1-s2.0-S0731708513003099-main (2).pdf

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

Contents lists available at ScienceDirect

Journal of of Pharmaceutical 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 / / ll o c a t e / j j p b a

Review

Forced degradation and impurity profiling: Recent trends in analytical perspectives Deepti Jain Deepti Jaina , Pawan Kumar Basniwa Basniwalla , b , * a b

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

a r t i c l e

i n f o

Article history: Received 9 May 2013 Received in revised form 28 28 June June 2013 Accepted 7 July 2013 Available online 31 31 July 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 of the the recent trends in analytical perspectives of of degradegradation and impurities profiling of of pharmaceuticals 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 analysis. 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.

1. Introduction

Abbreviations: 13 C NMR, 13 carbon nuclear magnetic resonance spectroscopy; 1D/ 2D NMR, one dimensional/two dimensional nuclear magnetic resonance; 1 H NMR, proton nuclear magnetic resonance spectroscopy; AAMRT, auto-associative multivariate regression trees; ACN, acetonitrile; APCI-MS, atmospheric-pressure chemicalionization mass spectrometry; API, active pharmaceutical ingredient; BADGE, bisphenol A diglycidyl ether; BEH, bridged ethylene hybrid; C6 H6 , benzene; CAD, charged aerosol detector; CCD, central composite design; CCl4 , tetrachloromethane; CEAD, coulometric electrode array detection; CH2 Cl2 , methylene chloride; CH3 COONH4 , ammonium acetate; CHCl2 CH2 Cl, 1,1,2-trichloro ethane; CHCl3 , chloroform; CID, collisioninduced dissociation; CO2 , carbon dioxide; COPD, chronic obstructive pulmonary disease; DAD/MS, diode array detector-mass spectrometry; DEPT, distortionless enhancement by polarization transfer; EDTA, ethylene diamine tetra acetic acid; ELSD, evaporative light scattering detector; EMEA, European agency for the evaluation of medicinal products; ESI/MSn , electronspray ionization multi-stage or tandem mass spectrometry; ESI-FTICR-MS, electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry; USFDA, US Food and Drug Administration; FTICR, Fourier transform ion cyclotron resonance; FT-IR, Fourier transform infrared; GCFID, gas chromatography-flame ionization detector; GC–MS, gas chromatography– mass spectrometry; GFC, gel filtration chromatography; GTIs, genotoxic impurities; H2 O, water; H3 PO4 , phosphoric acid; HCl, hydrochloric acid; HCOOH, formic acid; HCOONH4 , ammonium formate; HEIP, 1,1,1,3,3,3-hexafluoroisopropanol; HILIC, hydrophilic interaction chromatography; HPAE-IPAD, high-performance anion-exchange chromatography-integrated pulsed amperometric detection; HPLC, high performance liquid chromatography; HPLC/ESI-MS, high-performance liquid chromatography/ electrospray ionization mass spectrometry; HP-SEC, high-performance size-exclusion chromatography; HPTLC, high performance thin layer chromatography; ICH, International Conference on Harmonization; IFM, impurity fate mapping; IND, investigational new drugs; IPA, isoproyl alcohol; K2 HPO4 , dipotassium hydrogen phosphate; KH2 PO4 , potassium dihydrogen phosphate; KOH, potassium hydroxide; LC/MS/MS, liquid chromatography–tandem mass spectrometry; ESI-CID-MS/MS, electrospray ionization, collision-induced dissociation and tandem mass spectrometry; LC–ESI-MSn , liquid chromatography–electro spray ionization-tandem mass spectrometer; LC–ESI-QT/ c 2013 Elsevier B.V. All rights reserved. 0731-7085/$ - see front matter  http://dx.doi.org/10.1016/j.jpba.2013.07.013

“A clean bill of of health health of of public” public” is the ultimate motto of of pharmapharmaceutical 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 importance 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 ionization source and Q-trap mass analyzer; LC–MS, liquid chromatography–mass spectrometry; LiCl, lithium chloride; MDMA, 3,4-methylenedioxy-N-methylamphetamine; MECC, micellar electrokinetic capillary chromatography; MEKC, micellar electrokinetic chromatography; MeOH, methanol; MPLC, medium pressure liquid chromatography; MPTP, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; CE, capillary electrophoresis; MS, mass spectrometry; Na2 HPO4 , disodium phosphate; Na3 PO4 , sodium phosphate; NaCl, sodium chloride; NDA, New Drug Application; NH3 , ammonia; NH4 H2 PO4 , ammonium dihydrogen phosphate; NH4 OH, ammonium hydroxide; NOESY, nuclear overhauser effect spectroscopy; NSAIDs, non-steroidal anti-inflammatory drugs; OVIs, organic volatile impurities; PCA, principal component analysis; PDA, photodiode array; PDA-MS, photodiode array detector-mass spectrometry; PFPA, pentafluoropropionic acid anhydride; Q-TOF, quadrupole-time-of-flight; RI, refractive index; RRF, relative 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 of Pharmacy, Pharmacy, Jaipur Jaipur 302 004, Rajasthan, India. Tel.: +91 9414788171. (D. Jain) Jain) [email protected] E-mail addresses: [email protected] (D. (P.K. Basniwal).

12

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

a drug product is dependent not only on the toxicological properties of the of the active drug substance itself, but on the impurities that it contains. Another side of coin is that the formulation should be stable throughout shelf shelf life life of of product product with respect to its identity, strength, purity and quality of of drug. drug. Quality of of pharmaceuticals pharmaceuticals has to be monitored from the very beginning, i.e., from raw materials to the end, i.e., finished product, including marketing surveillance [1–3]. As per Webster’s dictionary impurity is something that is impure or makes something else impure. An impure substance may be defined as a substance of of interest interest mixed or impregnated with an extraneous or usually inferior substance substance[[4,5]. A number of of terms terms have been commonly used to describe organic impurities, such as starting material, intermediates, penultimate intermediate (final intermediate), by-products, transformation products, interaction products related products and degradation products. The United States Pharmacopoeia (USP) has different sections for impurities including impurities in official articles, ordinary impurities and organic volatile impurities. These are described as foreign substances, toxic impurities, concomitant components, signal impurities, ordinary impurities and organic volatile impurities (OVIs) [6] (Tables 1 and 2). ICH guidelines categories impurities as: organic impurities (starting materials, process-related impurities, intermediates and degradation products); inorganic impurities (salts, catalysts, ligands and heavy metals); other materials (filter aids and charcoal) and residual solvents (organic and inorganic liquids) [2]. ICH guidelines give simple classification of of the the impurities while none of of these these are unable to describe enantiomeric (chiral) impurities. Chiral impurities have the identical molecular formula and the same connectivity between various atoms, and they differ only in three-dimensional arrangement of of their their atoms in the space. The differences in pharmacological/ toxicological profiles have been observed with chiral impurities in vivo [7]. Therefore, it is quite obvious that the products intended for human consumption must be characterized as completely as possible. Monitoring and controlling of of impurities impurities generally give assurance of the quality and safety of a drug. Thus, the analytical activities concerning impurities in drugs are among the most important issues in modern pharmaceutical analysis [8,9]. Analytical monitoring of impurities in new drug substances is a key component of the recent guideline issued by the International Conference on Harmonization (ICH) [2]. Forced degradation studies provide data to support identification of possible of possible degradants; degradation pathways and intrinsic stability of the of the drug molecule and validation of of stability stability indicating analytical procedures. A draft guidance document suggests that results of of oneonetime forced degradation studies should be included in Phase 3 INDs (Investigational New Drugs). NDA (New Drug Application) registration requires data of of forced forced degradation studies as forced degradation products, degradation reaction kinetics, structure, mass balance, drug peak purity, etc. This forced degradation study provides information about degradation pathways of API, alone and in drug product, any possible polymorphic or enantiomeric substances and difference between drug related degradation and excipient interferences [24 24]]. Thus, forced degradation and impurity profiling is one of of the the key for IND as well as NDA registration document. Although different books [11 11,,12 12]] and review articles [13 13– –16 16]] have been published to summarize the study on impurity and degradation profiling, but still there is no report on recent years which enable to describe the recent analytical perspectives of of impurity impurity and degradation profiling. Keeping this view in the mind, present work has been aimed to review the analytical trends for forced degradation degradationstudies studies and impurity profiling of active of active pharmaceutical ingredients and pharmaceutical drug product. Articles published on forced degradation studies and impurity profiling during 2008–2012, were extensively reviewed and different parameters, such as matrix of analysis, therapeutic category of the drug, present impurity and degradant, column specification used for

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

separation, mobile phase composition used for elution, mode and/or wavelength of detection and year of publication were accounted to set the recent trend in analytical perspective. 2. Analytical perspectives 2.1. Yearly trend

