Forced degradation and impurity profiling

Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 11–35

Contents lists available at ScienceDirect

Journal of Pharmaceutical and Biomedical Analysis

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j p b a

Review

Forced degradation and impurity profiling: Recent trends in

analytical perspectives

Deepti Jain

a , Pawan Kumar Basniwal a , b , *

a School of Pharmaceutical Sciences, Rajiv Gandhi Technological University, Bhopal 462 033, Madhya Pradesh, India b 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 profiling

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 degra-

dation and impurities profiling of pharmaceuticals including active pharmaceutical ingredient (API) as well

as drug products during 2008–2012. These recent trends in forced degradation and impurity profiling 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 anal-

ysis. It focuses distinctly on comprehensive update of various analytical methods including hyphenated

techniques for the identification and quantification of thresholds of impurities and degradants in different

pharmaceutical matrices. c © 2013 Elsevier B.V. All rights reserved.

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 multi-

variate regression trees; ACN, acetonitrile; APCI-MS, atmospheric-pressure chemical-

ionization mass spectrometry; API, active pharmaceutical ingredient; BADGE, bisphe-

nol A diglycidyl ether; BEH, bridged ethylene hybrid; C 6 H 6 , benzene; CAD, charged

aerosol detector; CCD, central composite design; CCl 4 , tetrachloromethane; CEAD,

coulometric electrode array detection; CH 2 Cl 2 , methylene chloride; CH 3 COONH 4 , am-

monium acetate; CHCl 2 CH 2 Cl, 1,1,2-trichloro ethane; CHCl 3 , chloroform; CID, collision-

induced dissociation; CO 2 , carbon dioxide; COPD, chronic obstructive pulmonary

disease; DAD / MS, diode array detector-mass spectrometry; DEPT, distortionless en-

hancement by polarization transfer; EDTA, ethylene diamine tetra acetic acid; ELSD,

evaporative light scattering detector; EMEA, European agency for the evaluation of

medicinal products; ESI / MS n , 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; GC-

FID, gas chromatography-flame ionization detector; GC–MS, gas chromatography–

mass spectrometry; GFC, gel filtration chromatography; GTIs, genotoxic impurities;

H 2 O, water; H 3 PO 4 , phosphoric acid; HCl, hydrochloric acid; HCOOH, formic acid;

HCOONH 4 , ammonium formate; HEIP, 1,1,1,3,3,3-hexafluoroisopropanol; HILIC, hy-

drophilic 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, Interna-

tional Conference on Harmonization; IFM, impurity fate mapping; IND, investigational

new drugs; IPA, isoproyl alcohol; K 2 HPO 4 , dipotassium hydrogen phosphate; KH 2 PO 4 ,

potassium dihydrogen phosphate; KOH, potassium hydroxide; LC / MS / MS, liquid

chromatography–tandem mass spectrometry; ESI-CID-MS / MS, electrospray ioniza-

tion, collision-induced dissociation and tandem mass spectrometry; LC–ESI-MS n , liq-

uid chromatography–electro spray ionization-tandem mass spectrometer; LC–ESI-QT /

0731-7085/ $ - see front matter c © 2013 Elsevier B.V. All rights reserved.

http://dx.doi.org/10.1016/j.jpba.2013.07.013

1. Introduction

“A clean bill of health of public” is the ultimate motto of pharma-

ceutical 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 efficacy at an affordable cost. Thus, safety

and efficacy of pharmaceuticals are two fundamental issues of im-

portance in drug therapy. The safety of a drug is determined by its

pharmacological–toxicological profile as well as the adverse effects

caused by the impurities in bulk and dosage forms, i.e., the safety of

MS / MS, liquid chromatography–tandem mass spectrometry using electrospray ion-

ization source and Q-trap mass analyzer; LC–MS, liquid chromatography–mass spec-

trometry; 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; Na 2 HPO 4 , disodium phosphate; Na 3 PO 4 , sodium phosphate;

NaCl, sodium chloride; NDA, New Drug Application; NH 3 , ammonia; NH 4 H 2 PO 4 , am-

monium dihydrogen phosphate; NH 4 OH, ammonium hydroxide; NOESY, nuclear over-

hauser effect spectroscopy; NSAIDs, non-steroidal anti-inflammatory drugs; OVIs, or-

ganic volatile impurities; PCA, principal component analysis; PDA, photodiode ar-

ray; PDA-MS, photodiode array detector-mass spectrometry; PFPA, pentafluoropro-

pionic acid anhydride; Q-TOF, quadrupole-time-of-flight; RI, refractive index; RRF, rel-

ative response factor; SDS, sodium dodecyl sulfate; SDS-PAGE, sodium dodecyl sulfate

polyacrylamide gel electrophoresis; SFC, supercritical fluid chromatography; SPME,

headspace solid phase microextraction; TEA, triethylamine; TFA, trifluoroacetic 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: [email protected] (D. Jain) [email protected]

(P.K. Basniwal).


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12 D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 11–35

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Fig. 1. Year-wise publications for impurity and degradation profiling during 2008–

2012 .

drug product is dependent not only on the toxicological properties

f the active drug substance itself, but on the impurities that it con-

ains. Another side of coin is that the formulation should be stable

hroughout shelf life of product with respect to its identity, strength,

urity and quality of drug. Quality of pharmaceuticals has to be mon-

tored from the very beginning, i.e., from raw materials to the end,

.e., finished product, including marketing surveillance [ 1 –3 ].

As per Webster’s dictionary impurity is something that is impure

r makes something else impure. An impure substance may be de-

ned as a substance of interest mixed or impregnated with an extra-

eous or usually inferior substance [ 4 , 5 ]. A number of terms have been

ommonly used to describe organic impurities, such as starting ma-

erial, intermediates, penultimate intermediate (final intermediate),

y-products, transformation products, interaction products related

roducts and degradation products. The United States Pharmacopoeia

USP) has different sections for impurities including impurities in

fficial articles, ordinary impurities and organic volatile impurities.

hese are described as foreign substances, toxic impurities, concomi-

ant components, signal impurities, ordinary impurities and organic

olatile impurities (OVIs) [ 6 ] ( Tables 1 and 2 ).

ICH guidelines categories impurities as: organic impurities (start-

ng materials, process-related impurities, intermediates and degra-

ation products); inorganic impurities (salts, catalysts, ligands and

eavy metals); other materials (filter aids and charcoal) and resid-

al solvents (organic and inorganic liquids) [ 2 ]. ICH guidelines give

imple classification of the impurities while none of these are unable

o describe enantiomeric (chiral) impurities. Chiral impurities have

he identical molecular formula and the same connectivity between

arious atoms, and they differ only in three-dimensional arrange-

ent of their atoms in the space. The differences in pharmacological /

oxicological profiles have been observed with chiral impurities in

ivo [ 7 ].

Therefore, it is quite obvious that the products intended for hu-

an consumption must be characterized as completely as possible.

onitoring and controlling of impurities generally give assurance of

he quality and safety of a drug. Thus, the analytical activities con-

erning impurities in drugs are among the most important issues in

odern pharmaceutical analysis [ 8 , 9 ]. Analytical monitoring of im-

urities in new drug substances is a key component of the recent

uideline issued by the International Conference on Harmonization

ICH) [ 2 ].

Forced degradation studies provide data to support identification

f possible degradants; degradation pathways and intrinsic stability

f the drug molecule and validation of stability indicating analytical

rocedures. A draft guidance document suggests that results of one-

ime forced degradation studies should be included in Phase 3 INDs

Investigational New Drugs). NDA (New Drug Application) registra-

ion requires data of forced degradation studies as forced degradation

roducts, degradation reaction kinetics, structure, mass balance, drug

eak purity, etc. This forced degradation study provides information

bout degradation pathways of API, alone and in drug product, any

ossible polymorphic or enantiomeric substances and difference be-

ween drug related degradation and excipient interferences [ 24 ].

Thus, forced degradation and impurity profiling is one of the key

or IND as well as NDA registration document. Although different

ooks [ 11 , 12 ] and review articles [ 13 –16 ] have been published to

ummarize the study on impurity and degradation profiling, but still

here is no report on recent years which enable to describe the recent

nalytical perspectives of impurity and degradation profiling. Keep-

ng this view in the mind, present work has been aimed to review the

nalytical trends for forced degradation studies and impurity profiling

f active pharmaceutical ingredients and pharmaceutical drug prod-

ct. Articles published on forced degradation studies and impurity

rofiling during 2008–2012, were extensively reviewed and different

arameters, such as matrix of analysis, therapeutic category of the

rug, present impurity and degradant, column specification used for

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 profiling and stability indi-

cating assay methods during 2008–2012; which includes HPLC, cap-

illary electrophoresis, gas / liquid chromatography, thin-layer chro-

matography, etc. Fig. 1 has shown column graph of year-wise pub-

lications for impurity and degradation profiling during 2008–2012,

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 profil-

ing. Year-wise analytical perspectives were discussed as following:

2.1.1. 2008

2.1.1.1. Impurity profiling Refractive index (RI) detector as uni-

versal detector in analytical HPLC was employed for identifi-

cation of 12 impurities of clindamycin palmitate hydrochloride,

which were isolated by preparative HPLC and characterized by

LC–MS, FT-IR, NMR { 1 H, 13 C and distortionless enhancement by

polarization transfer (DEPT) } techniques [ 28 ] and same tech-

niques were also used for characterization of oxidation impurity

of clopidogrel as 5-[1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-6,7-

dihydrothieno[3,2-c]pyridin-5-ium [ 29 ]. Econazole nitrate is po-

tent broad-spectrum antifungal used for skin infections. Its two

main impurities were determined 4-chlorobenzyl alcohol and α-

(2,4-dichlorophenyl)-1 H -imidazole-1-ethanol in cream formulations

along with two preservatives [ 33 ]. HPLC-DAD and HPLC–MS were

compared for identification by peak tracking in impurity pro-

filing of quinolones, which provides spectral specificity and 2D

chromatographic correlation [ 38 ]. Four impurities of montelukast

sodium were identified during process development by LC–MS in

the range of 0.05–0.15% [ 44 ]. Normal phase of HPLC and chiral amy-

lase stationary phase were used to determine enantiomers impu-

rity of phenylethanolamine derivative by using n-hexane–ethanol–

triethylamine (TEA) as mobile phase [ 47 ]. HPLC equipped with coulo-

metric electrode array detection (CEAD) was used for determina-

tion of pipecuronium bromide and its four impurities, which pro-

vides 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 identified not

only by retention time but also by dominant channel and peak ra-

tios across the channels (as compared to standard), which is es-

pecially useful when evaluating component in a complex mixture

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 11–35 13

Table 1

Different terminology used for impurities [ 10 ].

