V.S. Goutam, S. Anusha, L. Srinivas, Development and
validation of the stability-indicating LCUV method for the determination of
cefditoren pivoxil, Journal of Pharmaceutical Analysis. 2 (2012) 466469.
W. Xu, X. Jia, W. Liu, X. Zhang, Y. Chen, L. Zhou, et al., Identication and characterization of three impurities in clocortolone pivalate, Journal of Pharmaceutical and Biomedical Analysis. 62 (2012) 167171.

A. Garca, F.J. Ruperez,


F. Ceppa, F. Pellati, C. Barbas, Development of chromatographic methods for the determination of genotoxic impurities in cloperastine
fendizoate, Journal of Pharmaceutical and Biomedical Analysis. 61 (2012) 230
236.
S. Thomas, S.C. Joshi, D. Vir, A. Agarwal, R.D. Rao, I. Sridhar, et al., Identication,
characterization and quantication of a new impurity in deferasirox active
pharmaceutical ingredient by LCESI-QT/MS/MS, Journal of Pharmaceutical
and Biomedical Analysis. 63 (2012) 112119.
S.M. Pawar, L.D. Khatal, S.Y. Gabhe, S.R. Dhaneshwar, LCUV and LCMS evaluation of stress degradation behavior of desvenlafaxine, Journal of Pharmaceutical Analysis. 2 (2012) 264271.
V.A.A. Chatpalliwara, P.K. Porwala, N. Upmanyu, Validated gradient stability
indicating HPLC method for determining diltiazem hydrochloride and related
substances in bulk drug and novel tablet formulation, Journal of Pharmaceutical Analysis. 2 (2012) 226237.
B.V. Subbaiah, K.K.S. Ganesh, G.V. Krishna, K. Vyas, R.V. Dev, K.S. Reddy, Isolation and characterisation of degradant impurities in dipyridamole formulation,
Journal of Pharmaceutical and Biomedical Analysis. 61 (2012) 256264.
S. Thomas, A. Bharti, P.K. Maddhesia, S. Shandilya, A. Agarwal, D. Vir, et al.,
Highly efcient, selective, sensitive and stability indicating RP-HPLCUV
method for the quantitative determination of potential impurities and characterization of four novel impurities in eslicarbazepine acetate active pharmaceutical ingredient by LC/ESI-IT/MS/MS, Journal of Pharmaceutical and
Biomedical Analysis. 61 (2012) 165175.
S.U. Nalwade, V.R. Reddy, D.D. Rao, N.K Morisetti, A validated stability indicating ultra performance liquid chromatographic method for determination
of impurities in esomeprazole magnesium gastro resistant tablets, Journal of
Pharmaceutical and Biomedical Analysis. 57 (2012) 109114.
Y. Yuan, M. Zhang, X.L. Fan, G.H. Wang, C.Q. Hu, S. Jin, et al., Impurity proling of
etimicin sulfate by liquid chromatography ion-trap mass spectrometry, Journal
of Pharmaceutical and Biomedical Analysis. 70 (2012) 212223.
S. Thomas, S. Shandilya, A. Bharti, A. Agarwal, A stability indicating simultaneous dual wavelength UVHPLC method for the determination of potential
impurities in fampridine active pharmaceutical ingredient, Journal of Pharmaceutical and Biomedical Analysis. 58 (2012) 136140.
G. Szekely, B. Henriques, M. Gil, A. Ramos, C. Alvarez, Design of experiments
as a tool for LCMS/MS method development for the trace analysis of the
potentially genotoxic 4-dimethylaminopyridine impurity in glucocorticoids,
Journal of Pharmaceutical and Biomedical Analysis. 70 (2012) 251258.
K.L.N. Rao, C. Krishnaiah, K.S. Babu, K.P. Reddy, Development and validation of a stability-indicating LC method for simultaneous determination of
related compounds of guaifenesin, terbutaline sulfate and ambroxol HCl
in cough syrup formulation, Journal of Saudi Chemical Society. (2012).
http://dx.doi.org/10.1016/j.jscs.2012.01.006.
A. Nageswari, K.V.S.R. Krishna Reddy, K. Mukkanti, Stability-indicating UPLC
method for determination of imatinib mesylate and their degradation products
in active pharmaceutical ingredient and pharmaceutical dosage forms, Journal
of Pharmaceutical and Biomedical Analysis. 66 (2012) 109115.