For this write-up, publications were extensively reviewed which were published on impurity, degradation profiling and stability indicating assay methods during 2008–2012; which includes HPLC, capillary electrophoresis, gas/liquid chromatography, thin-layer chromatography, etc. Fig. 1 has shown column graph of year-wise publications for impurity and degradation 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 profiling. Year-wise analytical perspectives were discussed as following: 2.1.1. 2008 2.1.1.1. Impurity profiling Refractive index (RI) detector as universal detector in analytical HPLC was employed for identification 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 28]] and same techniques were also used for characterization of oxidation impurity of clopidogrel of clopidogrel as 5-[1-(2-chloropheny 5-[1-(2-chlorophenyl)-2-methoxy-2l)-2-methoxy-2-oxoethyl]-6,7oxoethyl]-6,7dihydrothieno[3,2-c]pyridin-5-ium [29 29]. ]. Econazole nitrate is potent broad-spectrum antifungal used for skin infections. Its two main impurities were determined 4-chlorobenzyl alcohol and α (2,4-dichlorophenyl)-1H -imidazole-1-ethanol -imidazole-1-ethanol in cream formulations along with two preservatives [33 33]. ]. HPLC-DAD and HPLC–MS were compared for identification by peak tracking in impurity profiling of quinolones, which provides spectral specificity and 2D chromatographic correlation [38 38]. ]. Four impurities of montelukast sodium were identified during process development by LC–MS in the range of of 0.05–0.15% 0.05–0.15% [44 44]]. Normal phase of of HPLC HPLC and chiral amylase stationary phase were used to determine enantiomers impurity of phenylethanolamine derivative by using n-hexane–ethanol– triethylamine (TEA) as mobile phase [47 47]]. HPLC equipped with coulometric electrode array detection (CEAD) was used for determination of pipecuronium bromide and its four impurities, which provides very high sensitivity and selectivity. In coulometric electrode array system, multiple channels are set at different potentials to give a two-dimensional analysis (Fig. 2). A peak is identified not only by retention time but also by dominant channel and peak ratios across the channels (as compared to standard), which is especially useful when evaluating component in a complex mixture

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

13

Table 1 Different terminology used for impurities [10].

Impurity

Description

Starting material Intermediates

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

Penultimate intermediate By-products Transformation products Interaction products

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

Organic impurities Inorganic impurities Other materials Residual solvents Chiral impurities

Fig. 2. Chromatograms recorded from the mixture containing 1 µ g 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 determination of primaquine phosphate along with its related substance within run time of 5 min [50]. Two impurities of tazarotene were characterized by means of NMR analysis as ethyl 6-((4,4dimethyl-4H -thiochromen-6-yl)ethynyl)nicotinate and 1,4-bis(4,4dimethylthiochroman-6-yl)buta-1,3-diyne,which are by-product of synthetic process [53].

2.1.1.2. Forced degradation profiling HPLC with fluorescence detector 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 followed by alkaline forced degradation of bicalutamide, where an acid and an amine were identified as alkaline degradants [24]. Very interesting, 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 lthyroxine was determinedin presenceof eight degradationimpurities and its dosage form excipients [40]. A degradation product of pridinol mesylate was identified as the dehydrated and N-oxidation derivatives, 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 phosphate buffer and acetonitrile were used to separate three processrelated impurities and degradation products (different forced degradation conditions) of almotriptan malate [18]. In addition to four known impurities of carvedilol, one unknown degradation product was identified as N-[(2RS)-3-(9H -carbazol-4-yloxy)-2hydroxypropyl]-N-[2-(2-methoxyphenoxy)ethyl]hydroxylamine in tablet dosage form which was found as exceeded thresholds of ICH Q3B guidelines [27]. Reversible acetylcholinesterase inhibitor, donepezil hydrochloride was assayed along with four impurities and an excipient in oral pharmaceutical formulation, where selectivity of method was assured from forced degradation of the drug [32]. Degradation pathway for forced degradation behavior of enalapril maleate was identified in different stress conditions [34] and two degradation impurities of epirubicin were found in aqueous formulation [35].

14


Table 2 Representative chromatographic analytical methods of impurity and forced degradation profiling during 2008–2012.

S. no.

Name of drug

1.

2.

Methamphetamine hydrochloride Almotriptan malate

Matrix; therapeutic category

Impurity/degradant

Column/stationary phase

Mobile phase

Detection

API; psychostimulant

29 impurities

Capillary column, 30 m × 0.32 mm × 1. 0 mm

Nitrogen gas

2008 [17]

API; antimigraine

3 impurity

C18, 250 mm × 4.6 mm, 5 µ m

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

Mass selective detector 227 nm

234 nm

2008 [19]

215 nm

2008 [20]

247 nm

2008 [21]

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

2008 [22]

196, 230 and 296 nm

2008 [25]

240 nm

2008 [26]

196, 230 and 296 nm

2008 [25]

240 nm

2008 [27]

226 nm; LC/MS/MS

2008 [28]

220 and 300 nm LC/MS/MS

2008 [29]

239 nm

2008 [30]

235 nm

2008 [31]

270 nm

2008 [32]

220 nm

2008 [33]

3.

Alprazolam

Tablets; anxiolytic

20 degradant

C18, 150 mm × 4.6 mm, 5 µ m

4.

Atomoxetine hydrochloride

API; antidepressants

Phenyl methylamino-propanol and mandelic acid

C8, 50 mm × 4.6 mm, 3.5 µ m

5.

Atorvastatin calcium

Tablets; anti-hyperlipidemic

An acid degraded impurity

C18 (BEH), 100 mm × 2.1 mm, 1.7 µ m

6.

Betahistine

API and tablet; vasodilator

9 degradants

C18, 250 mm × 4.6 mm, 5 µ m

7.

API; steroid

2 impurities

8.

Betamethasone 17-valerate Bicalutamide

9.

Bovine obestatin

API and tablet; anticancer API; antibodies

2 degradants and 6 process-related impurities 3 impurities

C18, 250 mm × 4.6 mm, 5 µ m C18, 250 mm × 4.6 mm, 5 µ m C18, 250 mm × 4.6 mm, 5 µ m

10.

Budesonide

Tablets; steroid

10 impurities

C18, 125 mm × 4.6 mm, 5 µ m

11.

Canine obestatin

API; antibodies

9 impurities

C18, 250 mm × 4.6 mm, 5 µ m

12.

Carvedilol

Tablets; antihypertensive

5 impurities

C18, 100 mm × 4.6 mm, 5 µ m

13.

API; antibiotic

12 impurities

C18, 250 mm × 4.6 mm, 5 µ m

14.

Clindamycin palmitate HCl and clindamycin Clopidogrel

API; antiplatelet

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

C8, 250 mm × 4.6 mm, 5 µ m

15.

Dexamethasone

Dexamethasone-coated eluting stents; steroid

Process impurities and degradants

C8, 4.6 mm × 250 mm, 5 µ m

16.

API; hepatoprotective

5 degradants

C18, 250 mm × 4.6 mm 5 µ m

17.

Dimethyl-4,4 dimethoxy5,6,5 ,6 dimethylene dioxy-biphenyl2,2 -dicarboxylate (DDB) Donepezil HCl

API and tablet; anti-Alzheimer

4 impurities of side reaction and degradation

C18, 250 mm × 4.6 mm, 5 µ m

18.

Econazole nitrate

Cream; antifungal

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

C18, 300 mm × 3.9 mm, 10 µ m

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

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

Year [Ref.]

2008 [18]

2008 [23] 2008 [24]

15


Table 2 Continued

S. no.

Name of drug


Impurity/degradant


Mobile phase

Detection

Year [Ref.]

19.

Enalapril maleate

API; antihypertensive

5 degradants

C18, 250 mm × 4.6 mm, 5 µ m

210 nm

2008 [34]

20.

Epirubicin HCl

Injection; antibiotic

3 degradation impurities

C18, 250 mm × 4.6 mm, 5 µ m

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 µ m

247 nm

2008 [36]

22.

Fluorapacin

2 related substances

2008 [37]

Gatifloxacin

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

200–500 nm

2008 [38]

24.

Glimepiride

API; antidiabetic

5 degradants

C2, 250 mm × 4.6 mm, 5 µ m C18, 250 mm × 4.6 mm, 5 µ m; C18, 150 mm × 6 mm, 5 µ m; C18, 250 mm × 4. 6 mm, 5 µ m C8, 150 mm × 4.6 mm, 5 µ m

218 nm

23.

API and injection; anticancer API; antibacterial

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

235 nm

2008 [39]

25.