Impurity Description

Starting material Materials that are used to begin the synthesis of an API

Intermediates Produced during synthesis of the desired material, especially when they have been isolated and

characterized

Penultimate intermediate Last compound in synthesis chain prior to production of final compound. Also known as final

Intermediate

By-products Unplanned compounds produced in the reaction

Transformation products 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

Interaction 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

substance–excipient interactions and drug substance-container / closure interactions

Related products Similar chemical structures as the API and may exhibit potentially similar biological activity

Degradation products Produced because of decomposition of the material of interest or active ingredient

Foreign substances Introduced by contamination or adulteration, not as a consequence of synthesis or preparation, are

labeled foreign substances, e.g., pesticides in oral analgesics

Toxic impurities Have significant undesirable biological activity, even as minor components; and they require

individual identification and quantification by specific tests

Concomitant components Bulk pharmaceutical chemicals may contain concomitant components, e.g., antibiotics that are

mixtures and are geometric and optical isomers

Signal impurities Impurities include some process-related impurities or degradation products that provide key

information about process

Ordinary impurities Impurities in bulk pharmaceutical chemicals that are innocuous by virtue of having no significant

undesirable biological activity in amounts present are called ordinary impurities

Organic volatile impurities Residual solvents that may be found in drug substance. ICH classification: Class I ( to be avoided ): C 6 H 6 ,

CCl 4 , 1,2-dichloromethane, 1,1-dichloroethane, and 1,1,1-trichloroethane. Class II ( should be limited ):

ACN, CHCl 3 , CH 2 Cl 2 , pyridine CHCl 2 CH 2 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

Organic impurities Starting materials, process-related impurities, intermediates, and degradation products

Inorganic impurities Salts, catalysts, ligands, heavy metals or other residual metals

Other materials Filter aids and charcoal

Residual solvents Organic and inorganic liquids used during production and / or crystallization

Chiral impurities Differ only in the arrangement of their atoms in three-dimensional space. The differences in

pharmacological / toxicological profiles have been observed with chiral impurities in vivo

Fig. 2. Chromatograms recorded from the mixture containing 1 μg ml −1 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 de-

termination of primaquine phosphate along with its related sub-

stance within run time of 5 min [ 50 ]. Two impurities of tazarotene

were characterized by means of NMR analysis as ethyl 6-((4,4-

dimethyl-4 H -thiochromen-6-yl)ethynyl)nicotinate and 1,4-bis(4,4-

dimethylthiochroman-6-yl)buta-1,3-diyne, which are by-product of

synthetic process [ 53 ].

2.1.1.2. Forced degradation profiling HPLC with fluorescence detec-

tor was employed to study stability of betahistine in different forced

degradation conditions (heat, moisture, acid–base, and ultra-violet

light), where two potential degradation products were identified. The

dansylated products of UV-degraded betahistine were well separated

by thin-layer chromatography [ 22 ]. Second order reaction was fol-

lowed by alkaline forced degradation of bicalutamide, where an acid

and an amine were identified as alkaline degradants [ 24 ]. Very in-

teresting, four major degradation products of dexamethasone in its

coated drug-eluting stents and drug-loading solution were identified

which was used for local drug delivery to prevent restenosis [ 30 ].

Both + ESI and −ESI modes of LC–MS 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 l -

thyroxine was determined in presence of eight degradation impurities

and its dosage form excipients [ 40 ]. A degradation product of pridinol

mesylate was identified as the dehydrated and N-oxidation deriva-

tives, which was formed by first-order kinetics of the acid-catalyzed

degradation of pridinol [ 49 ].

2.1.1.3. Impurity and forced degradation profiling Mixture of phos-

phate buffer and acetonitrile were used to separate three process-

related impurities and degradation products (different forced

degradation conditions) of almotriptan malate [ 18 ]. In addition

to four known impurities of carvedilol, one unknown degrada-

tion product was identified as N-[(2RS)-3-(9 H -carbazol-4-yloxy)-2-

hydroxypropyl]-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 ]. Degra-

dation pathway for forced degradation behavior of enalapril maleate

was identified in different stress conditions [ 34 ] and two degradation

impurities of epirubicin were found in aqueous formulation [ 35 ].


Table 2

Representative chromatographic analytical methods of impurity and forced degradation profiling during 2008–2012.

S.

no. Name of drug

Matrix; therapeutic

category Impurity / degradant Column / stationary phase Mobile phase Detection

Year

[Ref.]

1.

Methamphetamine

hydrochloride

API; psychostimulant 29 impurities Capillary column, 30 m

× 0.32 mm × 1.0 mm

Nitrogen gas Mass

selective

detector

2008 [ 17 ]

2. Almotriptan

malate

API; antimigraine 3 impurity C18, 250 mm × 4.6 mm,

5 μm

Sodium phosphate

buffer (pH 7.6):ACN

(80:20)

227 nm 2008 [ 18 ]

3. Alprazolam Tablets; anxiolytic 20 degradant C18, 150 mm × 4.6 mm,

5 μm

ACN:CH 3 COOH (25

mM, pH 4.0);

gradient

234 nm 2008 [ 19 ]

4. Atomoxetine

hydrochloride

API; antidepressants Phenyl

methylamino-propanol

and mandelic acid

C8, 50 mm × 4.6 mm,

3.5 μm

O -Phosphoric acid

(25 mM, pH 2.5)

and Octane sulfonic

acid (25

mM):n-Propanol

(73:27)

215 nm 2008 [ 20 ]

5. Atorvastatin

calcium

Tablets;

anti-hyperlipidemic

An acid degraded impurity C18 (BEH), 100 mm ×2.1 mm, 1.7 μm

ACN:CH 3 COONH 4

buffer (pH 4.7; 0.01

M), gradient

247 nm 2008 [ 21 ]

6. Betahistine API and tablet;

vasodilator

9 degradants C18, 250 mm × 4.6 mm,

5 μm

ACN: sodium

acetate (0.02 mM,

pH 4.5); gradient

UV – 254 nm;

Fluorescence

336 and 531

nm

2008 [ 22 ]

7. Betamethasone

17-valerate

API; steroid 2 impurities C18, 250 mm × 4.6 mm,

5 μm

ACN:H 2 O (60:40) PDA-MS

detector

2008 [ 23 ]

8. Bicalutamide API and tablet;

anticancer

2 degradants and 6

process-related impurities

C18, 250 mm × 4.6 mm,

5 μm

0.01 M KH 2 PO 4 (pH

3.0):ACN (50:50)

215 nm 2008 [ 24 ]

9. Bovine obestatin API; antibodies 3 impurities C18, 250 mm × 4.6 mm,

5 μm

Eluent A: H 2 O (0.1%

formic acid); Eluent

B: ACN (0.1% formic

acid); gradient

196, 230 and

296 nm

2008 [ 25 ]

10. Budesonide Tablets; steroid 10 impurities C18, 125 mm × 4.6 mm,

5 μm

ACN:phosphate

buffer (pH 3.2, 28.6

mM) (30:70)

240 nm 2008 [ 26 ]

11. Canine obestatin API; antibodies 9 impurities C18, 250 mm × 4.6 mm,

5 μm



B: ACN (0.1% formic

acid); gradient

196, 230 and

296 nm

2008 [ 25 ]

12. Carvedilol Tablets;

antihypertensive

5 impurities C18, 100 mm × 4.6 mm,

5 μm

ACN:phosphate

buffer (pH 2.5; 0.01

M) (40:60)

240 nm 2008 [ 27 ]

13. Clindamycin

palmitate HCl and

clindamycin

API; antibiotic 12 impurities C18, 250 mm × 4.6 mm,

5 μm

CH 3 COONH 4

buffer:MeOH

(15:85)

226 nm;

LC / MS / MS

2008 [ 28 ]

14. Clopidogrel API; antiplatelet 5-[1-(2-Chlorophenyl)-2-

methoxy-2-oxoethyl]-6,7-

dihydrothieno[3,2-c]

pyridin-5-ium

C8, 250 mm × 4.6 mm, 5

μm

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

220 and 300

nm

LC / MS / MS

2008 [ 29 ]

15. Dexamethasone Dexamethasone-coated

eluting stents; steroid

Process impurities and

degradants

C8, 4.6 mm × 250 mm, 5

μm

HCOONH 4 (20 mM,

pH 3.8):ACN;

gradient

239 nm 2008 [ 30 ]

16. Dimethyl-4,4 ′ - dimethoxy-

5,6,5 ′ ,6 ′ - dimethylene

dioxy-biphenyl-

2,2 ′ -dicar-

boxylate

(DDB)

API; hepatoprotective 5 degradants C18, 250 mm × 4.6 mm

5 μm

ACN:H 2 O (60:40) 235 nm 2008 [ 31 ]

17. Donepezil HCl API and tablet;

anti-Alzheimer

4 impurities of side

reaction and degradation

C18, 250 mm × 4.6 mm,

5 μm

Phosphate buffer (5

mM, pH 3.67):

MeOH; gradient

270 nm 2008 [ 32 ]

18. Econazole nitrate Cream; antifungal 4-Chlorobenzyl alcohol

and

α-(2,4-dichloro-phenyl)

-1 H -imidazole-1-ethanol)

C18, 300 mm × 3.9 mm,

10 μm

MeOH: H 2 O;

gradient

220 nm 2008 [ 33 ]


Table 2

Continued

S.

no. Name of drug

Matrix; therapeutic


Year

[Ref.]

19. Enalapril maleate API; antihypertensive 5 degradants C18, 250 mm × 4.6 mm,

5 μm

ACN: phosphate

buffer (pH 3);

gradient

210 nm 2008 [ 34 ]

20. Epirubicin HCl Injection; antibiotic 3 degradation impurities C18, 250 mm × 4.6 mm,

5 μm

Eluent A: 0.1% TFA

Eluent B: ACN:

MeOH:TFA

(80:20:0.1);

gradient

254 nm 2008 [ 35 ]

21. Fenofibrate Tablets;

anti-hyperlipidemic;

Acid and alkali degraded

impurity of each

C18 (BEH), 100 mm ×2.1 mm, 1.7 μm

ACN:CH 3 COONH 4

buffer (10 mM, pH

4.7); gradient

247 nm 2008 [ 36 ]

22. Fluorapacin API and injection;

anticancer

2 related substances C2, 250 mm × 4.6 mm, 5

μm

ACN:H 2 O (85:15) 218 nm 2008 [ 37 ]

23. Gatifloxacin API; antibacterial 10 related substances C18, 250 mm × 4.6 mm,

5 μm; C18, 150 mm × 6

mm, 5 μm; C18, 250 mm

× 4.6 mm, 5 μm

TEA (1%, pH

4.3):ACN (87:13)

200–500 nm 2008 [ 38 ]

24. Glimepiride API; antidiabetic 5 degradants C8, 150 mm × 4.6 mm, 5

μm

ACN: CH 3 COONH 4

(20 mM, pH 3)

(20:80)

235 nm 2008 [ 39 ]

25. Human obestatin API; antibodies 4 impurities C18, 250 mm × 4.6 mm,

5 μm



B: ACN (0.1% formic

acid); gradient

196, 230 and

296 nm

2008 [ 25 ]

26. Levothyroxine API; thyroid hormone 8 impurities C2, 250 mm × 4.6 mm, 5

μm

Eluent A: TFA

(0.1%); Eluent B:

ACN; gradient

223 nm 2008 [ 40 ]

27. Lopinavir API; anti-HIV 8 related impurities C18, 250 mm × 4.6 mm,

5 μm

KH 2 PO 4 (0.02 M, pH

2.5): ACN; gradient

210 nm 2008 [ 41 ]

28.