[183] S. Schiesel, M. Lammerhofer, A. Leitner, W. Lindner, Quantitative highperforamance liquid chromatography-tandem mass spectrometry impurity
proling methods for the analysis of parentral infusion solutions for amino
acid supplementation containing l-alanyl-l-glutamine, Journal of Chromatography A. 12 (2012) 111120.
[184] T.S. Rajua, O.V. Kutty, V. Ganesh, P.Y. Swamy, A validated stability-indicating LC
method for the separation of enantiomer and potential impurities of linezolid
using polar organic mode, Journal of Pharmaceutical Analysis. 2(4) (2012) 272
278.
[185] S. Sonawane, P. Gide, Application of experimental design for the optimization
of forced degradation and development of a validated stability-indicating LC
method for luliconazole in bulk and cream formulation, Arabian Journal of
Chemistry. (2012). http://dx.doi.org/10.1016/j.arabjc.2012.03.019.
[186] J. Lee, Y. Park, W. Yang, H. Chung, W. Choi, H. Inoue, et al., Cross-examination of
liquidliquid extraction (LLE) and solid-phase microextraction (SPME) methods for impurity proling of methamphetamine, Forensic Science International. 215 (2012) 175178.
[187] S. Milovanovic, B. Otasevic, M. Zecevic, L. Zivanovic, A. Protic, Development
and validation of reversed phase high performance liquid chromatographic
method for determination of moxonidine in the presence of its impurities,
Journal of Pharmaceutical and Biomedical Analysis. 59 (2012) 151156.
[188] G. Navaneethan, K. Karunakaran, K.P. Elango, Development and application
of stability-indicating HPLC method for the determination of nevirapine and
its impurity in combination drug product, Acta Chromatographica. 24 (2012)
113.
[189] S. Thomas, A. Bharti, K. Tharpa, A. Agarwal, Quantication of potential impurities by a stability indicating UV-HPLC method in niacinamide active pharmaceutical ingredient, Journal of Pharmaceutical and Biomedical Analysis. 60
(2012) 8690.
[190] T. Gao, Y. Liu, Y. Ji, X. Wu, J. Xu, Structural elucidation of impurities
in 5-n-butyl-4-{4-[2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4dihydro-2-(2,6-dichloro-phenyl)-3H-1,2,4-triazol-3-one (Ib), a novel nonpeptide angiotensin AT1 receptor antagonist, Journal of Pharmaceutical and
Biomedical Analysis. 66 (2012) 381386.
[191] N. Venugopal, A.V.B. Reddy, K.G. Reddy, V. Madhavi, G. Madhavi, Method
development and validation study for quantitative determination of 2chloromethyl-3,4-dimethoxy pyridine hydrochloride a genotoxic impurity in
pantoprazole active pharmaceutical ingredient (API) by LC/MS/MS, Journal of
Pharmaceutical and Biomedical Analysis. 70 (2012) 592597.
[192] L. Tana, K.B. Wlasichuk, D.E. Schmidt, R.L. Campbell, P. Hirtzer, L. Cheng, et al.,
A high pH based reversed-phase high performance liquid chromatographic
method for the analysis of aminoglycoside plazomicin and its impurities, Journal of Pharmaceutical and Biomedical Analysis. 66 (2012) 7584.
[193] H. Hashem, A.E. Ibrahim, M. Elhenawee, A rapid stability indicating LC-method for determination of praziquantel in presence of its
pharmacopoeial impurities, Arabian Journal of Chemistry.
(2012).
http://dx.doi.org/10.1016/j.arabjc.2012.07.005.
[194] S. Thomas, S. Shandilya, A. Bharati, S.K. Paul, A. Agarwal, C.S. Mathela, Identication, characterization and quantication of new impurities by LCESI/MS/MS
and LCUV methods in rivastigmine tartrate active pharmaceutical ingredient,
Journal of Pharmaceutical and Biomedical Analysis. 57 (2012) 3951.
[195] G. Mustafa, A. Ahuja, S. Baboota, J. Ali, Box-Behnken supported validation
of stability-indicating high performance thin-layer chromatography (HPTLC)
method: an application in degradation kinetic proling of ropinirole, Saudi
Pharmaceutical Journal. 21 (2012) 93102.