Human obestatin

API; antibodies

4 impurities

C18, 250 mm × 4.6 mm, 5 µ m

196, 230 and 296 nm

2008 [25]

26.

Levothyroxine

API; thyroid hormone

8 impurities

C2, 250 mm × 4.6 mm, 5 µ m

223 nm

2008 [40]

27.

Lopinavir

API; anti-HIV

8 related impurities

210 nm

2008 [41]


29 impurities

GC-FID

2008 [42]

API; antiischemic


C18, 250 mm × 4.6 mm, 5 µ m Capillary, 30 m × 0.32 mm × 1. 0 µ m Amino, 100 mm × 3.2 mm, 3 µ m; cyano, 100 mm × 2. 1 mm, 5 µ m; silica, 100 mm × 2.1 mm, 3 µ m; sulfobetaine, 100 mm × 2.1 mm, 5 µ m C18, 100 mm × 4.6 mm, 3 µ m

ACN: CH3 COONH4 (20 mM, pH 3) (20:80) Eluent A: H2 O (0.1% formic acid); Eluent B: ACN (0.1% formic acid); gradient Eluent A: TFA (0.1%); Eluent B: ACN; gradient KH2 PO4 (0.02 M, pH 2.5): ACN; gradient Nitrogen gas ACN:HCOONH4 (5 mM, pH 5) (85:15)

Electrospray interface detector

2008 [43]

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

225 nm

2008 [44]

196, 230 and 296 nm

2008 [25]

200–500 nm

2008 [45]

196, 230 and 296 nm

2008 [25]

227 nm

2008 [46]

28. 29.

Methamphetamine Mildronate


30.

Montelukast sodium

API; antiallergic

4 impurities

31.

Mouse obestatin

API; antibodies

3 impurities

C18, 250 mm × 4.6 mm, 5 µ m

32.

Moxifloxacin

API; antibacterial


C18, 250 mm × 4.6 mm, 5 µ m; C18, 150 mm × 6 mm, 5 µ m; C18, 250 mm × 4. 6 mm, 5 µ m

33.

Ovine obestatin

API; antibodies

5 impurities

C18, 250 mm × 4.6 mm, 5 µ m

34.

Paclitaxel

API; anticancer

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

Phenyl, 150 mm × 4.6 mm, 3 µ m

16


Table 2 Continued

S. no.

Impurity/degradant


Mobile phase

Detection

Year [Ref.]

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

11 impurities

ASH, 250 mm × 4.6 mm, 5 µ m

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

254 nm

2008 [47]

4 impurities

Cyano, 250 mm × 4.6 mm, 5 µ m

37.

Pridinol mesylate

API; muscle relaxant

2 degradant

C18, 250 mm × 4.6 mm, 5 µ m

38.

Primaquine phosphate Primaquine phosphate Salicylaldehyde isonicotinoyl hydrazone

API; antimalarial

2 impurities

API; antimalarial

2 impurities

API; chelating agent

41.

Tamsulosin

42.

Tazarotene

Capsule, tablet and API; antihypertensive API; anti-Acne

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

C18 (BEH), 50 mm × 2.1 mm, 1.7 µ m C18, 250 mm × 4.6 mm, 5 µ m C18, 250 mm × 4.6 mm, 5 µ m

43.

Tenatoprazole

API; peptic ulcer

6 degradants

44.

Levofloxacin

API; antibacterial

3 process related impurities and 1 oxidative degradant

C18, 250 mm × 4.6 mm, 5 µ m

45.

Aalicylic acid and betamethasone dipropionate

Lotion; anti-inflammatory

C8, 150 mm × 4.6 mm, 4 µ m

46.

Anastrozole

Tablet; anti-cancer

Salicylic acid related: 7 betamethasone dipropio-nate related: 15 potential leachables: 5 5 impurities

47.

Biapenem

API; antibiotic

4 impurities

48.

API; antimalarial

4 process related impurities

49.

Chloroquine and hydroxychloroquine Citalopram

API; antidepressant

1 impurity

50.

Cyclosporin A

51.

Diacerein

Soft gelatin capsules; Immunomodulator API; antiarrtheritis

4 degradants and 2 related compounds 2 related impurities

52.

Eletriptan

API; antimigraine

1 degradants (oxidative)

C18, 150 mm × 3.9 mm, 5 µ m

53.

Fatty alcohol ethoxylates

Surfactant

6 impurities

C1, 4.6 mm × 150 mm

54.

Gentamicin

API; antibiotic


Hydro-RP, 250 mm × 4.6 mm, 5 µ m

55.

Heparin sodium

API; anticoagulant

6 impurities

AS11-HC, 250 mm × 4 mm, 9 µ m

56.

Ibuprofen

API; analgesic

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

35.

36.

39. 40.

Name of drug


2 by-product

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

C3, 250 mm × 4.6 mm, 5 µ m C18, 4.6 mm × 150 mm, 5 µ m C18, 250 mm × 4.6 mm, 5 µ m C18, 100 mm × 30 mm 5 µ m C18, 250 mm × 4 mm, 5 µ m C18, 250 mm × 4.6 mm, 5 µ m

2008 [48] Tetramethylammonium Electrochemihydroxide (4.53 g/L, cal pH 6.4):ACN (6:4) detection 220 nm MeOH:IPA:potassium phosphate (50 mM, pH 6.0) (51:9:40) TFA (0.01%):ACN 265 nm (75:25) TFA (0.01%): ACN 265 nm (75:25) Phosphate buffer LC–ESI-MS (10 mM + 2 mM EDTA, pH 6):MeOH (40:60)

2008 [49]

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

CH3 COONH4 (10 mM):ACN; gradient Helium gas

280 nm

2008 [52]

MS detection

2008 [53]

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

306 nm

2009 [54]

294 nm

2009 [55]

240 nm

2009 [56]

H2 O:ACN; gradient

215 nm

2009 [57]

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

220 nm

2009 [58]

220 nm

2009 [59]

225 nm

2009 [60]

220 nm

2009 [61]

254 nm

2009 [62]

225 nm

2009 [63]

ELSD detector

2009 [64]

ESI/MSn detection

2009 [65]

215 nm

2009 [66]

220 and 285 nm

2009 [67]

17


Table 2 Continued

S. no.

Name of drug


57.

Icofungipen

API; antifungal

58.

Lamivudine

API; anti-HIV

59.

Lansoprazole

60.

Year [Ref.]

Impurity/degradant


Mobile phase

Detection

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

C18, 100–5 AB

ACN:H2 O (25:75)

210 and 254 nm

2009 [68]

C18, 250 mm × 4.6 mm, 5 µ m

277 nm

2009 [69]

API; peptic ulcer

5 enantiomers and related impurities

Chiral, 250 mm × 4.6 mm

310 nm

2009 [70]

Metformin

Tablet; antidiabetic

Related compound: 1-cyanoguanidine

Nova-Pak silica, 150 mm × 3. 9 mm, 4 µ m

232 nm

2009 [71]

61.

Moxifloxacin HCl

API; antibacterial

4 synthesis-related impurities

C18, 50 mm × 4.6 mm, 5 µ m

290 nm

2009 [72]

62.

Nevirapine analogue

API; anti-HIV

3 impurities

Cyano, 4.6 mm × 150 mm, 5µ m

ESI/MSn detection

2009 [73]

63.

Nimodipine

3 impurities

2009 [74]

Norethisterone

API; analgesic

66.

Phenazopyridine HCl Pridinol mesylate

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

ESI/MSn detection 254 nm

2009 [75]

65.

C8, 250 mm × 4.6 mm, 5 µ m C18, 50 mm × 2.1 mm, 5 µ m C3, 250 mm × 4.6 mm, 5 µ m C18, 250 mm × 4.6 mm, 5 µ m

236 nm

64.

Tablet; antihypertensive Tablet; steroid

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

245 nm

2009 [77]

67.

Puerarin

Injection; vasodilator

9 impurities

250 nm

2009 [78]

68.

Rizatriptan benzoate

API; antimigraine

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

225 nm

2009 [79]

69.

Ropinirole HCl

API; anti-Parkinsons

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

X-BridgeTM , 3 mm × 100 mm, 3.5 µ m

250 nm

2009 [80]

70.

Salidroside

API; antidepressant

3 impurities

275 nm

2009 [81]

71.

Sertraline

API; antidepressant

9 impurities

2009 [82]

Taranabant

API; anti-obesity

6 impurities

220 nm

2009 [83]

73.

Tropicamide

API; ophthalmology

3 impurities

TFA (0.4%):ACN (80:20) H3 PO4 in H2 O (0.1%):ACN; gradient MeOH:H2 O (30:70)

225 nm

72.