Methamphetamine

API; psychostimulant 29 impurities Capillary, 30 m × 0.32

mm × 1.0 μm

Nitrogen gas GC-FID 2008 [ 42 ]

29. Mildronate API; antiischemic 6 related impurities Amino, 100 mm × 3.2

mm, 3 μm; cyano, 100

mm × 2.1 mm, 5 μm;

silica, 100 mm × 2.1

mm, 3 μm; sulfobetaine,

100 mm × 2.1 mm, 5 μm

ACN:HCOONH 4 (5

mM, pH 5) (85:15)

Electrospray

interface

detector

2008 [ 43 ]

30. Montelukast

sodium

API; antiallergic 4 impurities C18, 100 mm × 4.6 mm,

3 μm

Eluent A: Na 2 HPO 4 buffer (50 mM, pH

3.7): ACN (4:1);

Eluent A: Na 2 HPO 4 buffer (50 mM, pH

3.7): ACN (1:4);

gradient

225 nm 2008 [ 44 ]

31. Mouse obestatin API; antibodies 3 impurities C18, 250 mm × 4.6 mm,

5 μm

Eluent A: H 2 O

(HCOOH 0.1%);

Eluent B: ACN

(HCOOH 0.1%);

gradient

196, 230 and

296 nm

2008 [ 25 ]

32. Moxifloxacin API; antibacterial 4 related substances C18, 250 mm × 4.6 mm,

5 μm; C18, 150 mm × 6

mm, 5 μm; C18, 250 mm

× 4.6 mm, 5 μm

Eluent A: TEA (1%,

pH 2.5):MeOH

(70:30); Eluent B:

phosphate buffer

(pH 2.5):ACN

(85:15); gradient

200–500 nm 2008 [ 45 ]

33. Ovine obestatin API; antibodies 5 impurities C18, 250 mm × 4.6 mm,

5 μm

Eluent A: H 2 O

(HCOOH 0.1%);

Eluent B: ACN

(HCOOH 0.1%);

gradient

196, 230 and

296 nm

2008 [ 25 ]

34. Paclitaxel API; anticancer 10-Deacetylbaccatin III,

baccatin III, 10-deacet-yl-

7-xylosyltaxol C,

photo-degradant, taxol C,

ceph-alomannine,

10-deacetyl-7-epitaxol,

7-Epi-taxol

Phenyl, 150 mm × 4.6

mm, 3 μm

H 2 O:ACN (52:48) 227 nm 2008 [ 46 ]


Table 2

Continued

S.

no. Name of drug

Matrix; therapeutic


Year

[Ref.]

35.

Phenylethanolamine

derivatives

API; antiasthamatic 11 impurities ASH, 250 mm × 4.6 mm,

5 μm

n-

Hexane:gthanol:TEA

(98:2:0.1)

254 nm 2008 [ 47 ]

36. Pipecuronium

bromide

Powder for injection;

steroid

4 impurities Cyano, 250 mm × 4.6

mm, 5 μm Tetramethylammonium

hydroxide (4.53 g / L,

pH 6.4):ACN (6:4)

Electrochemi-

cal

detection

2008 [ 48 ]

37. Pridinol mesylate API; muscle relaxant 2 degradant C18, 250 mm × 4.6 mm,

5 μm MeOH:IPA:potassium

phosphate (50 mM,

pH 6.0) (51:9:40)

220 nm 2008 [ 49 ]

38. Primaquine

phosphate

API; antimalarial 2 impurities C18 (BEH), 50 mm × 2.1

mm, 1.7 μm

TFA (0.01%):ACN

(75:25)

265 nm 2008 [ 50 ]

39. Primaquine

phosphate

API; antimalarial 2 impurities C18, 250 mm × 4.6 mm,

5 μm

TFA (0.01%): ACN

(75:25)

265 nm 2008 [ 50 ]

40. Salicylaldehyde

isonicotinoyl

hydrazone

API; chelating agent 2 ′ -Hydroxy-acetophen-

one, Isonicotinoyl

hydrazone, 2 ′ -hydroxy

propiophenone

Isonicotinoylhydrazone

C18, 250 mm × 4.6 mm,

5 μm

Phosphate buffer

(10 mM + 2 mM

EDTA, pH 6):MeOH

(40:60)

LC–ESI-MS 2008 [ 51 ]

41. Tamsulosin Capsule, tablet and API;

antihypertensive

9 process impurities C18, 250 mm × 4.6 mm,

5 μm

CH 3 COONH 4 (10

mM):ACN; gradient

280 nm 2008 [ 52 ]

42. Tazarotene API; anti-Acne 2 by-product Capillary, 30 m × 0.25

mm, 0.25 μm

Helium gas MS detection 2008 [ 53 ]

43. Tenatoprazole API; peptic ulcer 6 degradants C18, 250 mm × 4.6 mm,

5 μm

MeOH:acetate

buffer (10 mM, pH

4.5) (55:45)

306 nm 2009 [ 54 ]

44. Levofloxacin API; antibacterial 3 process related

impurities and 1 oxidative

degradant

C18, 250 mm × 4.6 mm,

5 μm

Eluent A: NaH 2 PO 4 (25 mM) + 0.5%

TEA (pH 6); EluentB:

MeOH; gradient

294 nm 2009 [ 55 ]

45. Aalicylic acid and

betamethasone

dipropionate

Lotion;

anti-inflammatory

Salicylic acid related: 7

betamethasone

dipropio-nate related: 15

potential leachables: 5

C8, 150 mm × 4.6 mm, 4

μm

Methanesulfonic

acid:ACN (0.05%);

gradient

240 nm 2009 [ 56 ]

46. Anastrozole Tablet; anti-cancer 5 impurities C3, 250 mm × 4.6 mm, 5

μm

H 2 O:ACN; gradient 215 nm 2009 [ 57 ]

47. Biapenem API; antibiotic 4 impurities C18, 4.6 mm × 150 mm,

5 μm

CH 3 COONH 4 (1

mM): ACN; gradient

220 nm 2009 [ 58 ]

48. Chloroquine and

hydroxychloro-

quine

API; antimalarial 4 process related

impurities

C18, 250 mm × 4.6 mm,

5 μm

TFA

(0.06%):ACN:IPA

(87:12:1)

220 nm 2009 [ 59 ]

49. Citalopram API; antidepressant 1 impurity C18, 100 mm × 30 mm 5

μm

NH 3 :H 2 O:ACN

(0.1:50:50)

225 nm 2009 [ 60 ]

50. Cyclosporin A Soft gelatin capsules;

Immunomodulator

4 degradants and 2 related

compounds

C18, 250 mm × 4 mm, 5

μm

THF:phosphoric

acid (0.05M) (44:56)

220 nm 2009 [ 61 ]

51. Diacerein API; antiarrtheritis 2 related impurities C18, 250 mm × 4.6 mm,

5 μm

Acetic acid

(0.10%):ACN (53:

47)

254 nm 2009 [ 62 ]

52. Eletriptan API; antimigraine 1 degradants (oxidative) C18, 150 mm × 3.9 mm,

5 μm

MeOH:H 2 O + TEA

(1%) (30:70) (pH

6.52)

225 nm 2009 [ 63 ]

53. Fatty alcohol

ethoxylates

Surfactant 6 impurities C1, 4.6 mm × 150 mm Eluent A:

H 2 O:MeOH (80:20);

Eluent B: MeOH;

gradient

ELSD

detector

2009 [ 64 ]

54. Gentamicin API; antibiotic 33 related impurities Hydro-RP, 250 mm ×4.6 mm, 5 μm

Eluent A: MTFA

(50m, pH 2); Eluent

B: MeOH; gradient

ESI / MS n

detection

2009 [ 65 ]

55. Heparin sodium API; anticoagulant 6 impurities AS11-HC, 250 mm × 4

mm, 9 μm

Eluent A: H 2 O;

Eluent B: NaCl (2.5

M + 20 mM Tris,

pH 3); gradient

215 nm 2009 [ 66 ]

56. Ibuprofen API; analgesic 3-[4-(2-

Methylpropyl)phenyl]propanoic

acid

ZirChrom-CARB, 150 mm

× 4.6 mm, 5 μm; C18,

150 mm × 4.6 mm, 5

μm; Zr-PS, 150 mm ×4.6 mm, 5 μm; C18, 150

mm × 3.0 mm, 7 μm

ACN:phosphate

buffer (25 mM, pH

2.1) (40:60)

220 and 285

nm

2009 [ 67 ]


Table 2

Continued

S.

no. Name of drug

Matrix; therapeutic


Year

[Ref.]

57. Icofungipen API; antifungal (1R,2S)-2-(Cinnamyl

amino) -4-methylene

cyclopentane carboxylic

acid

C18, 100–5 AB ACN:H 2 O (25:75) 210 and 254

nm

2009 [ 68 ]

58. Lamivudine API; anti-HIV 5 degradants C18, 250 mm × 4.6 mm,

5 μm

Eluent A: MeOH;

Eluent B:

CH 3 COONH 4 buffer

(10 mM, pH4);

gradient

277 nm 2009 [ 69 ]

59. Lansoprazole API; peptic ulcer 5 enantiomers and related

impurities

Chiral, 250 mm × 4.6

mm

Methyl-tert-butyl

ether:ethyl

acetate:ethanol

diethylamine

(60:40:5:0.1)

310 nm 2009 [ 70 ]

60. Metformin Tablet; antidiabetic Related compound:

1-cyanoguanidine

Nova-Pak silica, 150 mm

× 3.9 mm, 4 μm

NH 4 H 2 PO 4 buffer:MeOH

(21:79)

232 nm 2009 [ 71 ]

61. Moxifloxacin HCl API; antibacterial 4 synthesis-related

impurities

C18, 50 mm × 4.6 mm, 5

μm

H 2 O + TEA

(2%):ACN 90:10 (pH

6.0)

290 nm 2009 [ 72 ]

62. Nevirapine

analogue

API; anti-HIV 3 impurities Cyano, 4.6 mm × 150

mm, 5 μm

Eluent A: H 2 O

(HCOOH 0.1%);

Eluent B: ACN

(HCOOH 0.1%);

gradient

ESI / MS n

detection

2009 [ 73 ]

63. Nimodipine Tablet;

antihypertensive

3 impurities C8, 250 mm × 4.6 mm, 5

μm

ACN:H 2 O

(67.5:32.5)

236 nm 2009 [ 74 ]

64. Norethisterone Tablet; steroid 19-Norandrostenedione C18, 50 mm × 2.1 mm, 5

μm

MeOH:H 2 O (53:47) ESI / MS n

detection

2009 [ 75 ]

65. Phenazopyridine

HCl

API; analgesic 3-Phenyl-5-phenylazo-

pyridine-2,6-diamine

C3, 250 mm × 4.6 mm, 5

μm

H 2 O:ACN (25:75) 254 nm 2009 [ 76 ]

66. Pridinol mesylate API, tablet, injection,

Patches;

antihypertensive

3-Piperidino-propiophen-

one, hydrochloride,

1-(3,3-diphenylprop-2-en-

1-yl)piperidine

C18, 250 mm × 4.6 mm,

5 μm

Potassium

phosphate buffer

(50 mM, pH

6.4):MeOH:2-

propanol

(20:69:11)

245 nm 2009 [ 77 ]

67. Puerarin Injection; vasodilator 9 impurities C18, 250 mm × 4.6 mm,

5 μm

Formic acid (0.1%):

MeOH; gradient

250 nm 2009 [ 78 ]

68. Rizatriptan

benzoate

API; antimigraine Rizatriptan-1,2-dimer and

Rizatriptan-2,2-dimer

C8, 250 mm × 4.6 mm, 5

μm

Ammonium

dihydrogen

ortho-phosphate

(20 mM) + 2 ml

TEA (pH 2): ACN;

gradient

225 nm 2009 [ 79 ]

69. Ropinirole HCl API; anti-Parkinsons 4-[2-

(Dipropylamino)ethyl]-

1 H -indol-2,3-dione

X-Bridge TM , 3 mm × 100

mm, 3.5 μm

ACN:sodium

heptane sulfonate

(5 mM) (21.6:78.4)

(pH 2)

250 nm 2009 [ 80 ]

70. Salidroside API; antidepressant 3 impurities C18, 150 mm × 4.6 mm,

5 μm

MeOH:H 2 O (13:87) 275 nm 2009 [ 81 ]

71. Sertraline API; antidepressant 9 impurities C18, 250 mm × 4.6 mm,

5 μm

TFA (0.4%):ACN

(80:20)

225 nm 2009 [ 82 ]

72. Taranabant API; anti-obesity 6 impurities C18, 250 mm × 4.6 mm,

5 μm

H 3 PO 4 in H 2 O

(0.1%):ACN;

gradient

220 nm 2009 [ 83 ]

73. Tropicamide API; ophthalmology 3 impurities C18, 150 mm × 4.6 mm,

5 μm

MeOH:H 2 O (30:70) 225, 247 and

257 nm

2009 [ 84 ]

74. Valsartan API; antihypertensive 5 impurities C18, 250 mm × 4.6 mm,

5 μm

Elunent A:

CH 3 COONH 4 (10

mM, pH 3.0) Eluent

B: H 2 O:ACN (1:4);

gradient

210 nm 2009 [ 85 ]

75. Zafirlukast API; antiasthamatic 5 impurities C18, 250 mm × 4.6 mm,

5 μm

Eluent A: phosphate

buffer + 1-decane

sulfonic acid

sodium (pH 4):

MeOH (85:15);

Eluent B:

ACN:MeOH:H 2 O

(85:10:5)

220 nm 2009 [ 86 ]

76. Zotarolimus Coated stents;

immunomodulator

3 degradant C8, 250 mm × 4.6 mm, 5

μm

CH 3 COONH 4 (10

mM, pH 3.8): ACN;

gradient

278 nm 2009 [ 87 ]


Table 2

Continued

S.

no. Name of drug

Matrix; therapeutic


Year

[Ref.]