[196] C.B. Mattos, V.B. Deponti, F. Barreto, C.M.O. Simoes,


C.R.A. Frohner, R.J. Nunes,
et al., Development of a stability-indicating LC method for determination of a
synthetic chalcone derivative in a nanoemulsion dosage form and identication of the main photodegradation product by LCMS, Journal of Pharmaceutical and Biomedical Analysis. 70 (2012) 652656.
[197] B. Wang, H. Wang, E. Wang, W. Yan, W.Y.P. Li, Isolation and structure characterization of related impurities in sodium tanshinone IIA sulfonate by LC/
ESI-MSn and NMR, Journal of Pharmaceutical and Biomedical Analysis. 6768
(2012) 3641.
[198] V. Srinivasan, H. Sivaramakrishnan, B. Karthikeyan, Detection, isolation and characterization of principle synthetic route indicative
impurity in telmisartan, Arabian Journal of Chemistry.
(2012).
http://dx.doi.org/10.1016/j.arabjc.2012.03.022.
[199] D.G. Erika, A. Silvio, G. Giorgio, Forced degradation study of thiocolchicoside:
characterization of its degradation products, Journal of Pharmaceutical and
Biomedical Analysis. 61 (2012) 215223.
[200] M. Dendenia, N. Cimetiere, A. Amrane, N. Ben Hamida, Impurity proling of
trandolapril under stress testing: structure elucidation of by-products and
development of degradation pathway, International Journal of Pharmaceutics.
438 (2012) 6170.
[201] Y. Xia, C. Wu, W. Liu, F. Feng, Z. Li, A novel process related impurity and forced
degradation study of synthetic wogonin: development of a liquid chromatographic method for purity control, Journal of Pharmaceutical and Biomedical
Analysis. 71 (2012) 168172.

Z. Mandelova,
J. Brichac,
et al., Iden[202] M. Dousa, P. Gibala, S. Radl,
O. Klecan,
tication, preparation and UHPLC determination of process-related impurity
in zolmitriptan, Journal of Pharmaceutical and Biomedical Analysis. 58 (2012)
16.
[203] A.S. Ivanov, S.V. Shishkov, A.A. Zhalnina, Synthesis and characterization of
organic impurities in bortezomib anhydride produced by a convergent technology, Scientia Pharmaceutica. 80 (2012) 6775.

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
[204] M. Dumarey, A.M.V. Nederkassel, I. Stanimirova, M. Daszykowskia, F. Bensaidc,
M. Lees, et al., Recognizing paracetamol formulations with the same synthesis
pathway based on their trace-enriched chromatographic impurity proles,
Analytica Chimica Acta. 655 (2009) 4351.
[205] T.D. Ho, M.D. Joshi, M.A. Silver, J.L. Anderson, Selective extraction of genotoxic
impurities and structurally alerting compounds using polymeric ionic liquid
sorbent coatings in solid-phase microextraction: Alkyl halides and aromatics,
Journal of Chromatography A. 1240 (2012) 2944.
[206] P.K. Basniwal, P.K. Shrivastava, R. Dubey, D. Jain, Supercritical uid extraction:
a new milestone in extraction technology, Indian Journal of Pharmaceutical

35

Sciences. 67 (2005) 532539.


[207] A.J. Alexander, T.F. Hooker, F.P. Tomasella, Evaluation of mobile phase gradient
supercritical uid chromatography for impurity proling of pharmaceutical
compounds, Journal of Pharmaceutical and Biomedical Analysis. 70 (2012)
7786.
[208] P.K. Basniwal, D. Jain, Simvastatin: review of updates on recent trends in pharmacokinetics, pharmacodynamics, drugdrug interaction, impurities and analytical methods, Current Pharmaceutical Analysis. 8 (2012) 135156.