Potassium phosphate buffer (50 mM, pH 6.4):MeOH:2propanol (20:69:11) Formic acid (0.1%): MeOH; gradient Ammonium dihydrogen ortho-phosphate (20 mM) + 2 ml TEA (pH 2): ACN; gradient ACN:sodium heptane sulfonate (5 mM) (21.6:78.4) (pH 2) MeOH:H2 O (13:87)

2009 [84]

74.

Valsartan


5 impurities

225, 247 and 257 nm 210 nm

75.

Zafirlukast

API; antiasthamatic

5 impurities

C18, 250 mm × 4.6 mm, 5 µ m

220 nm

2009 [86]

76.

Zotarolimus

Coated stents; immunomodulator

3 degradant

C8, 250 mm × 4.6 mm, 5 µ m

278 nm

2009 [87]

API, tablet, injection, Patches; antihypertensive

19-Norandrostenedione

C18, 250 mm × 4.6 mm, 5 µ m C8, 250 mm × 4.6 mm, 5 µ m

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

H2 O:ACN (25:75)

Elunent A: CH3 COONH4 (10 mM, pH 3.0) Eluent B: H2 O:ACN (1:4); gradient Eluent A: phosphate buffer + 1-decane sulfonic acid sodium (pH 4): MeOH (85:15); Eluent B: ACN:MeOH:H2 O (85:10:5) CH3 COONH4 (10 mM, pH 3.8): ACN; gradient

2009 [76]

2009 [85]

18


Table 2 Continued

S. no.


Impurity/degradant


Mobile phase

Detection

Year [Ref.]

API; antiplatelet

2 impurities

C18, 250 mm × 20 mm, 5 µ m

MeOH:H2 O (55:45)

210 nm

2010 [88]

78.

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

API; diuretics

1 degradant and 4 process-related impurities

C18, 250 mm × 4.6 mm, 5 µ m

254 nm

2010 [89]

79.

Acetylspiramycin

API; antibiotics

C18, 250 mm × 4.6 mm, 5 µ m

232 nm

2010 [90]

80.

Albuterol sulfate and ipratropium bromide

Nasal solution; anti-asthamatic

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

Eluent A: NaH2 PO4 (0.02M, pH 3.0):ACN (950:50); Eluent B: H2 O:ACN (150:850); gradient ACN:CH3 COONH4 (0.1 M, pH 7.2) (50:50) Eluent A: KH2 PO4

210 nm

2010 [91]

81.

Alizapride

API; antiemetic

2 degradants

C18, 150 mm × 4.6 mm, 5 µ m

82.


API; anti-hyperlipidemic

4 impurities

C18, 150 mm × 4.6 mm, 3.5 µ m

83.

Barnidipine


4 degradants

C18, 250 mm × 4.6 mm, 5 µ m

84.

Clopidogrel bisulfate

API and tablet; antiplatelet

5 impurities

Chiral, 250 mm × 4.6 mm, 5 µ m

85.

CU201(antitumor peptidic dimer)

API; anticancer

11 forced degradants and 3 impurities

C8, 150 mm × 4.6 mm, 3 µ m

86.

Desloratadine

Tablet; antiallergic

5 impurities and forced degradants

C18 (BEH), 50 mm × 2.1 mm, 1.7 µ m

87.

Duloxetine HCl

API; antidepressant


C18, 250 mm × 4.6 mm, 5 µ m

88.

Enalapril maleate


Several degradation impurities

RP-S, 250 mm × 4.6 mm, 5 µ m

89.

Eprosartan


Impurity: dibenzoic acid

C2, 250 mm × 4.6 mm mm, 5 µ m

90.

Escitalopram

API; antidepressant

3 process-related impurities

C18, 150 mm × 4.6 mm, 3 µ m

91.

Ezetimibe

Process-related impurity

92.

Felbamate

API; anti-hyperlipidemic API and tablets; antiepileptic

C18, 250 mm × 4.6 mm, 5 µ m C18 (BEH), 100 mm × 2.1 mm, 1.7 µ m

77.

Name of drug

3-Hydroxy-2-phenylpropyl carbamate and 2-Phenyl-propane-1,3-diol

C8, 250 mm × 4.6 mm, 5 µ m

+

Heptane-1-sulfonic acid sodium salt in H2 O (pH 4); Eluent B: ACN; gradient Eluent A: 225 nm CH3 COONa buffer (20 mM, pH 4); Eluent B: MeOH; gradient Eluent A: HCOONH4 246 nm (pH 4, 10 mM):ACN (60:40); Eluent B: ACN; gradient ACN:phosphate 250 nm buffer (pH 7) (75:25) n240 nm Hexane:ethanol:diethyl amine (95:5:0.05) Eluent A: H2 O (0.1% 266 nm formic acid); Eluent B: ACN (0.1% Formic acid), gradient Eluent A: 280 nm KH2 PO4 buffer (10 mM, pH 2.5):MeOH:ACN (80:15:5); Eluent B: buffer:THF: ACN (30:5:70) Eluent A: KH2 PO4 230 nm (10 mM + 0.2% TEA, pH 2.5); Eluent B: ACN:MeOH (20:80); gradient Eluent A: phosphate 215 nm buffer (20 mM, pH 6.8): ACN (95:5); Eluent B: phosphate buffer (20 mM, pH 6.8):ACN (34:66); gradient Eluent A: TEA buffer 234 nm (pH 3); Eluent B: ACN; gradient HCOONH4 (1.5 240 nm g/1000 ml H2 O):ACN; gradient H2 O:ACN; gradient 232 nm KH2 PO4 buffer (pH 3.5):MeOH (68:32)

210 nm

2010 [92]

2010 [93]

2010 [94]

2010 [96]

2010 [97]

2010 [98]

2010 [99]

2010 [100]

2010 [101] 2010 [102] 2010 [103] 2010 [104]

19


Table 2 Continued

S. no.

Name of drug


Impurity/degradant


Mobile phase

Detection

93.

Fentanyl

API; analgesic

16 impurities

C18, 150 mm × 3.0 mm, 5 µ m

215 nm

2010 [105]

94.

Filgrastim

API; hematopoietic stimulator

5 impurities

C8, 250 mm × 4.6 mm, 5 µ m

215 nm

2010 [106]

95.

GW876008 (corticotropinrelease factor 1 antagonist)

API; antidepressant

4 impurities

C8, 150 mm × 4.6 mm, 3.5 µ m

220 nm

2010 [107]

96.

l

-Aspartic acid and l-alanine

API; food supplement

C3, 150 mm × 4.6 mm, 5 µ m

CAD detection

2010 [108]

97.

Omeprazole

API and tablets; peptic ulcer

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

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

299 nm

2010 [109]

98.

Orlistat

Capsules; anti-obesity

18 impurities

C18, 4.6 mm × 150 mm, 5 µ m

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 µ m

220 nm

2010 [111]

100.

Pentoxifylline

API; antidiabetic

3 degradants

C18, 250 mm × 4.6 mm, 5 µ m

274 nm

2010 [112]

101.

Piracetam

4 impurities

Pregabalin

C18, 250 mm × 4.6 mm, 10 µ m C8, 250 mm × 4.0 mm, 5 µ m

205 nm

102.

API; neurovascular enhancer API and tablet; antipsychotic

2010 [113] 2010 [114]

103.

Rabeprazole sodium

API; peptic ulcer

Methylthio impurity of rabeprazole

C8, 150 mm × 4.6 mm, 5 µ m

104.

Raltegravir

API; anti-HIV

5 impurities

105.

API; anti-HIV

9 impurities

106.

RG7128 (HCV polymerase inhibitor) Rifaximin

C18, 250 mm × 4.6 mm, 5 µ m C18, 100 mm × 19 mm, 5 µ m

API; antibiotic

1 impurity

107.

Ritonavir

API; anti-HIV

21 degradants

108.

Sertraline

API; antidepressant

3 non-chiral related impurities

109.

Valsartan


7 degradants

C18 (BEH), 100 mm × 2.1 mm, 1.7 µ m

110.

Vestipitant

API; antiemetic

3 biphenyl impurities

C18, 150 mm × 4.6 mm, 5 µ m

111.

Abacavir

API; anti-HIV

8 degradants

112.

ALB 109564

API; anticancer

4 impurities

C18, 250 mm × 4.6 mm, 5 µ m C18, 250 mm × 10 mm, 5 µ m

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

215 nm

2 impurities

Chiral, 250 mm × 4.6 mm, 10 µ m

C18, 150 mm × 19 mm, 5 µ m C18, 250 mm × 4.6 mm, 5 µ m C18, 150 mm × 4.6 mm, 5 µ m

345 and 450 nm

Year [Ref.]