77. 10- O -(N,N-

dimethyl

aminoethyl)-gink-

golide B methane

sulfonate

API; antiplatelet 2 impurities C18, 250 mm × 20 mm,

5 μm

MeOH:H 2 O (55:45) 210 nm 2010 [ 88 ]

78. Acetazolamide API; diuretics 1 degradant and 4


C18, 250 mm × 4.6 mm,

5 μm

Eluent A: NaH 2 PO 4 (0.02M, pH

3.0):ACN (950:50);

Eluent B: H 2 O:ACN

(150:850); gradient

254 nm 2010 [ 89 ]

79. Acetylspiramycin API; antibiotics 17 impurities

(process-related,

degradant and starting

materials)

C18, 250 mm × 4.6 mm,

5 μm

ACN:CH 3 COONH 4

(0.1 M, pH 7.2)

(50:50)

232 nm 2010 [ 90 ]

80. Albuterol sulfate

and ipratropium

bromide

Nasal solution;

anti-asthamatic

Albuterol sulfate related:

8; Ipratropium bromide

related: 5

C8, 250 mm × 4.6 mm, 5

μm

Eluent A: KH 2 PO 4 +

Heptane-1-sulfonic

acid sodium salt in

H 2 O (pH 4); Eluent

B: ACN; gradient

210 nm 2010 [ 91 ]

81. Alizapride API; antiemetic 2 degradants C18, 150 mm × 4.6 mm,

5 μm

Eluent A:

CH 3 COONa buffer

(20 mM, pH 4);

Eluent B: MeOH;

gradient

225 nm 2010 [ 92 ]

82. Atorvastatin

calcium

API;

anti-hyperlipidemic


3.5 μm

Eluent A: HCOONH 4

(pH 4, 10 mM):ACN

(60:40); Eluent B:

ACN; gradient

246 nm 2010 [ 93 ]

83. Barnidipine API; antihypertensive 4 degradants C18, 250 mm × 4.6 mm,

5 μm

ACN:phosphate

buffer (pH 7)

(75:25)

250 nm 2010 [ 94 ]

84. Clopidogrel

bisulfate

API and tablet;

antiplatelet

5 impurities Chiral, 250 mm × 4.6

mm, 5 μm

n-

Hexane:ethanol:diethyl

amine (95:5:0.05)

240 nm 2010 [ 96 ]

85. CU201(antitumor

peptidic dimer)

API; anticancer 11 forced degradants and 3

impurities

C8, 150 mm × 4.6 mm, 3

μm



B: ACN (0.1% Formic

acid), gradient

266 nm 2010 [ 97 ]

86. Desloratadine Tablet; antiallergic 5 impurities and forced

degradants

C18 (BEH), 50 mm × 2.1

mm, 1.7 μm

Eluent A:

KH 2 PO 4 buffer (10

mM, pH

2.5):MeOH:ACN

(80:15:5); Eluent B:

buffer:THF: ACN

(30:5:70)

280 nm 2010 [ 98 ]

87. Duloxetine HCl API; antidepressant 3 related impurities C18, 250 mm × 4.6 mm,

5 μm

Eluent A: KH 2 PO 4 (10 mM + 0.2%

TEA, pH 2.5); Eluent

B: ACN:MeOH

(20:80); gradient

230 nm 2010 [ 99 ]

88. Enalapril maleate API; antihypertensive Several degradation

impurities

RP-S, 250 mm × 4.6 mm,

5 μm

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

215 nm 2010

[ 100 ]

89. Eprosartan API; antihypertensive Impurity: dibenzoic acid C2, 250 mm × 4.6 mm

mm, 5 μm

Eluent A: TEA buffer

(pH 3); Eluent B:

ACN; gradient

234 nm 2010

[ 101 ]

90. Escitalopram API; antidepressant 3 process-related

impurities

C18, 150 mm × 4.6 mm,

3 μm

HCOONH 4 (1.5

g / 1000 ml

H 2 O):ACN; gradient

240 nm 2010

[ 102 ]

91. Ezetimibe API;

anti-hyperlipidemic

Process-related impurity C18, 250 mm × 4.6 mm,

5 μm

H 2 O:ACN; gradient 232 nm 2010

[ 103 ]

92. Felbamate API and tablets;

antiepileptic

3-Hydroxy-2-phenyl-

propyl carbamate and

2-Phenyl-propane-1,3-diol

C18 (BEH), 100 mm ×2.1 mm, 1.7 μm

KH 2 PO 4 buffer (pH

3.5):MeOH (68:32)

210 nm 2010

[ 104 ]


Table 2

Continued

S.

no. Name of drug

Matrix; therapeutic


Year

[Ref.]

93. Fentanyl API; analgesic 16 impurities C18, 150 mm × 3.0 mm,

5 μm

Eluent A: phosphate

buffer (pH 2);

Eluent B: Eluent

A:ACN (1:1);

gradient

215 nm 2010

[ 105 ]

94. Filgrastim API; hematopoietic

stimulator


μm

Eluent A: TFA (0.1%)

in ACN:H 2 O;

(10:90); Eluent B:

TFA (0.1%) in

ACN:H 2 O (80:20);

gradient

215 nm 2010

[ 106 ]

95. GW876008

(corticotropin-

release factor 1

antagonist)

API; antidepressant 4 impurities C8, 150 mm × 4.6 mm,

3.5 μm

Eluent A: H 2 O:TFA

(100:0.05); Eluent

B: MeOH:ACN: TFA

(50:50: 0.05);

gradient

220 nm 2010

[ 107 ]

96. l -Aspartic acid

and l -alanine

API; food supplement Succinic acid, citric acid,

malic acid, maleic acid,

fumaric acid, glycine,

glutamic acid

C3, 150 mm × 4.6 mm, 5

μm

MeOH:H 2 O (50:50) CAD

detection

2010

[ 108 ]

97. Omeprazole API and tablets; peptic

ulcer

9 impurities Chiral, 250 mm × 4.6

mm, 10 μm

Methyl tert-

butylether:ethyl

acetate:

ethanol:diethylamine

(60:40:5:0.1)

299 nm 2010

[ 109 ]

98. Orlistat Capsules; anti-obesity 18 impurities C18, 4.6 mm × 150 mm,

5 μm

ACN + H 3 PO 4 (0.005%):H 2 O +

H 3 PO 4 (0.005%)

(86:14)

210 nm 2010

[ 110 ]

99. Oxytocin API; uterine stimulant

(hormone)

Acetic acid, carbamido

oxytocin, α-dimer,

acetyl-oxytocin, β-dimer

and five impurities

C18, 250 mm × 4.0 mm,

5 μm

Eluent A:

ACN:KH 2 PO 4 (pH

4.4):H 2 O

(15:15:70); Eluent

B: ACN:KH 2 PO 4 (pH

4.4):H 2 O (70:

15:15)

220 nm 2010

[ 111 ]

100. Pentoxifylline API; antidiabetic 3 degradants C18, 250 mm × 4.6 mm,

5 μm

Formic acid

(0.05%):ACN;

gradient

274 nm 2010

[ 112 ]

101. Piracetam API; neurovascular

enhancer


10 μm

TEA:ACN (85:15)

(pH 6.5)

205 nm 2010

[ 113 ]

102. Pregabalin API and tablet;

antipsychotic


μm

MeOH:acetate

buffer (10 mM, pH

5.0) (15:85)

345 and 450

nm

2010

[ 114 ]

103. Rabeprazole

sodium

API; peptic ulcer Methylthio impurity of

rabeprazole

C8, 150 mm × 4.6 mm, 5

μm

Eluent A: phosphate

buffer (pH 7.6):ACN

(98:2) Eluent B:

ACN; gradient

284 nm 2010

[ 115 ]

104. Raltegravir API; anti-HIV 5 impurities C18, 250 mm × 4.6 mm,

5 μm

H 2 O:ACN:TFA

(0.02%); gradient

240 and 304

nm

2010

[ 116 ]

105. RG7128 (HCV

polymerase

inhibitor)

API; anti-HIV 9 impurities C18, 100 mm × 19 mm,

5 μm

Formate buffer (10

mM, pH 3.5):ACN;

gradient

276 nm 2010

[ 117 ]

106. Rifaximin API; antibiotic 1 impurity C18, 150 mm × 19 mm,

5 μm

ACN:MeOH:H 2 O

(36:32:32)

276 nm 2010

[ 118 ]

107. Ritonavir API; anti-HIV 21 degradants C18, 250 mm × 4.6 mm,

5 μm

H 2 O:MeOH:ACN

(40:20:40)

210 nm 2010

[ 119 ]

108. Sertraline API; antidepressant 3 non-chiral related

impurities

C18, 150 mm × 4.6 mm,

5 μm

Phosphate buffer

(10 mM, pH

2.8):MeOH (63:37)

220 nm 2010

[ 120 ]

109. Valsartan API; antihypertensive 7 degradants C18 (BEH), 100 mm ×2.1 mm, 1.7 μm

Eluent A: acetic acid

buffer (1%): ACN

(90:10); Eluent B:

acetic acid buffer

(1%): ACN (10:90);

gradient

225 nm 2010

[ 121 ]

110. Vestipitant API; antiemetic 3 biphenyl impurities C18, 150 mm × 4.6 mm,

5 μm

TFA (0.1%) in D 2 O:

TFA (0.1%) in ACN,

gradient

254 nm 2010

[ 122 ]

111. Abacavir API; anti-HIV 8 degradants C18, 250 mm × 4.6 mm,

5 μm

H 2 O:ACN (90:10) 220 nm 2011

[ 123 ]

112. ALB 109564 API; anticancer 4 impurities C18, 250 mm × 10 mm,

5 μm


TFA) Eluent B: ACN

(0.1% TFA)

215 nm 2011

[ 124 ]


Table 2

Continued

S.

no. Name of drug

Matrix; therapeutic


Year

[Ref.]

