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Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
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Journal of Pharmaceutical and Biomedical Analysis

journal homepage: www.elsevier.com/locate/jpba
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).
12
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
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].
14
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)
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]
15
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
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
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]
29 impurities
GC-FID
2008 [42]
API; antiischemic
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)
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
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
Table 2
Continued
S.
no.
Impurity/degradant
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
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
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
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
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
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
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
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
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
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
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
C18, 250 mm 4.6 mm,

5 m
230 nm
2010 [99]
88.
Enalapril maleate
Several degradation
impurities
RP-S, 250 mm 4.6 mm,

5 m
215 nm
2010
[100]
89.
Eprosartan
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)
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
19
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
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
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)
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
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
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
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
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
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]
21
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
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
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
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
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
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
22 impurities
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
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]
23
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
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
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
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
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

supplement
7 impurities
QN-AX, 150 mm 4
mm, 5 m
177.
l-Alanyl-lglutamine

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
6 degradants
C18, 250 mm 4.6 mm,

5 m
mm 1.0 m
180.
Methamphetamine
20 impurities
Helium gas
Mass
selective
detector
Year
[Ref.]
24
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
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.
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
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
193.
Thiocolchicoside
API; muscle relaxant
Methyl
4 ,4 -dibromometh-yl
biphenyl-2-carboxylate
6 degradants
194.
Trandolapril
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
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
(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
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
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
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
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
[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
O. Galanopoulou, S. Rozou, E.A. Vyza, HPLC analysis, isolation and identication
of a new degradation product in carvedilol tablets, Journal of Pharmaceutical
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
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
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
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
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,
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
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
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
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,
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
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
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
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
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,
32
[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
[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,
[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
[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
[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
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,
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
[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,
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,
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
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
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
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
D.J. Milanowskia, J. Keilmana, C. Guob, U. Mocek, Isolation and identication
of ve impurities of ALB 109564(a) drug substance, Journal of Pharmaceutical
C. Sitaram, R. Rupakula, B.N. Reddy, Determination and characterization of
degradation products of anastrozole by LCMS/MS and NMR spectroscopy,
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,
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,
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,
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
[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
[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
[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
[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]
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
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,
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
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
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
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,
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
[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,
[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
[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
[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,
[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
[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.
[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.

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Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135

Contents lists available at ScienceDirect

Journal of Pharmaceutical and Biomedical Analysis

Forced degradation and impurity proling: Recent trends in

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

c 2013 Elsevier B.V. All rights reserved.

a drug product is dependent not only on the toxicological properties

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

Materials that are used to begin the synthesis of an API

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

dansylated products of UV-degraded betahistine were well separated

C18, 250 mm 4.6 mm,

C18, 150 mm 4.6 mm,

C8, 50 mm 4.6 mm,

An acid degraded impurity

C18 (BEH), 100 mm

API and tablet;

C18, 250 mm 4.6 mm,

API and tablet;

C18, 250 mm 4.6 mm,

C18, 125 mm 4.6 mm,

C18, 250 mm 4.6 mm,

C18, 100 mm 4.6 mm,

C18, 250 mm 4.6 mm,

C8, 250 mm 4.6 mm, 5

Process impurities and

C8, 4.6 mm 250 mm, 5

C18, 250 mm 4.6 mm

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

API and tablet;

C18, 250 mm 4.6 mm,

C18, 300 mm 3.9 mm,

196, 230 and

196, 230 and

220 and 300

C18, 250 mm 4.6 mm,

C18, 250 mm 4.6 mm,

Acid and alkali degraded

C18 (BEH), 100 mm

C2, 250 mm 4.6 mm, 5

API and injection;

C18, 250 mm 4.6 mm,

196, 230 and

API; thyroid hormone

C2, 250 mm 4.6 mm, 5

C18, 250 mm 4.6 mm,

ACN: CH3 COONH4

Eluent A: Na2 HPO4

196, 230 and

196, 230 and

C18, 250 mm 4.6 mm,

C18, 250 mm 4.6 mm,

C18, 250 mm 4.6 mm,

Phenyl, 150 mm 4.6

ASH, 250 mm 4.6 mm,

Cyano, 250 mm 4.6

API; muscle relaxant

C18, 250 mm 4.6 mm,

API; chelating agent

C18 (BEH), 50 mm 2.1

C18, 250 mm 4.6 mm,

Capsule, tablet and API;