284 nm

2010 [115]

240 and 304 nm 276 nm

2010 [116] 2010 [117]

276 nm

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

210 nm 220 nm

225 nm

2010 [121]

254 nm

2010 [122]

220 nm

2011 [123] 2011 [124]

20


Table 2 Continued

S. no.

Name of drug


Impurity/degradant


Mobile phase

Detection

113.

Anastrozole

API; anticancer

3 degradant

Artemisinin

API; antimalarial

115.

Atazanavir sulfate

API; anti-HIV

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

116.

Auraptene

API; immunomodulator

5 impurities

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

215 nm

114.


117.

Boron phenylalanine

API; anticancer

4 impurities

230, 256 and 270 nm

118.

Candesartan cilexetil Carbamazepine

API; antibiotics

Process related impurity

API; antiepileptic

7 impurities

120.

Casopitant mesylate

API; antidepressant and antiemetic

De-fluorinated casopitant mesylate analogue

121.

Ciclesonide

4 degradants

C18, 250 mm × 4.6 mm, 10 µ m

242 nm

2011 [133]

122.

Colistin (Polymyxin E)

API and metered dose inhalers; antiasthamatic API; antibiotic

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

35 impurities

C18, 250 mm × × 4.6 mm, 5 µ m

215 nm

2011 [134]

123.

Entacapone


4 forced degradants

C18, 250 mm × 4.6 mm, 5 µ m; C3, 250 mm × 4.6 mm, 5 µ m

310 nm

2011 [135]

124.

Etimicin sulfate

API; antibiotic

6 impurities

C18, 150 mm × 4.6 mm, 5 µ m

ELSD

2011 [136]

125.

Ezetimibe


5 degradation and process-related impurities

C18, 150 mm × 4.6 mm, 5 µ m

210 and 235 nm

2011 [137]

126.

Febuxostat

API; anti-gout

4 impurities

C18, 150 mm × 4.6 mm, 5 µ m

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

315 nm

2011 [138]

127.

Fesoterodine

API; antispasmodic

5 degradants

C18, 100 mm × 4.6 mm, 5 µ m

128.

API; antidiabetic


C18, 250 mm × 4.6 mm, 5 µ m

129.

G004 (hypo-glycaemic agent) Gentamicin

API; antibiotic

5 impurities

C18, 50 mm × 4.6 mm, 1.8 µ m

130.

Lactic acid

11 impurities

131.

Larotaxel

Sugarcane juice; humectants API; anticancer

132.

Lincomycin and spectinomycin

API; antibiotic

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

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

119.

5 Related impurities

C18, 150 mm × 4.6 mm, 5 µ m C18, 150 mm × 4.6 mm, 5 µ m

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

DAD/MS 250 nm

324 nm

210 nm 230 nm LC/MS/MS

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

ESI/MSn detection

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

2011 [128] 2011 [129]

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

2011 [139]

2011 [140] 2011 [141]

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

21


Table 2 Continued

S. no.

Name of drug


Impurity/degradant


Mobile phase

Detection

133.

Lornoxicam

API; analgesic

Degradants

C18, 250 mm × 4.6 mm, 5 µ m

MS detector

2011 [144]

134.

Memantine

Tablets; anticancer

Maillard reaction impurities

Hydro RP, 100 mm × 3 mm, 2.5 µ m

CAD detection

2011 [145]

135.

Meprobamate

API; antipsychotic

C18, 250 mm × 4.6 mm, 5 µ m

200 nm

2011 [146]

136.

Mometasone furoate Mometasone furoate

API; steroid

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

KH2 PO4 buffer (10 mM, pH 3.3):MeOH; gradient Heptafluoro buturic acid (0.6%):ACN: isopropyl alcohol:H2 O; gradient H2 O:ACN (8:2)

H2 O:ACN; gradient

245 nm

API; steroid

8 impurities

Carbon dioxide (SFC grade)

245 nm

2011 [147] 2011 [147]

138.

Naproxen

API; analgesic

2011 [148]

Olanzapine

API and drug product; antipsychotics

220 nm

2011 [149]

140.

Olanzapine

API and tablet; antipsychotics

8 degradants

C18 (BEH), 100 mm × 2.1 mm, 1.7 µ m

250 nm

2011 [150]

141.

Olaquindox

API; anti-amoebic

12 degradants

200–400 nm

142.

Palonosetron HCl

API; antiemetic

9 degradants

C18, 150 mm × 2 mm, 5 µ m π Nap, 250 mm × 4. 6 mm, 5 µ m

2011 [151] 2011 [152]

143.

Perindopril tert-butylamine


4 impurities

C4, 4.6 mm × 250 mm, 5 µ m

144.

Phosphorothioate oligonucleotides

API; diagnostic agent

5 synthesis impurities

C18 (BEH), 1 mm × 150 mm, 3.5 µ m

145.

Polymyxin B

API; antibiotic

38 impurities

C18, 250 mm × 4.6 mm, 5 µ m

146.

Streptomycin sulfate Sulindac

API; antibiotic

21 impurities

API; analgesic

E-sulindac, sulfide and sulfone form

YMCPack Pro, 250 mm × 4.6 mm; 3 µ m C18, 53 mm × 7 mm, 1.5 µ m

Ursodeoxycholic acid Valsartan

API; billiary cirrhosis



2 photodegradant

CH3 COONa (40 mM, pH 4.7):MeOH (60:40) EDTA disodium salt dihydrate (50 mM, pH 3):ACN (6:4) Eluent A: NaH2 PO4 (20 mM) buffer (pH 6.8): ACN: MeOH (5:2:3) Eluent B: H2 O: ACN (1:9) HCOOH (0.1%): ACN; gradient Eluent A: Phosphate buffer (20 mM + 2 ml TEA, pH 2.5); Eluent B: phosphate buffer: ACN (50:50); gradient Butyl acetate (0.24%) + ethyl acetate (0.30%) + SDS (2%) + n-butanol (7.75%) + dihydrogen phosphate (20 mM, pH 3.7) Eluent A: TEA (16 mM) + HFIP (400 mM, pH 7.0) in H2 O; Eluent B: TEA (16 mM) + HFIP (400 mM) in MeOH; gradient ACN:sodium sulfate (4.46 g/l, pH 2.3) (20:80) + 10% phosphoric acid PFPA (20 mM): acetone (99:1) ACN: phosphate buffer (pH 2, 10 mM); gradient Acetic acid: MeOH (0.1%) (30:70) ACN: KH2 PO4 (20 mM, pH 3) (40:60)

254 nm

139.

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

137.

147.

148. 149.

C18, 250 mm × 4.6 mm mm, 5 µ m C18, 250 mm × 4.6 mm, 5 µ m; 2-ethyl-pyridine: 250 mm × 4. 6 mm, 5 µ m;Cyano: 250 mm × 4.6 mm, 5 µ m C18, 100 mm × 4.6 mm, 5 µ m C8, 250 mm × 4.0 mm, 4 µ m

C18, 150 mm × 4.6 mm, 5 µ m Cyano, 250 mm × 4.6 mm, 5 µ m

210 nm

Year [Ref.]

215 nm

2011 [153]

LC–MS/MS

2011 [154]

215 nm

2011 [134]

CAD/MS Detection 340 nm

2011 [155] 2011 [156]

RI detection

2011 [157] 2011 [158]

226 nm

22


Table 2 Continued

S. no.

Name of drug


Impurity/degradant


Mobile phase

Detection

150.

Zafirlukast

API; antiasthamatic

8 impurities

C18, 250 mm × 4.6 mm, 5 µ m

220 nm

2011 [159]

151.

Rapamycin

API; immunomodulator

9 degradant

Diol-120-NP, 250 mm × 4.6 mm, 5 µ m

278, 248, 230 and 210 nm

2012 [160]

152.

4-Methyl thioamphetamine


22 impurities

Capillary, 30 m × 0.25 mm, 0.25 µ m

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

2012 [161]

153.

Halobetasol propionate Artemisinin

API; steroids

Acetamide and arylsulfonate Extract residue impurities

C18, 100 mm × 2.10 mm, 2.6 µ m C18, 250 mm × 4.6 mm, 5 µ m

ACN:H2 O; gradient

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

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

220 nm

2012 [165]

318 nm

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

154.

Artemisia annua extracts; antimalarial

155.



7 impurities

C18, 250 mm × 4.6 mm, 3.5 µ m

156.

Azelnidipine

Solution; anti-hypertensive

4 degradants

C18, 100 mm × 4.6 mm, 3 µ m

157.