113. Anastrozole API; anticancer 3 degradant C3, 100 mm × 4.6 mm, 3

μm

HCOONH 4 (10

mM):ACN (60:40)

215 nm 2011

[ 125 ]

114. Artemisinin API; antimalarial Artemisitene,

9-epi-artimisinin

C18, 150 mm × 2.1 mm,

5 μm

ACN:H 2 O (60:40) +

0.1% formic acid

DAD / MS 2011

[ 126 ]

115. Atazanavir sulfate API; anti-HIV 13 process impurities and

degradants

C8, 150 mm × 4.6 mm, 3

μm

Eluent A: H 2 O:0.025

M CH 3 COONH 4 ;

Eluent B: ACN;

gradient

250 nm 2011

[ 127 ]

116. Auraptene API; immunomodulator 5 impurities C18, 150 mm × 4.6 mm,

5 μm


[ 128 ]

117. Boron

phenylalanine

API; anticancer 4 impurities C18, 150 mm × 4.6 mm,

5 μm

Eluent A:TFA:H 2 O:

MeOH (0.1:85:15);

Eluent B: MeOH;

gradient

230, 256 and

270 nm

2011

[ 129 ]

118. Candesartan

cilexetil

API; antibiotics Process related impurity Cyano, 250 mm × 4.6

mm, 5 μm

TFA (pH 3):ACN;

gradient

210 nm 2011

[ 130 ]

119. Carbamazepine API; antiepileptic 7 impurities Cyano, 250 mm × 4.6

mm, 5 μm

THF:CH 3 OH:H 2 O

(3:12:85)

230 nm 2011

[ 131 ]

120. Casopitant

mesylate

API; antidepressant and

antiemetic

De-fluorinated casopitant

mesylate analogue

C18, 150 mm × 4.6 mm,

3.5 μm

Eluent A: H 2 O +

0.2% NH 4 OH; Eluent

B: ACN + 0.2%

NH 4 OH; gradient

LC / MS / MS 2011

[ 132 ]

121. Ciclesonide API and metered dose

inhalers;

antiasthamatic


10 μm

Ethanol:H 2 O

(70:30)

242 nm 2011

[ 133 ]

122. Colistin

(Polymyxin E)

API; antibiotic 35 impurities C18, 250 mm × × 4.6

mm, 5 μm

ACN:sodium sulfate

(4.46 mM, pH 2.3)

(20:80) + 10%

phosphoric acid;

gradient

215 nm 2011

[ 134 ]

123. Entacapone API; anti-Parkinsons 4 forced degradants C18, 250 mm × 4.6 mm,

5 μm; C3, 250 mm × 4.6

mm, 5 μm

Potassium

phosphate buffer

(30 mM, pH

2.75):MeOH (50:50)

310 nm 2011

[ 135 ]

124. Etimicin sulfate API; antibiotic 6 impurities C18, 150 mm × 4.6 mm,

5 μm

Eluent A: H 2 O:NH 3

(25%):CH 3 COOH

(96:3.6:0.4); Eluent

B: MeOH; gradient

ELSD 2011

[ 136 ]

125. Ezetimibe API;

anti-hyperlipidemic

5 degradation and


C18, 150 mm × 4.6 mm,

5 μm

Eluent A: TFA

(0.05%):MeOH

(49:51); Eluent B:

ACN:Eluent A (3:1);

gradeint

210 and 235

nm

2011

[ 137 ]

126. Febuxostat API; anti-gout 4 impurities C18, 150 mm × 4.6 mm,

5 μm

Eluent A:

CH 3 COONH 4 (10 m

M, pH 3.5); Eluent

B: ACN; gradient

315 nm 2011

[ 138 ]

127. Fesoterodine API; antispasmodic 5 degradants C18, 100 mm × 4.6 mm,

5 μm ACN:MeOH:CH 3 COONH 4

(30 mM, pH 3.8)

(30:15:55)

208 nm 2011

[ 139 ]

128. G004

(hypo-glycaemic

agent)

API; antidiabetic 4 related impurities C18, 250 mm × 4.6 mm,

5 μm

Acetic acid (0.1%) +

TEA (0.1%):MeOH

(20:80)

233 nm 2011

[ 140 ]

129. Gentamicin API; antibiotic 5 impurities C18, 50 mm × 4.6 mm,

1.8 μm

Eluent A: TFA (0.1%

pH 2.5); Eluent B:

TFA (0.1% pH 2.5 +

TEA Eluent C: ACN;

gradient

ESI / MS n

detection

2011

[ 141 ]

130. Lactic acid Sugarcane juice;

humectants


5 μm

NH 4 H 2 PO 4 (20 mM,

pH 2.2)

210 nm 2011

[ 142 ]

131. Larotaxel API; anticancer 5 Related impurities C18, 250 mm × 4.6 mm,

5 μm


[ 143 ]

132. Lincomycin and

spectinomycin

API; antibiotic Lincomycin related

impurities: 4 and

spectino-mycin related

impurities: 5

C18, 50 mm × 4.6 mm,

1.8 μm

TFA (0.05%, pH

3.0):ACN (90:10)

ESI / MS n

detection

2011

[ 141 ]


Table 2

Continued

S.

no. Name of drug

Matrix; therapeutic


Year

[Ref.]

133. Lornoxicam API; analgesic Degradants C18, 250 mm × 4.6 mm,

5 μm

KH 2 PO 4 buffer (10

mM, pH 3.3):MeOH;

gradient

MS detector 2011

[ 144 ]

134. Memantine Tablets; anticancer Maillard reaction

impurities

Hydro RP, 100 mm × 3

mm, 2.5 μm

Heptafluoro buturic

acid (0.6%):ACN:

isopropyl

alcohol:H 2 O;

gradient

CAD

detection

2011

[ 145 ]

135. Meprobamate API; antipsychotic Carbamic acid-2-

carbamoyloxymethyl-2-

methyl-pent-3-enyl

ester

C18, 250 mm × 4.6 mm,

5 μm

H 2 O:ACN (8:2) 200 nm 2011

[ 146 ]

136. Mometasone

furoate

API; steroid 8 impurities C18, 250 mm × 4.6 mm

mm, 5 μm


[ 147 ]

137. Mometasone

furoate


5 μm; 2-ethyl-pyridine:

250 mm × 4.6 mm, 5

μm;Cyano: 250 mm ×4.6 mm, 5 μm

Carbon dioxide (SFC

grade)

245 nm 2011

[ 147 ]

138. Naproxen API; analgesic 2-(6-Methoxynaphtha-

len-2-yl)acrylic

acid

C18, 100 mm × 4.6 mm,

5 μm

CH 3 COONa (40 mM,

pH 4.7):MeOH

(60:40)

254 nm 2011

[ 148 ]

139. Olanzapine API and drug product;

antipsychotics


μm

EDTA disodium salt

dihydrate (50 mM,

pH 3):ACN (6:4)

220 nm 2011

[ 149 ]

140. Olanzapine API and tablet;

antipsychotics

8 degradants C18 (BEH), 100 mm ×2.1 mm, 1.7 μm

Eluent A: NaH 2 PO 4 (20 mM) buffer (pH

6.8): ACN: MeOH

(5:2:3) Eluent B:

H 2 O: ACN (1:9)

250 nm 2011

[ 150 ]

141. Olaquindox API; anti-amoebic 12 degradants C18, 150 mm × 2 mm, 5

μm

HCOOH (0.1%):

ACN; gradient

200–400 nm 2011

[ 151 ]

142. Palonosetron HCl API; antiemetic 9 degradants π Nap, 250 mm × 4.6

mm, 5 μm

Eluent A: Phosphate

buffer (20 mM + 2

ml TEA, pH 2.5);

Eluent B: phosphate

buffer: ACN (50:50);

gradient

210 nm 2011

[ 152 ]

143. Perindopril

tert-butylamine

API; antihypertensive 4 impurities C4, 4.6 mm × 250 mm, 5

μm

Butyl acetate

(0.24%) + ethyl

acetate (0.30%) +

SDS (2%) +

n-butanol (7.75%)

+ dihydrogen

phosphate (20 mM,

pH 3.7)

215 nm 2011

[ 153 ]

144. Phosphorothioate

oligonucleotides

API; diagnostic agent 5 synthesis impurities C18 (BEH), 1 mm × 150

mm, 3.5 μm

Eluent A: TEA (16

mM) + HFIP (400

mM, pH 7.0) in H 2 O;

Eluent B: TEA (16

mM) + HFIP (400

mM) in MeOH;

gradient

LC–MS / MS 2011

[ 154 ]

145. Polymyxin B API; antibiotic 38 impurities C18, 250 mm × 4.6 mm,

5 μm

ACN:sodium sulfate

(4.46 g / l, pH 2.3)

(20:80) + 10%

phosphoric acid

215 nm 2011

[ 134 ]

146. Streptomycin

sulfate

API; antibiotic 21 impurities YMCPack Pro, 250 mm ×4.6 mm; 3 μm

PFPA (20 mM):

acetone (99:1)

CAD / MS

Detection

2011

[ 155 ]

147. Sulindac API; analgesic E-sulindac, sulfide and

sulfone form

C18, 53 mm × 7 mm, 1.5

μm

ACN: phosphate

buffer (pH 2, 10

mM); gradient

340 nm 2011

[ 156 ]

148. Ursodeoxycholic

acid

API; billiary cirrhosis 5 related impurities C18, 150 mm × 4.6 mm,

5 μm

Acetic acid: MeOH

(0.1%) (30:70)

RI detection 2011

[ 157 ]

149. Valsartan API; antihypertensive 2 photodegradant Cyano, 250 mm × 4.6

mm, 5 μm

ACN: KH 2 PO 4 (20

mM, pH 3) (40:60)

226 nm 2011

[ 158 ]


Table 2

Continued

S.

no. Name of drug

Matrix; therapeutic


Year

[Ref.]

150. Zafirlukast API; antiasthamatic 8 impurities C18, 250 mm × 4.6 mm,

5 μm

Eluent A: phosphate

buffer + 1-decane

sulfonic acid

sodium (pH 4):

MeOH (85:15);

Eluent B:

ACN:MeOH:H 2 O

(85:10:5); gradient

220 nm 2011

[ 159 ]

151. Rapamycin API; immunomodulator 9 degradant Diol-120-NP, 250 mm ×4.6 mm, 5 μm

Hexanes:2-

propanol;

gradient

278, 248, 230

and 210 nm

2012

[ 160 ]

152. 4-Methyl

thioamphetamine


mm, 0.25 μm

Helium Mass

selective

detector

2012

[ 161 ]

153. Halobetasol

propionate

API; steroids Acetamide and

arylsulfonate

C18, 100 mm × 2.10

mm, 2.6 μm

ACN:H 2 O; gradient 230, 220 and

205 nm

2012

[ 162 ]

154. Artemisinin Artemisia annua

extracts; antimalarial

Extract residue impurities C18, 250 mm × 4.6 mm,

5 μm

ACN:H 2 O:MeOH

(50:30:20)

192, 200,

205, 210 and

215 nm

2012

[ 163 ]

155. Atorvastatin

calcium

API;

anti-hyperlipidemic


3.5 μm

Eluent A: phosphate

buffer (pH 5.4);

Eluent B: ACN:THF

(90:10); gradient

220 nm 2012

[ 164 ]

156. Azelnidipine Solution;

anti-hypertensive


3 μm

Eluent A: KH 2 PO 4 (15

mM):ACN:MeOH

(8:1:1) Eluent B:

ACN; gradient

220 nm 2012

[ 165 ]

157. Benzopyrido-

oxathiazepine

API; anticancer 10 degradants C18, 150 mm × 2.1 mm,

3 μm

ACN:H 2 O (60:40) +

0.1% formic acid

318 nm 2012

[ 166 ]

158. Bupropion

hydrochloride

API and tablets;

Anti-depressant

Alkaline degradates,

3-chlorobenzoic acid

C18, 4.6 mm × 150 mm,

5 μm

NH 4 H 2 PO 4 (1.2%,

pH 4.5):ACN (80:20)

210 nm 2012

[ 167 ]

159. Caffeine API; stimulant 4 impurities C18, 150 mm × 4.6 mm,

5 μm, 29 columns;

Others, 150 mm × 4.6

mm mm, 5 μm, 6

columns

THF:ACN:CH 3 COONH 4

(pH 4.5) (40:50:10)

275 nm 2012

[ 168 ]

160. Cefditoren pivoxil API and tablet;

Antibiotic

1 degradants C18, 250 mm × 4.6 mm;

5 μm

ACN:H 2 O (50:50) 218 nm 2012

[ 169 ]

161. Clocortolone

pivalate


5 μm

ACN:H 2 O (70:30) 254 nm 2012

[ 170 ]

162. Cloperastine

fendizoate

API; cough relaxant Methyl p-toluene

sulfonate and 2-chloro

ethyl p-toluene sulfonate

C8, 250 mm × 4.6 mm, 5

μm

Phosphate buffer

(10 mM, pH

3.0):MeOH with

10% ACN (45:55)

227 nm 2012

[ 171 ]

163. Deferasirox API; Antidote of Iron 2-[3,5-Bis(2-hydroxy-

phenyl)-[1,2,4]-triazol-1-

yl]-benzoic

acid

C8, 250 mm × 4.6 mm, 5

μm

Eluent A:H 2 O:TFA

(100:0.05); Eluent

A: ACN:MeOH:TFA

(50:50:0.05)

gradient

LC–ESI-QT /

MS / MS

2012

[ 172 ]

164. Desvenlafaxine API and tablet;

Antidepressant

1 degradants (acid) C18, 250 mm × 4.6 mm,

5 μm

TEA (0.2%)

+ CH 3 COONH 4 (50

mM, pH 6.5):MeOH

(40:60)

228 nm 2012

[ 173 ]

165. Diltiazem HCl API and tablet;

Anti-hypertensive

6 related substances C18, 150 mm × 4.6 mm,

5.0 μm

TEA (0.2%):ACN;

gradient

240 nm 2012

[ 174 ]

166. Dipyridamole API; antiplatelet 2 impurities C2, 150 mm × 4.6 mm, 5

μm

Eluent A: KH 2 PO 4 buffer (10 mM, pH

7.0):MeOH (50:50);

Eluent B:

MeOH:KH 2 PO 4 (10

mM) buffer; (95:5);

gradeint

295 nm 2012

[ 175 ]

167. Eslicarbazepine

acetate

API; antiepileptic 15 impurities C8, 250 mm × 4.6 mm, 5

μm

Eluent A: KH 2 PO 4 (10 mM, pH 5): ACN

(95:5); Eluent B:

ACN:H 2 O (80:20);

gradient

215 nm 2012

[ 176 ]


Table 2

Continued

S.

no. Name of drug

Matrix; therapeutic


Year

[Ref.]

168. Esomeprazole

magnesium

Tablets, pepetic ulcer 7 impurities C18 (BEH), 50 mm × 2.1

mm, 1.7 μm

Eluent A: glycine

buffer (40 mM, pH

9); Eluent B:

ACN:H 2 O (90:10);

gradient

305 nm 2012

[ 177 ]

169. Etimicin sulfate API; antibiotic 26 impurities C18, 250 mm × 4.6 mm,

5 μm

Eluent A: H 2 O:NH 3

(25%):CH 3 COOH

(96:3.6:0.2); Eluent

B: MeOH; gradient

ESI / MS n

detection

2012

[ 178 ]

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 μm

Eluent A: 1-octane

sulfonic acid

sodium (10 mM) +

CH 3 COONH 4 (10

mM) + 0.1% TEA

(pH 4):MeOH

(95:5); Eluent B:

MeOH; gradient

240 and 282

nm

2012

[ 179 ]

171. Glucocorticoids API; steroid 4-Dimethyl aminopyridine C18, 50 mm × 2 mm, 3

μm



B: ACN (0.1% formic

acid); gradient

190–400 nm 2012

[ 180 ]

172. Guaifenesin,

terbutaline sulfate

and ambroxol HCl

Cough syrup; cough

relaxant

13 related substances C18, 250 mm × 4.6 mm,

5 μm

Eluent A: NH 4 H 2 PO 4 (20 mM) +

1-heptane sulfonic

acid sodium salt

buffer (1%) (pH

2.6):ACN:MeOH

(95:4:1); Eluent

B:ACN NH 4 H 2 PO 4 (20 mM) +

1-heptane sulfonic

acid sodium salt

buffer (1.0%) (pH

9.5) (6:4); gradient

222 nm 2012

[ 181 ]

173. Imatinib mesylate Capsules; anticancer 8 impurities C18 (BEH), 50 mm × 2.1

mm, 1.7 μm

Eluent A:

CH 3 COONH 4 (50

mM, pH 9.5); Eluent

B: ACN:MeOH

(40:60); gradient

237 nm 2012

[ 182 ]

174. l -Alanyl- l -

glutamine

API; food supplement 5 impurities C18, 150 mm × 3 mm, 3

μm



B: ACN (0.1% formic

acid); gradient

ESI / MS n

detection

2012

[ 183 ]

175. l -Alanyl- l -

glutamine

Infusion solution; food

supplement

9 impurities Polysulfoethyl A, 150

mm × 4.6 mm, 5 μm

Eluent A: NH 4 OH

(100 mM): H 2 O

(1:9); Eluent B:

NH 4 OH (100 mM):

ACN (1:9); gradient

ESI / MS n

detection

2012

[ 183 ]

176. l -Alanyl- l -

glutamine


supplement

7 impurities QN-AX, 150 mm × 4

mm, 5 μm

CH 3 COONH 4 (20

mM, pH 4.5):ACN

(60:40)

ESI / MS n

detection

2012

[ 183 ]

177. l -Alanyl- l -

glutamine


supplement

7 impurities QN-AX, 150 mm × 4

mm 5 μm

Eluent A: formic

acid buffer (100

mM, pH 3.5):H 2 O

(1:9); Eluent B:

formic acid buffer

(100 mM, pH

3.5):ACN (1:9);

gradient

ESI / MS n

detection

2012

[ 183 ]

178. Linezolid API; antibiotic 6 impurities Chiral, 250 mm × 4.6

mm, 5 μm

ACN:ethanol:n-

butyl amine:TFA

(96:4:0.10:0.16)

254 nm 2012

[ 184 ]

179. Luliconazole API and cream;

antifungal


5 μm

MeOH:H 2 O (80:20) 296 nm 2012

[ 185 ]

180.

Methamphetamine


mm × 1.0 μm

Helium gas Mass

selective

detector

2012

[ 186 ]


Table 2

Continued

S.

no. Name of drug

Matrix; therapeutic


Year

[Ref.]

181. Moxonidine Tablet; antihpertensive 5 impurities C18, 250 mm × 4.6 mm,

5 μm

MeOH:potassium

phosphate buffer

(50 mM), (15:85)

(pH 3.5)

255 nm 2012

[ 187 ]

182. Nevirapine API; anti-HIV 2 impurities ABZ, 150 mm × 4.6 mm,

5 μm

Ammonium

phosphate buffer

(50 mM, pH

4.5):ACN (7:3)

220 nm 2012

[ 188 ]

183. Niacinamide API; vitamin Niacin, isonicotinamide,

picolinamide,

3-cyano-pyridine,

niacinamide N-oxide

C18, 250 mm × 4.6 mm,

5 μm

CH 3 COONH 4 (20

mM, pH 5):ACN

(97:3)

254 nm 2012

[ 189 ]

184. Nonpeptide

(angiotensin AT1

receptor

antagonist)

API; antihypertensive 4 impurities C18, 250 mm × 4.6 mm,

5 μm

Phosphoric acid (pH

3.5):ACN (51:49)

210 nm 2012

[ 190 ]

185. Pantoprazole API; peptic ulcer 2-Chloromethyl-3,4-

dimethoxy pyridine

HCl

C18, 50 mm × 4.6 mm, 3

μm

CH 3 COONH 4 (10

mM):ACN (79:21)

210 nm 2012

[ 191 ]

186. Plazomicin API; antibiotic 3 impurities C18, 4.6 mm × 150 mm,

3.5 μm

NH 4 OH (25

mM):ACN; gradient

210 nm 2012

[ 192 ]

187. Praziquantel API andTablet;

Anthelmintic

2 impurities Silica, 4.0 mm × 125

mm, 100 / 5 μm

ACN:CH 3 COONH 4

(25 mM) (40:60)

210 nm 2012

[ 193 ]

188. Rivastigmine

tartrate

API; anti-Alzheimer 11 impurities C18, 250 mm × 4.6 mm,

5 μm

Eluent A: KH 2 PO 4 (10 mM, pH

7.6):ACN (90:10);

Eluent B:

ACN:MeOH (60:40);

gradient

210 nm 2012

[ 194 ]

189. Ropinirole API; anti-Parkinsons 5 degradants Silica gel 60F-254 Toluene:ethyl

acetate:NH 3 (6 M)

(5:6:0.5)

250 and 254

nm

2012

[ 195 ]

190. SCD: chalcone

derivative

Nanoemulsion;

antiprotozoal

2 degradants C18, 150 mm × 4 mm, 5

μm

MeOH:H 2 O (70:30)

(pH 5,TFA)

330 nm 2012

[ 196 ]

191. Sodium

tanshinone IIA

sulfonate

API; antioxidant 8 impurities C18, 250 mm × 4.6 mm,

5 μm

CH 3 COONH 4

(0.2%):MeOH

(35:65)

271 nm 2012

[ 197 ]

192. Telmisartan API; antihypertensive Methyl

4 ′ ,4 ′ -dibromometh-yl

biphenyl-2-carboxylate

C18, 125 mm × 4.6 mm,

5 μm

KH 2 PO 4 +

sodium-1-pentane

sulfonate (pH 3)

230 nm 2012

[ 198 ]

193. Thiocolchicoside API; muscle relaxant 6 degradants C18, 250 mm × 4.6 mm,

5 μm

Ammonium

formate buffer (10

mM; pH 3):ACN;

gradient

MS / MS

Detection

2012

[ 199 ]

194. Trandolapril API; antihypertensive 16 degradants C18 (BEH), 138 mm ×2.1 mm, 1.7 μm

Ammonium

hydrogen carbonate

(10 mM, pH

8.14):ACN (68:32)

190 and 500

nm

2012

[ 200 ]

195. Wogonin API; anxiolytic 2 degradants C18, 250 mm × 4.6 mm,

5 μm

MeOH:CH 3 COONH 4

buffer (5 mM)

(75:25)

275 nm 2012

[ 201 ]

196. Zolmitriptan API; antimigraine 6 impurities Phenyl, 100 mm × 3

mm, 2.7 μm

KH 2 PO 4 (20 mM) +

sodium 1-hexan

sulfonate (5 mM, pH

2):ACN; gradient

220 nm 2012

[ 202 ]

197. Bortezomib API; anticancer 3 impurities C18, 250 mm × 4.6 mm,

5 μm

Eluent A:

HCOOH:ACN:H 2 O

(1:300:700); Eluent

B: HCOOH:ACN:H 2 O

(800:200:1);

gradient

270 nm 2012

[ 203 ]

2

2

s

f

c

1

d

p

mW

.1.2. 2009

.1.2.1. Impurity profiling Both techniques of LC–MS, ion trap mass

pectrometry and time of flight mass spectrometry were used

or characterization of impurities in chloroquine and hydroxy-

hloroquine bulk drug samples [ 59 ]. 1-(1,1-Bis(4-fluorophenyl)-

,3-dihydroisobenzofuran-5-yl)-4-(dimethylamino) butan-1-one hy-

robromide as an impurity of citalopram was isolated by semi-

reparative HPLC and structure was established by using Q-TOF

ass analyzer, NMR and IR spectroscopy. Overlaid FT-IR spectra

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

to each other with difference of peak at 1681 cm

−1 and 2229

cm

−1 from C O and C N, respectively [ 60 ]. Principally, cy-

closporin 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 deter-

mined [ 61 ]. Two monoacylated diacerein impurities of diacerein with

same molecular weight ( M = 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 confirmed by NMR spectroscopy, which were character-

ized as 5-acetoxy-4-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2-

carboxylic acid (1.14%) and 4-acetoxy-5-hydroxy-9,10-dioxo-9,10-

dihydroanthracene-2-carboxylic acid (1.24%) [ 62 ]. Polyethylene gly-

col (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 gra-

dient elution were used to study the same [ 64 ]. Atmospheric pres-

sure chemical ionization (APCI) of mass spectroscopy was applied for

identification of gentamicin impurities, where no suppression in ion-

ization 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 purification, respectively [ 66 ]. As zirconia-

based 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 ibupro-

fen [ 67 ]. Salidroside is phenolic glycoside of genus Rhodiola, used for

treatment of cardiovascular and cerebrovascular diseases. The biosyn-

thetic pathways for impurities icariside D2, 4-hydroxyphenacyl- d -

glucopyranoside 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 mini-

mizes chiral hydrogen bonding and establishes weak dipole effect for

high selectivity of separation [ 82 ]. Off-line HPLC–FT-IR coupling was

used for identification of tropicamide along with its major impurity

(apotropicamide) in raw material [ 84 ].