Benzopyridooxathiazepine Bupropion hydrochloride Caffeine

API; anticancer

10 degradants

API and tablets; Anti-depressant API; stimulant

Alkaline degradates, 3-chlorobenzoic acid 4 impurities

C18, 150 mm × 2.1 mm, 3 µ m C18, 4.6 mm × 150 mm, 5 µ m C18, 150 mm × 4.6 mm, 5 µ m, 29 columns; Others, 150 mm × 4. 6 mm mm, 5 µ m, 6 columns C18, 250 mm × 4.6 mm; 5 µ m C18, 200 mm × 4.6 mm, 5 µ m C8, 250 mm × 4.6 mm, 5 µ m

158. 159.

160.

Cefditoren pivoxil

161.

Clocortolone pivalate Cloperastine fendizoate

162.

API and tablet; Antibiotic API; steroid

1 degradants

API; cough relaxant

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

3 impurities

163.

Deferasirox

API; Antidote of Iron

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

C8, 250 mm × 4.6 mm, 5 µ m

164.

Desvenlafaxine

API and tablet; Antidepressant

1 degradants (acid)

C18, 250 mm × 4.6 mm, 5 µ m

165.

Diltiazem HCl


166.

Dipyridamole

API and tablet; Anti-hypertensive API; antiplatelet

C18, 150 mm × 4.6 mm, 5.0 µ m C2, 150 mm × 4.6 mm, 5 µ m

167.

Eslicarbazepine acetate

API; antiepileptic

15 impurities

2 impurities

C8, 250 mm × 4.6 mm, 5 µ m

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

210 nm 275 nm

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

ACN:H2 O (50:50)

218 nm

ACN:H2 O (70:30)

254 nm

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

227 nm

Year [Ref.]

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

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

LC–ESI-QT/ MS/MS

2012 [172]

228 nm

2012 [173]

240 nm

2012 [174] 2012 [175]

295 nm

215 nm

2012 [176]

23


Table 2 Continued

S. no.

Name of drug


Impurity/degradant


Mobile phase

Detection

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

305 nm

2012 [177]

ESI/MSn detection

2012 [178]

240 and 282 nm

2012 [179]

190–400 nm

2012 [180]

222 nm

2012 [181]

237 nm

2012 [182]

ESI/MSn detection

2012 [183]

ESI/MSn detection

2012 [183]

ESI/MSn detection

2012 [183]

ESI/MSn detection

2012 [183]

254 nm

2012 [184]

296 nm

Helium gas

Mass selective detector

2012 [185] 2012 [186]

168.

Esomeprazole magnesium

Tablets, pepetic ulcer

7 impurities

C18 (BEH), 50 mm × 2.1 mm, 1.7 µ m

169.

Etimicin sulfate

API; antibiotic

26 impurities

C18, 250 mm × 4.6 mm, 5 µ m

170.

Fampridine

API; agent multiple sclerosis

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

C18, 250 mm × 4.6 mm, 5 µ m

171.

Glucocorticoids

API; steroid

4-Dimethyl aminopyridine

C18, 50 mm × 2 mm, 3 µ m

172.

Guaifenesin, terbutaline sulfate and ambroxol HCl

Cough syrup; cough relaxant


C18, 250 mm × 4.6 mm, 5 µ m

173.

Imatinib mesylate

Capsules; anticancer

8 impurities

C18 (BEH), 50 mm × 2. 1 mm, 1.7 µ m

174.

l

-Alanyl-lglutamine

API; food supplement

5 impurities

C18, 150 mm × 3 mm, 3 µ m

175.

l

-Alanyl-lglutamine

Infusion solution; food supplement

9 impurities

Polysulfoethyl A, 150 mm × 4. 6 mm, 5 µ m

176.

l

-Alanyl-lglutamine


7 impurities

QN-AX, 150 mm × 4 mm, 5 µ m

177.

l

-Alanyl-lglutamine


7 impurities

QN-AX, 150 mm × 4 mm 5 µ m

178.

Linezolid

API; antibiotic

6 impurities

Chiral, 250 mm × 4.6 mm, 5 µ m

179.

Luliconazole

API and cream; antifungal API; psychostimulant

6 degradants

C18, 250 mm × 4.6 mm, 5 µ m Capillary, 30 m × 0.32 mm × 1. 0 µ m

180. Methamphetamine

20 impurities

Year [Ref.]

24


Table 2 Continued

S. no.

Name of drug


Impurity/degradant


Mobile phase

Detection

181.

Moxonidine

Tablet; antihpertensive

5 impurities

C18, 250 mm × 4.6 mm, 5 µ m

255 nm

2012 [187]

182.

Nevirapine

API; anti-HIV

2 impurities

ABZ, 150 mm × 4.6 mm, 5 µ m

220 nm

2012 [188]

183.

Niacinamide

API; vitamin

C18, 250 mm × 4.6 mm, 5 µ m

254 nm

2012 [189]

184.


C18, 250 mm × 4.6 mm, 5 µ m

Phosphoric acid (pH 3.5):ACN (51:49)

210 nm

2012 [190]

185.

Nonpeptide (angiotensin AT1 receptor antagonist) Pantoprazole

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

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

C18, 50 mm × 4.6 mm, 3 µ m

CH3 COONH4 (10 mM):ACN (79:21)

210 nm

2012 [191]

186.

Plazomicin

API; antibiotic

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

Praziquantel

2 impurities

188.

Rivastigmine tartrate

API andTablet; Anthelmintic API; anti-Alzheimer

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

189.

Ropinirole


5 degradants

Silica gel 60F-254

190.

Nanoemulsion; antiprotozoal API; antioxidant

2 degradants

C18, 150 mm × 4 mm, 5 µ m C18, 250 mm × 4.6 mm, 5 µ m

192.

SCD: chalcone derivative Sodium tanshinone IIA sulfonate Telmisartan


C18, 125 mm × 4.6 mm, 5 µ m

193.

Thiocolchicoside

API; muscle relaxant

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

194.

Trandolapril


16 degradants

C18 (BEH), 138 mm × 2.1 mm, 1.7 µ m

195.

Wogonin

API; anxiolytic

2 degradants

C18, 250 mm × 4.6 mm, 5 µ m

196.

Zolmitriptan

API; antimigraine

6 impurities

Phenyl, 100 mm × 3 mm, 2.7 µ m

197.

Bortezomib

API; anticancer

3 impurities

C18, 250 mm × 4.6 mm, 5 µ m

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

210 nm

187.

C18, 4.6 mm × 150 mm, 3.5 µ m Silica, 4.0 mm × 125 mm, 100/5 µ m C18, 250 mm × 4.6 mm, 5 µ m

191.

API; peptic ulcer

11 impurities

8 impurities

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

C18, 250 mm × 4.6 mm, 5 µ m

210 nm 210 nm

Year [Ref.]

250 and 254 nm

2012 [195]

330 nm

2012 [196] 2012 [197]

271 nm

230 nm

2012 [198]

MS/MS Detection

2012 [199]

190 and 500 nm

2012 [200]

275 nm

2012 [201]

220 nm

2012 [202]

270 nm

2012 [203]

has shown (Fig. 3) that structure of impurity and drug related to each other with difference of peak at 1681 cm−1 and 2229 cm−1 from C O and C N, respectively [60]. Principally, cyclosporin A is used as immunosuppressive agent for prophylaxis against allograft rejection after organ transplantation. Impurities of ® this agent in Neoral capsules and its generic versions were determined [61]. Two monoacylated diacerein impurities of diacerein with same molecular weight (M W = 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 characterized as 5-acetoxy-4-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2carboxylic acid (1.14%) and 4-acetoxy-5-hydroxy-9,10-dioxo-9,10dihydroanthracene-2-carboxylic acid (1.24%) [62]. Polyethylene glycol (PEG) present as impurity in fatty alcohol ethoxylates(FAEs) which are used as surfactants. Gradient elution favor the separation of PEG and FAEs as these have dramatic difference in hydrophobicity of PEG and FAEs, while evaporative light scattering detection (ELSD) is not compactable with gradient elution, so both isocratic and gradient elution were used to study the same [64]. Atmospheric pressure chemical ionization (APCI) of mass spectroscopy was applied for identification of gentamicin impurities, where no suppression in ionization was observed at high TFA concentration [65]. Over sulfated chondroitin sulfate (OSCS) and dermatan sulfate were estimated in heparin API by using a polymer-based strong anion exchange (SAX) column with gradient elution form, which were present due to over sulfating and incomplete purification, respectively [66]. As zirconiabased stationary phase coated with graphitized carbon offers wide pH and temperatures range for separation, was applied to analyze 3[4-(2-methylpropyl)phenyl]propanoic acid as an impurity of ibuprofen [67]. Salidroside is phenolic glycoside of genus Rhodiola, used for treatmentof cardiovascularand cerebrovasculardiseases. The biosynthetic pathways for impurities icariside D2, 4-hydroxyphenacyl-dglucopyranoside and picein were proposed [81]. Column packed with dimethyl beta-cyclodextrinused as chiral stationary phases, was used to determine related enantiomeric impurities of sertraline as it minimizes chiral hydrogen bonding and establishes weak dipole effect for high selectivity of separation [82]. Off-line 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 tenatoprazole (novel proton pump inhibitor) was carried out to establish 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 sensitive towards acidic/alkaline degradation, in this sequence, impurities 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 zotarolimus coated stents has revealed that coated stunt should protect from moisture and heat, as these produce different type of degradants [87].