2.1.2.2. Forced degradation profiling Forced degradation of tenato-

prazole (novel proton pump inhibitor) was carried out to estab-

lish intrinsic stability, and found susceptible in acidic, oxidative and

photolytic condition [ 54 ], while with levofloxacin only oxidative

degradant was identified [ 55 ]. As beta-lactam antibiotics are sen-

sitive towards acidic / alkaline degradation, in this sequence, impuri-

ties in biapenem aqueous solution were identified as two dimmers

and three hydrolytic degradants and the degradation pathway was

also discussed [ 58 ]. Forced degradation study of zotarolimus and zo-

tarolimus 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 profiling Anti-inflammatory

lotion containing betamethasone dipropionate and salicylic acid was

analyzed by stability-indicating HPLC method, where 27 analytes

were determined including salicylic acid and betamethasone dipro-

pionate 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 ]. Mech-

anistic explanation for origin of degradation products of lamivudine

and identification 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 met-

formin hydrochloride and 1-cyanoguanidine in tablet by using iso-

cratic 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 confirmed by a series of

photo- and oxidative stress studies [ 73 ]. Impurities were identified

and elucidated in taranabant (anti-obesity agent) prepared by cya-

nuric 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 five impurities including two regioisomers of zafirlukast

were identified, characterized, synthesized and their synthetic path-

ways and fragmentation pathways were discussed [ 85 , 86 ].

2.1.3. 2010

2.1.3.1. Impurity profiling 10- O -(N,N-dimethylaminoethyl)-

ginkgolide B methanesulfonate is derivative of ginkgolide B,

obtained from Ginkgo biloba and used as platelet-activating fac-

tor 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-dehydro-

ginkgolide B [ 88 ]. Complexity of acetylspiramycin was revealed by

LC / MS n investigation, where 31 unknown and 17 known impurities

were identified. These impurities were raised due to starting ma-

terials 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 confirmed

by synthesis [ 102 ]. 2-(4-Hydroxybenzyl)-N,5-bis(4-fluorophenyl)-

5-hydroxypentanamide was identified as process-related impurity

in ezetimibe by LC / MS / MS and NMR, where 2D-NOESY NMR tech-

niques was used to assign chemical shift [ 103 ]. Impurity containing

samples of filgrastim (recombinant human granulocytecolony

stimulating factor) were analyzed by liquid chromatography assays

and chromatographic data were correlated with biological activity

of filgrastim [ 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 ]. Post-

column derivatization with o -phtaldialdehyde / 2-mercaptoethanol

was used for fluorescence 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 five impurities (rabeprazole-N-oxide,

rabeprazole sulfone, rabeprazole sulfide, methoxy rabeprazole and

mercapto-1 H -benzimidazole) [ 115 ]. Impurities originated during

building of methyloxadiazoyl portion of raltegravir and presence of

desfluoro analog due to raw material were characterized by LC–MS

incorporating a quadrupole time of flight mass spectrometer [ 116 ].

Nine impurities in diester prodrug of cytidine analog at low level


(

c

c

c

m

[

2

p

w

c

d

A

c

l

t

[

t

o

a

w

y

[

t

t

h

t

f

2

w

i

t

w

r

p

f

[

H

i

2

2

a

d

w

o

e

o

fi

u

a

5

e

e

w

f

3

c

i

L

g

s

M

Fig. 4. Schematic diagram showing Maillard reaction between lactose and meman-

tine. (Reuse with the permission of Elsevier Limited, The Boulevard, Langford Lane,

Kidlington, Oxford OX5 1GB, UK.)

0.05–0.10%) were identified and purified by heart-cut and recycle

hromatographic techniques [ 117 ]. Combined application of liquid

hromatography, NMR and high resolution NMR was employed for

haracterization of mutagenic impurities in vestipitant. Starting

aterial for the synthesis was identified as root cause of impurities

122 ].

.1.3.2. Forced degradation profiling Hydrolytic forced degradation

roduct of acetazolamide, carbonic anhydrase inhibitor was formed,

hile it was found to be stable towards heat and light [ 89 ]. Alizapride

arboxylic acid and alizapride N-oxide were two degradants of forced

egradation of alizapride (potent anti-emetic), were investigated in

PI as well as its pharmaceutical formulations [ 92 ]. New calcium

hannel blocker, barnidipine was exposed to natural and stressing

ight irradiation and HPLC and spectrophotometry were used to de-

ermine pyridine derivative as the main photodegradation products

94 ]. Raman et al. have resolved duloxetine hydrochloride and its posi-

ional isomer raised from forced degradation [ 99 ]. Forced degradation

f enalapril maleate in presence of magnesium monoperoxyphthalate

nd investigated by HPLC and UPLC–MS methods. First order kinetics

as followed by autocatalytic degradation of the drug, where hydrol-

sis of ethylic ester and intermolecular cyclization were observed

100 ]. Fentanyl was found to be susceptible towards acid and oxida-

ive conditions during forced degradation but degradants were found

o be no-toxic [ 105 ]. Forced degradation pathways of ritonavir under

ydrolysis, oxidation, thermal and photolysis conditions were inves-

igated. Carbamate and urea linkages present in ritonavir, so it was

ound more prone to hydrolysis [ 119 ].

.1.3.3. Impurity and forced degradation profiling Clopidogrel purity

as determined in bulk samples and pharmaceutical dosage forms

n presence of its impurities and forced degradation products respec-

ively [ 96 ], while BEH technology equipped with C18-UPLC column

as employed to determine purity of desloratadine within 8 min of

un time [ 98 ]. Degradation profile of pentoxifylline has revealed a

rominent oxidative degradant as gem-dihydroperoxide [ 112 ] and

our impurities of piracetam were determined in tablet dosage form

113 ]. Non-chiral related impurities of sertraline were determined by

PLC [ 120 ], while valsartan was determined by UPLC in presence of

ts degradants and impurities in APIs and its dosage forms [ 121 ].

.1.4. 2011

.1.4.1. Impurity profiling Artemisinin is isolated from Artemisia

nnua L. and used for production of other anti-malarial as artemisinin

erivatives. Two impurities artemisitene and 9-epi-artemisinin

ere identified in artemisinin API [ 126 ]. Five unknown impurities

f atazanavir sulfate were characterized using spectral data and

stablish mechanistic pathway [ 127 ]. Process-related substances

f citrus auraptene (chemopreventive agent) were also identi-

ed as umbelliferone, ( E )-6,7-dihydroxy-3,7-dimethyl-2-octene-

mbelliferone, ( E )-6,7-epoxy-3,7-dimethyl-2-octene-umbelliferone

nd 4-methylauraptene [ 128 ]. 2-Ethoxy-1-[[2 ′ -(1-ethyl-1 H -tetrazol-

-yl)biphenyl-4-yl]methyl]-1 H -benzimidazole-7-carboxylic acid

thyl ester as a process related impurity in candesartan cilex-

til was characterized and quantified at trace-level of < 0.2%,

hich was further confirmed by its synthesis [ 130 ]. In similar

ashion tetrabenzo[b,f,b ′ f ′ ]azepino[4 ′ ,5 ′ :4,5] thieno[2,3-d]azepine-

,9-dicarboxamide as unknown impurity of antiepileptic drug

arbamazepine was characterized [ 131 ]. Carryover impurity from

ntermediate stage and raw materials of febuxostat was explored by

C–MS Q-TOF instrument, which is indicated for hyperuricemia and

out [ 138 ]. Precolumn or postcolumn derivatization of aminoglyco-

ides is essential to enable either UV or fluorescence detection, so LC /

S / MS method was employed to determine gentamicin, lincomycin,

and spectinomycin in the presence of their impurities in pharma-

ceutical 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 fermenta-

tion 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, memantine–dimethylamino

glycine, memantine–galactose and memantine–glucose adducts

by HPLC using charged aerosol detection. Heptafluorobuturic acid

was introduced in mobile phase to improve resolution and peak

shapes of the impurities [ 145 ]. No mutagenic potential of 2-(6-

methoxynaphthalen-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 quantification

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

fibrsosis [ 157 ].

2.1.4.2. Forced degradation profiling Boron neutron capture therapy

is a two stage cancer treatment, where one of lead drug candi-

dates 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 pheny-

lalanine has been observed in lyophilized samples of mannitol-drug

[ 129 ]. Desisobutyryl-ciclesonide was identified as hydrolytic degra-

dation 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 es-

tablished 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 dou-

ble bond [ 144 ]. Anti-HIV drugs, abacavir sulfate and atazanavir sul-

fate 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 de-

graded samples of olaquindox were studied by HPLC combined with

hybrid ion trap / time-of-flight mass spectrometry and especially its

degradation products were correlated with its phototoxicity and

photoallergic reaction [ 151 ]. Two photo-degraded products of val-

sartan were characterized as: N-[2 ′ -(1 H -tetrazol-5-yl)-biphenyl-4-

ylmethyl]-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 profiling Forced degradation

and impurity profiling of etimicin sulfate, new aminoglycoside an-

tibiotic with lower toxicity has revealed that starting material, syn-

thetic 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 crys-

tals, while stereochemical purity of ezetimibe was determined by

HPLC [ 137 ]. 7,8-Cyclopropyl baccatin III, 10-deacetyl larotaxel, 10-

deacetyl-7,8-cyclopropyl baccatin III and 2 ′ ,13-bissidechain larotaxel

were identified 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-2-

carbamoyloxymethyl-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 π nap column containing

naphthalethyl stationary phase has been employed to achieve better

resolution than conventional column, in between palonosetron hy-

drochloride, degradation products and its isomeric impurities, which

has strong π–π and hydrophobic interactions [ 152 ].

2.1.5. 2012

2.1.5.1. Impurity profiling Pharmaceutical impurities may act as

genotoxins, which impose genetic mutation in DNA and may trig-

ger 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 aro-

matics) and related structurally alerting compounds were analyzed

by using polymeric ionic liquids as selective solid-phase microex-

traction 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 pi-

valate were characterized process impurities [ 170 ]. Alkyl halide (2-

chloroethanol) and sulfonate esters (methyl p-toluenesulfonate and

2-chloroethyl p-toluenesulfonate) as genotoxic impurities in clop-

erastine fendizoate were determined by two different chromato-

graphic methods, GC–MS and HPLC-DAD, respectively, due to dif-

ferent physical and chemical properties of these impurities. Fendi-

zoate was removed by strong anion-exchange (SAX)-SPE before GC-

MS analysis, as a step of sample purification [ 171 ]. Although, six im-

purities were reported in deferasirox, but a new impurity was charac-

terized 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 liquid–liquid extraction and solid-phase microex-

traction [ 186 ] and common synthetic impurities identification [ 161 ]

were reported for impurity profiling in methamphetamine and 4-

methylthioamphetamine, 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. Ammo-

nium acetate was used to improve detection sensitivity of this geno-

toxic 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 impuri-

ties, 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

identified as principle synthetic route impurity in telmisartan based

on spectral data deriving from 2D-NMR and MS [ 198 ]. Zolmitriptan-

dimer was characterized as impurity in zolmitriptan by means of LC–

MS and NMR studies which was identified as by-product of its last

step Fischer indole synthesis [ 202 ]. When a fluid has temperature

and pressure are higher than corresponding critical values, known

as supercritical fluid [ 206 ] and it is used in supercritical fluid chro-

matography (SFC) for impurity profiling of pharmaceutical products.

The elution profile in SFC is generally orthogonal to RPLC data, which

were very useful in assessing purity of API’s. SFC method is more

complex than RPLC due to difficult to understand solute (complex

molecule)-stationary phase interactions [ 207 ].

2.1.5.2. Forced degradation profiling Due to autoxidation, epoxides

and ketones were formed through free radical-mediated reactions

involving alkene and alcohol sites of rapamycin, which were identi-

fied by forced degradation studies [ 160 ]. 2,2 ′ -Azobisisobutyronitrile

as a radical initiator was used to understand mechanistic oxida-

tive degradation pathway of azelnidipine in solution, which may

be helpful to stabilize its dosage form [ 165 ]. Forced degradation

behavior of 1-(4-methoxyphenylethyl)-11 H -benzo[f]-1,2-dihydro-

pyrido[3,2,c][1,2,5]oxathiazepine 5,5 dioxide, new potent anticancer

agent was in different stress conditions, where degradation prod-

ucts were elucidated by means of ESI-orbitrap-MS [ 166 ]. Stability-

indicating 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 in-

herent chemical stability of thiocolchicoside, a glycoside of Colchicum

autumnale , forced degradation study was performed, where degra-

dation pathways for hydrolytic and oxidative conditions were eluci-

dated [ 199 ]. First order kinetic was followed by trandolapril hydrol-

ysis in acidic and neutral conditions and this degradation profile was

investigated by two techniques UPLC-DAD and UPLC–MS / MS [ 200 ].

2.1.5.3. Impurity and forced degradation profiling HPLC and spec-

trophotometric methods were applied to determine bupropion hy-

drochloride, its alkaline degradates and 3-chlorobenzoic acid as im-

purity [ 167 ]. Preparative HPLC, LC–MS / MS, UPLC-TOF-MS, NMR and

FT-IR spectroscopy were employed to study forced degradation of


d

a

t

t

t

5

a

i

p

w

p

k

fi

t

S

a

4

t

t

w

u

a

r

s

p

i

w

p

w

r

o

f

f

u

[

2

c

o

M

2

c

(

d

[

p

n

f

w

i

r

(

g

p

r

(

p

a

p

g

v

o

Fig. 5. General outline of the impurity fate mapping framework. (Reuse with the per-

mission of Elsevier Limited, The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB,

UK.)

ipyridamole product and two additional impurities were also char-

cterized [ 175 ]. Total 15 impurities and eslicarbazepine were de-

ermined by stability indicating RP-HPLC–UV method and charac-

erized by LC / ESI-IT / MS / MS n . Acridine-9-carboxylic acid was iden-

ified as degraded impurity, while (10S)-10-hydroxy-10,11-dihydro-

H -dibenzo[b,f]azepine-5-carbox-amide was found as both degraded

s well as process impurity and remaining all were process related

mpurities [ 176 ]. 26 impurities were detected in commercial sam-

les of etimicin sulfate, a semi-synthetic aminoglycoside antibiotic

ith less chronic nephro- and ototoxicity, by liquid chromatogra-

hy ion-trap mass spectrometry by using C18 column with an al-

aline aqueous mobile phase. The source of impurities were identi-

ed as starting material for synthesis and its residual impurities, in-

ermediates, synthetic by-products and degradation products [ 178 ].

even potential impurities (isoniacin, niacin, isonicotinamide, 3-

minopyridine, 2-aminopyridine, fampridine n-oxide and 3-hydroxy-

-aminopyridine) of fampridine were determined by using C18 sta-

ionary phase in gradient mode and ultraviolet dual wavelength de-

ection technique. Fampridine is used to improve walking in patients

ith multiple sclerosis and its major oxidative degradation prod-

ct was also determined as fampridine n-oxide [ 179 ]. About 24 an-

lytes including guaifenesin, terbutaline sulfate, ambroxol HCl, their

elated compounds and degradation product were determined by

tability-indicating LC method [ 181 ]. In similar way, niacinamide and

otential impurities (niacinamide n-oxide, isonicotinic acid, niacin,

sonicotinamide, picolinamide, 3-cyanopyridine) were also analyzed

here niacinamide n-oxide was identified as oxidative degradation

roduct [ 189 ]. In addition to six known impurities, three impurities

ere identified as rivastigmine N-oxide, rivastigmine p -isomer and

ivastigmine o -isomer. Rivastigmine N-oxide was also identified as

xidative degradant of the drug [ 194 ]. Sodium tanshinone IIA sul-

onate is used in China for treating cardiovascular disease is isolated

rom roots of Salvia miltiorrhiza . Starting material, synthetic byprod-

cts and degradation were identified as main sources the impurities

197 ]. Process related impurity (6-chloro-5,7-dihydroxy-8-methoxy-

-phenyl-4 H -chromen-4-one) and degradation product of alkaline

ondition (5,7-dihydroxy-6-methoxy-2-phenyl-4 H -chromen-4-one)

f synthetic wogonin crude drug were characterized by HPLC–Q-TOF–

S / MS technique [ 201 ].

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

oncepts in impurity and degradation profiling

Response surface design by means of central composite design

CCD) was employed to forced degradation profile of eletriptan hy-

robromide by HPLC, where only oxidative degradant was observed

63 ]. Response surface methodology of statistical analysis was ap-

lied to optimize chromatographic parameters for determination of

imodipine and its impurities in tablets [ 74 ]. Different paracetamol

ormulations were analyzed in relation to their synthetic pathways,

hich differ in starting materials, solvents, reagents, catalysts and

ntermediates. It was assumed that drug may have different impu-

ity profile, which were analyzed with principal component analysis

PCA), hierarchical clustering and auto-associative multivariate re-

ression trees (AAMRT) by using chromatographic data [ 204 ]. Two

rocess-related impurities, 3-piperidinopropiophenone hydrochlo-

ide (intermediate) and 1-(3,3-diphenylprop-2-en-1-yl)piperidine

by-product) were determined in pridinol mesylate, where mobile

hase composition (pH and organic component) were optimized by

n experimental design (Design Expert v. 7) [ 77 ]. Chemometrical ap-

roach was applied to study ropinirole and its impurity’s chromato-

raphic behavior [ 78 ].

Impurity fate mapping (IFM) approach ( Fig. 5 ) was applied for in-

estigation and control of impurities in the manufacturing process

f pazopanib hydrochloride, which requires an aggressive chemical

and analytical search for potential impurities in the starting materi-

als, intermediates and drug substance, and experimental studies to

track their fate through the manufacturing process in order to un-

derstand the process capability for rejecting such impurities. Com-

prehensive IFM provide elements of control strategies for impuri-

ties [ 95 ]. The regression coefficient plots of resolution between peak

pairs were included in the experimental design to optimize sepa-

ration of oxytocin and its related substances [ 117 ]. Multiobjective

optimization technique was employed to optimize microemulsion

liquid chromatographic (MELC) method through Derringer’s desir-

ability 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 sulfide) was reduced using Platinum

C18 Rocket column (53 mm × 7 mm, 1.5 μm particle size) and ex-

perimental 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 modifier at beginning of gradient, percentage of organic

modifier at end of gradient and gradient time. Fig. 6 shows the prob-

ability surfaces in different directions of the space around the opti-

mal solution (for each graph, two factors were fixed 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 op-

timize the method [ 180 ]. Full factorial design and surface response

curve were used to study forced degradation profiling 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 us-

ing 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 compo-

sitional parameters and evaluate interaction effects for validation of

stability-indicating HPTLC method which was applied to degradation

kinetic profiling of ropinirole [ 195 ].

As above we have discussed trends in analytical perspective on im-

purity and forced degradation profiling of pharmaceuticals including

different techniques used in impurity profiling, experimental design,

different conditions of analysis (mobile phase, column, types of elu-

tion and detection wavelength) and therapeutic category of API. Sta-

tistical tools have been applied to analyze above various parameters

of impurity and forced degradation profiling and these parameters


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.)

Fig. 7. Response surface plot showing effect of different ratios of toluene ( X 1), ethyl

acetate ( X 2) and ammonia solution ( X 3) on retardation factor ( Y ). (Reuse with the

permission of Elsevier Limited, The Boulevard, Langford Lane, Kidlington, Oxford OX5

1GB, UK.)

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

2008–2012.

are going to be discuss in following.

2.3. Column

Column is heart of the chromatography which can be selected de-

pending upon their pore size, surface area, carbon load, particle size,

length, chemistry of column. The degree of retention of a neutral hy-

drophobic 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

profiling ( 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

combination of hydrophilic stationary phases and hydrophobic mo-

bile 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 enan-

tiomers and its reported impurities using Chiralpak IA with mix-

ture of mobile phase consisting of methyl-tert-butyl ether:ethyl ac-

etate: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 liq-

uid chromatography (UPLC) equipped with BEH column was used

for determination of atorvastatin, fenofibrate 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

Maximum work on active pharmaceutical ingredient (API) for im-

purity and degradation profiling, which was totalled to 73% during

2008–2012 ( Fig. 9 ). Maximum of 14% of total work was on tablet

doasge form and followed by capsules, creams and injections. Al-

though, 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 determina-

tion 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 five years for impurity and degradation profiling.


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

2008–2012.

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

profiling during 2008–2012.

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

profiling during 2008–2012.

2

i

d

m

i

i

m

l

J

.6.Therapeutic categories

Although, most of all therapeutic categories have been taken

nto consideration for impurity and forced degradation profiling, but

rug candidate belongs to chemotherapeutic category were maxi-

um used for this study as 18% ( Fig. 11 ) and followed by drugs act-

ng on cardiovascular system (16%), central nervous system (15%),

mmunomodulator (6%), GIT (6%), antineoplastics (6%), psychophar-

acological agents (4%), etc. Recently, ten impurities of antihyper-

ipidemic drug (simvastatin) were summarized by Basniwal and

ain [ 208 ].

3. Conclusion

The present review describes comprehensive update on recent

trends in analytical perspectives of degradation and impurities pro-

filing of pharmaceuticals including active pharmaceutical ingredient

(API) as well as drug products during 2008–2012, which may serve

and ample view to all the interest group.

Acknowledgements

One of the authors, Pawan Kumar Basniwal, earnestly indebted

to Science and Engineering Research Board (SERB), DST, New Delhi,

India, for the financial support for this research work under Fast Track

Scheme for Young Scientists.

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Forced degradation and impurity profiling