2.1.2.3. Impurity and forced degradation profiling Anti-inflammatory lotion containing betamethasone dipropionate and salicylic acid was

25

analyzed by stability-indicating HPLC method, where 27 analytes were determined including salicylic acid and betamethasone dipropionate related compounds [56]. As per ICH guidelines, anastrozole, its potential impurities and degradation products were determined in tablet dosage form, which consists1% of API as anastrozole[57]. Mechanistic 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 metformin hydrochloride and 1-cyanoguanidine in tablet by using isocratic elution as per USP requirements for new methods for assay determination [71]. Formation of impurity of nevirapine analogue HIV-non-nucleoside reverse transcription inhibitor was established as by-product of side reaction, which was confirmed by a series of photo- and oxidative stress studies [73]. Impurities were identified and elucidated in taranabant (anti-obesity agent) prepared by cyanuric chloride-mediated coupling reaction (end-game synthesis) and forced degradation revealed that impurities were unstable compared to drug [83]. Five related impurities of valsartan (antihypertensive drug) and five impurities including two regioisomers of zafirlukast were identified, characterized, synthesized and their synthetic pathways 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 factor antagonist. Two related impurities were characterized as 10-O-(N,N-dimethylaminoethyl)-11,12-seco-ginkgolide B and 10-O-(N,N-dimethylaminoethyl)-11,12,2,15-diseco-3,14-dehydroginkgolide B [88]. Complexity of acetylspiramycin was revealed by LC/MSn investigation, where 31 unknown and 17 known impurities were identified. These impurities were raised due to starting materials and synthetic process [90]. Number of related impurities in albuterol sulfate and ipratropium bromide was determined in nasal solution [91]. Ion trap and Q-TOF mass analyzer were employed to determine mass of unknown impurities of ecitalopram which is used as antidepressant. Spectral data of 1 H and 13 C NMR were used to elucidate the structure of impurities which was 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 techniques 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]. Postcolumn 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-1H -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

26


(0.05–0.10%) were identified and purified by heart-cut and recycle chromatographic techniques [117]. Combined application of liquid chromatography, NMR and high resolution NMR was employed for characterization of mutagenic impurities in vestipitant. Starting material for the synthesis was identified as root cause of impurities [122].

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

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

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

and spectinomycin in the presence of their impurities in pharmaceutical formulation [141]. Carboxylic acid impurities as pyruvic, oxalic, formic, succinic, itaconic, aconitic, acrylic, citric, propionic and fumaric acids were quantify in lactic acid prepared from fermentation of sugarcane juice and compared to commercial samples while acetic, malic and butyric acids were not observed in any of sample [142]. Four Maillard reaction (reaction between amino compounds and reducing sugar, Fig. 4) impurities without chromophore were determined as memantine-lactose, 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-(6methoxynaphthalen-2-yl) acrylic acid as unknown polar impurity of naproxen was found by Ames test (biological assay method) using Salmonella typhimurium [148]. MELC offers UV detection near 200 nm, proteins solubilization in complex matrices and fast analysis time. Impurities in streptomycin sulfate was determined by reversed phase ion-pair HPLC method using charged aerosol detection at the level of 4.6% and 16.0%, which offers straightforward 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 candidates is boron phenylalanine, which is used in large dose. Boron phenylalanine was found to be more prone to alkali, oxidative and acidic degradation, where mannitol-mediated degradation to phenylalanine has been observed in lyophilized samples of mannitol-drug [129]. Desisobutyryl-ciclesonide was identified as hydrolytic degradation product of inhaled corticosteroids ciclesonide, which was due to presence of ester linkage, while stable in oxidation, thermal and


photolysis conditions [133]. Intrinsic stability of fesoterodine was established according to ICH guidelines by forced degradation [139] and 1-(4-(2-(2-bromobenzenesulfonamino)ethyl)phenylsuphonyl)3-(trans-4-methyl cyclohexyl) urea was characterized as impurity of G004, a sulfonylurea derivative potential hypoglycaemic agent [140]. Major forced degradation product of lornoxicam was formed due to amide hydrolysis and oxygen addition across the enolic double bond [144]. Anti-HIV drugs, abacavir sulfate and atazanavir sulfate and anti-cancer drug anastrozole were studied to understand the forced degradation behavior under different stressed conditions [147,149]. Olanzapine and its degradation products were determined in API and pharmaceutical dosage forms [150], while its oxidative degradation impurities were characterized as hydroxymethylidene thione and acetoxymethylidene thione [149]. Different forced degraded samples of olaquindox were studied by HPLC combined with hybrid ion trap/time-of-flight mass spectrometry and especially its degradation products were correlated with its phototoxicity and photoallergic reaction [151]. Two photo-degraded products of valsartan were characterized as: N-[2 -(1H -tetrazol-5-yl)-biphenyl-4ylmethyl]-N-isobutylpentanamideformed by decarboxylationand 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 antibiotic with lower toxicity has revealed that starting material, synthetic byproducts and degradation products were main source of the impurities [136]. Structure of degradation product and (R,R,S) stereoisomer of ezetimibe were elucidated by different spectroscopy along other impurities and particle size and shape of ezetimibe crystals, while stereochemical purity of ezetimibe was determined by HPLC [137]. 7,8-Cyclopropyl baccatin III, 10-deacetyl larotaxel, 10deacetyl-7,8-cyclopropylbaccatin 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-2carbamoyloxymethyl-2-methyl-pent-3-enyl ester was characterized as process related impurity, which must be controlled to less than 0.05% as per ICH/FDA/EMEA regulatory guidelines due to daily dose of meprobamte is >2 g/day [146]. Cosmosil π nap column containing naphthalethyl stationary phase has been employed to achieve better resolution than conventional column, in between palonosetron hydrochloride, degradation products and its isomeric impurities, which has strong 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 trigger cancer (carcinogen). Acetamide and arylsulfonate are commonly detected potential genotoxic impurities (GTIs) in APIs. Molecularly imprinted polymers were synthesized and used as scavenger resins for removal of acetamide and arylsulfonates from API and halobetasol propionate was used as a model API in rebinding test [162]. Due to regulatory requirements, GTIs analysis is becoming topic of interest in analytical chemistry. In this context, GTIs (alkyl halides and aromatics) and related structurally alerting compounds were analyzed by using polymeric ionic liquids as selective solid-phase microextraction sorbent coatings [205]. Caffeine and its related impurities were used to study 35 columns to classify as per their selectivity [168]. Three impurities of synthetic corticosteroid, clocortolone pivalate were characterized process impurities [170]. Alkyl halide (2chloroethanol) and sulfonate esters (methyl p-toluenesulfonate and

27

2-chloroethyl p-toluenesulfonate) as genotoxic impurities in cloperastine fendizoate were determined by two different chromatographic methods, GC–MS and HPLC-DAD, respectively, due to different physical and chemical properties of these impurities. Fendizoate was removed by strong anion-exchange (SAX)-SPE before GCMS analysis, as a step of sample purification [171]. Although, six impurities were reported in deferasirox, but a new impurity was characterized as 2-[3,5-bis(2-hydroxy-phenyl)-[1,2,4]-triazol-1-yl]-benzoic acid, which can be minimized by controlling the concentration of 2-hydrazino-benzoic acid in 4-hydrazinobenzoic acid [172]. Cross examination by liquid–liquid extraction and solid-phase microextraction [186] and common synthetic impurities identification [161] were reported for impurity profiling in methamphetamine and 4methylthioamphetamine,respectively. Chloromethyl-3,4-dimethoxy pyridine hydrochloride, is generally used as counter-ions to form salt or protecting group appears as genotoxic impurity in APIs. Ammonium acetate was used to improve detection sensitivity of this genotoxic impurity by LC/MS/MS technique, where it increases ionization [191]. High pH mobile phase (pH > 11) with XBridge C18 column was employed for analysis of aminoglycoside plazomicin and its impurities, which allows higher loadings of drug and its impurities. Thus, higher pH of mobile phase compensates lower UV absorption of the drug [192]. Methyl 4 ,4 -dibromo methyl biphenyl-2-carboxylatewas identified as principle synthetic route impurity in telmisartan based on spectral data deriving from 2D-NMR and MS [198]. Zolmitriptandimer was characterized as impurity in zolmitriptan by means of LC– MS and NMR studies which was 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 chromatography (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 identified by forced degradation studies [160]. 2,2 -Azobisisobutyronitrile as a radical initiator was used to understand mechanistic oxidative degradation pathway of azelnidipine in solution, which may be helpful to stabilize its dosage form [165]. Forced degradation behavior of 1-(4-methoxyphenylethyl)-11H -benzo[f]-1,2-dihydropyrido[3,2,c][1,2,5]oxathiazepine5,5 dioxide, new potent anticancer agent was in different stress conditions, where degradation products were elucidated by means of ESI-orbitrap-MS [166]. Stabilityindicating LC methods were reported to determine cefditoren pivoxil and synthetic chalcone derivative, respectively, in presence of degradants formed due to forced degradation [196]. To establish inherent chemical stability of thiocolchicoside, a glycoside of Colchicum autumnale, forced degradation study was performed, where degradation pathways for hydrolytic and oxidative conditions were elucidated [199]. First order kinetic was followed by trandolapril hydrolysis in acidic and neutral conditions and this degradation profile was investigated by two techniques UPLC-DAD and UPLC–MS /MS [200].

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

28


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

2.2. Quality by design (QbD) and design of experimental (DoE) concepts in impurity and degradation profiling

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

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

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


29

Fig. 8. Different columns used for impurity and forced degradation profiling during 2008–2012.

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

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

are going to be discuss in following. 2.3. Column

Column is heart of the chromatography which can be selected depending upon their pore size, surface area, carbon load, particle size, length, chemistry of column. The degree of retention of a neutral hydrophobic analyte on a wholly alkyl phase (C18 or C8) can be inferred from the carbon load value. Maximum C18 and C8 columns were used, 62% and 9%, respectively, for impurity and forced degradation 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

Maximum work on active pharmaceutical ingredient (API) for impurity 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. Although, other dosage forms were also subjected to perform this study, such as coated eluting stents [30,87], powder for injection [48], lotion [56], soft gelatin capsules [61], patches [77], nasal solution [91], plant extracts [163], syrup [181], and nanoemulsion [196].

2.5. Elution: isocratic and gradient

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

30


3. Conclusion

The present review describes comprehensive update on recent trends in analytical perspectives of degradation and impurities profiling 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

Fig. 9. Different matrix used for impurity and forced degradation profiling during 2008–2012.

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. References

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.

2.6.Therapeutic categories

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

[1] D. Roy, Implementation of revised schedule ‘M’ and SSI, The Indian Pharmacist. (2003) 8–11. [2] ICH. Impurities in new drug substances Q3A (R2), in: International Conference on Harmonization. Geneva, Switzerland, IFPMA, 2006. [3] J.G. Hardman, L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Gilman, Good and Gilman’s The Pharmaceutical Basics of Therapeutics,ninth ed., New York, McGraw-Hill, 1999, pp. 3–63. [4] S. Gorog, Identification and Determination of Impurities in Drugs, Amsterdam, Elsevier Science, 2000, 748. [5] S. Ahuja, Impurities Evaluation of Pharmaceuticals, New York, Marcel Dekker Inc., 1998, 42. [6] The United State Pharmacopeia USP 24. The National Formulary NF 19, 2000, Twinbrook Parkway, Rockville, MD, United State Pharmacopeial Convention, Inc. 12601, 1998, pp. 1876–1878, 20852. [7] J.M. Daniels, E.R. Nestmann, A. Kerr, Development of stereoisomeric (chiral) drugs: a brief review of scientific and regulatory considerations, Drug Information Journal. 31 (1997) 639–646. [8] S. Husain, R. Nageswara Rao, Monitoring of process impurities in drugs, in: Z. Deyl, I. Miksik, F. Tagliaro, E. Tesarova (Eds.), Advanced Chromatographic and Electromigration Methods in Biosciences. Amsterdam, Elsevier Science, 1998, pp. 834–888. [9] R. Nageswara Rao, V. Nagaraju, An overview of the recent trends in development of HPLC methods for determination of impurities in drugs, Journal of Pharmaceutical and Biomedical Analysis. 33 (2003) 335–377. [10] K.M. Alsante, A. Ando, R. Brown, J. Ensing, T.D. Hatajik, W. Kong, et al., The role of degradant profiling in active pharmaceutical ingredients and drug products, Advanced Drug Delivery Reviews. 59 (2007) 29–37. [11] S. Ahuja,K.M.Alsante, Handbook of Isolation and Characterization of Impurities in Pharmaceuticals, Amsterdam, Elsevier, 2003. [12] R.J. Smith, M.L. Webb, Analysis of Drug Impurities, Oxford, Blackwell, 2007. ¨ og, ¨ The importance and the challenges of impurity profiling in modern [13] S. Gor pharmaceutical analysis, Trends in Analytical Chemistry. 25 (2006) 755–757. ¨ og, ¨ Recent advances in the impurity profiling of drugs, Current [14] D. Bartos, S. Gor Pharmaceutical Analysis. 4 (2008) 215–230. [15] S.W. Baertschi, Analytical methodologies for discovering and profiling degradation-related impurities, Trends in Analytical Chemistry. 25 (2006), 758–567. [16] D.Q. Liu, L. Wu, M. Sun, P.A. MacGregor, On-line H/D exchange LC–MS strategy for structural elucidation of pharmaceutical impurities, Journal of Pharmaceutical and Biomedical Analysis. 44 (2007) 320–329. [17] J.X. Zhang, D.M. Zhang, X.G. Han, Identification of impurities and statistical classification of methamphetamine hydrochloride drugs seized in China, Forensic Science International. 182 (2008) 13–19. [18] A.P. Kumar, V.R.L. Ganesh, D.V.S. Rao, C. Anil, B.V. Rao, V.S. Hariharakrishnan, et al., A validated reversed phase HPLC method for the determination of process-related impurities in almotriptan malate API, Journal of Pharmaceutical and Biomedical Analysis. 46 (2008) 792–798. [19] A.L. Huidobroa, P. Pruimb, P. Schoenmakersb, C. Barbas, Ultra rapid liquid chromatography as second dimension in a comprehensive two-dimensional method for the screening of pharmaceutical samples in stability and stress studies, Journal of Chromatography A. 1190 (2008) 182–190. [20] P.F. Gavin, B.A. Olsen, A quality by design approach to impurity method development for atomoxetine hydrochloride (LY139603), Journal of Pharmaceutical and Biomedical Analysis. 46 (2008) 431–441. [21] A.A. Kadav, D.N. Vora, Stability indicating UPLC method for simultaneous determination of atorvastatin, fenofibrate and their degradation products in tablets, Journal of Pharmaceutical and Biomedical Analysis. 48 (2008) 120–126. [22] A. Khedr, M. Sheha, Stress degradation studies on betahistine and development of a validated stability-indicating assay method, Journal of Chromatography B. 869 (2008) 111–117. [23] M. Li, M. Lin, A. Rustum, Application of LC–MSn in conjunction with mechanism-based stress studies in the elucidation of drug impurity structure: rapid identification of a process impurity in betamethasone 17-valerate

D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 11–35 [204] M. Dumarey, A.M.V. Nederkassel, I. Stanimirova, M. Daszykowskia, F. Bensaidc, M. Lees, et al., Recognizing paracetamol formulations with the same synthesis pathway based on their trace-enriched chromatographic impurity profiles, Analytica Chimica Acta. 655 (2009) 43–51. [205] T.D. Ho, M.D. Joshi, M.A. Silver, J.L. Anderson, Selective extraction of genotoxic impurities and structurally alerting compounds using polymeric ionic liquid sorbent coatings in solid-phase microextraction: Alkyl halides and aromatics, Journal of Chromatography A. 1240 (2012) 29–44. [206] P.K. Basniwal, P.K. Shrivastava, R. Dubey, D. Jain, Supercritical fluid extraction: a new milestone in extraction technology, Indian Journal of Pharmaceutical

35

Sciences. 67 (2005) 532–539. [207] A.J. Alexander, T.F. Hooker, F.P. Tomasella, Evaluation of mobile phase gradient supercritical fluid chromatography for impurity profiling of pharmaceutical compounds, Journal of Pharmaceutical and Biomedical Analysis. 70 (2012) 77–86. [208] P.K. Basniwal, D. Jain, Simvastatin: review of updates on recent trends in pharmacokinetics, pharmacodynamics, drug–drug interaction, impurities and analytical methods, Current Pharmaceutical Analysis. 8 (2012) 135–156.

1-s2.0-S0731708513003099-main (2).pdf

Recommend Documents