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School of Pharmaceutical Sciences, Rajiv Gandhi Technological University, Bhopal 462 033, Madhya Pradesh, India
LBS College of Pharmacy, Jaipur 302 004, Rajasthan, India
a r t i c l e
i n f o
Article history:
Received 9 May 2013
Received in revised form 28 June 2013
Accepted 7 July 2013
Available online 31 July 2013
Keywords:
Impurity
Forced degradation proling
Analytical perspectives
active pharmaceutical ingredient
Drug products
a b s t r a c t
This review describes an epigrammatic impression of the recent trends in analytical perspectives of degradation and impurities proling of pharmaceuticals including active pharmaceutical ingredient (API) as well
as drug products during 20082012. These recent trends in forced degradation and impurity proling were
discussed on the head of year of publication; columns, matrix (API and dosage forms) and type of elution
in chromatography (isocratic and gradient); therapeutic categories of the drug which were used for analysis. It focuses distinctly on comprehensive update of various analytical methods including hyphenated
techniques for the identication and quantication of thresholds of impurities and degradants in different
pharmaceutical matrices.
c 2013 Elsevier B.V. All rights reserved.
1. Introduction
A clean bill of health of public is the ultimate motto of pharmaceutical industries. The objective of the pharmaceutical industries
is to protect the public health by enabling the patients to get proper
medicine in proper dose and efcacy at an affordable cost. Thus, safety
and efcacy of pharmaceuticals are two fundamental issues of importance in drug therapy. The safety of a drug is determined by its
pharmacologicaltoxicological prole as well as the adverse effects
caused by the impurities in bulk and dosage forms, i.e., the safety of
MS/MS, liquid chromatographytandem mass spectrometry using electrospray ionization source and Q-trap mass analyzer; LCMS, liquid chromatographymass spectrometry; LiCl, lithium chloride; MDMA, 3,4-methylenedioxy-N-methylamphetamine;
MECC, micellar electrokinetic capillary chromatography; MEKC, micellar electrokinetic
chromatography; MeOH, methanol; MPLC, medium pressure liquid chromatography;
MPTP, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; CE, capillary electrophoresis;
MS, mass spectrometry; Na2 HPO4 , disodium phosphate; Na3 PO4 , sodium phosphate;
NaCl, sodium chloride; NDA, New Drug Application; NH3 , ammonia; NH4 H2 PO4 , ammonium dihydrogen phosphate; NH4 OH, ammonium hydroxide; NOESY, nuclear overhauser effect spectroscopy; NSAIDs, non-steroidal anti-inammatory drugs; OVIs, organic volatile impurities; PCA, principal component analysis; PDA, photodiode array; PDA-MS, photodiode array detector-mass spectrometry; PFPA, pentauoropropionic acid anhydride; Q-TOF, quadrupole-time-of-ight; RI, refractive index; RRF, relative response factor; SDS, sodium dodecyl sulfate; SDS-PAGE, sodium dodecyl sulfate
polyacrylamide gel electrophoresis; SFC, supercritical uid chromatography; SPME,
headspace solid phase microextraction; TEA, triethylamine; TFA, triuoroacetic acid;
Tris, trisaminomethane; UPLC, ultra performance liquid chromatography.
* Corresponding author at: LBS College of Pharmacy, Jaipur 302 004, Rajasthan, India.
Tel.: +91 9414788171.
E-mail addresses: deepti2515@yahoo.com (D. Jain) pawanbasniwal@gmail.com
(P.K. Basniwal).
12
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
Fig. 1. Year-wise publications for impurity and degradation proling during 2008
2012 .
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
13
Table 1
Different terminology used for impurities [10].
Impurity
Description
Starting material
Intermediates
Penultimate intermediate
By-products
Transformation products
Interaction products
Related products
Degradation products
Foreign substances
Toxic impurities
Concomitant components
Signal impurities
Ordinary impurities
Organic volatile impurities
Organic impurities
Inorganic impurities
Other materials
Residual solvents
Chiral impurities
Fig. 2. Chromatograms recorded from the mixture containing 1 g ml1 of PIB and
its four impurities on coulometric electrodes at increasing potentials: 300, 400, 500,
600, 700, 800, 850, and 900 mV. (Reuse with the permission of Elsevier Limited, The
Boulevard, Langford Lane, Kidlington, Oxford, OX5 1GB, UK.)
2.1.1.2. Forced degradation proling HPLC with uorescence detector was employed to study stability of betahistine in different forced
degradation conditions (heat, moisture, acidbase, and ultra-violet
light), where two potential degradation products were identied. The
2.1.1.3. Impurity and forced degradation proling Mixture of phosphate buffer and acetonitrile were used to separate three processrelated impurities and degradation products (different forced
degradation conditions) of almotriptan malate [18]. In addition
to four known impurities of carvedilol, one unknown degradation product was identied as N-[(2RS)-3-(9H-carbazol-4-yloxy)-2hydroxypropyl]-N-[2-(2-methoxyphenoxy)ethyl]hydroxylamine in
tablet dosage form which was found as exceeded thresholds of
ICH Q3B guidelines [27]. Reversible acetylcholinesterase inhibitor,
donepezil hydrochloride was assayed along with four impurities and
an excipient in oral pharmaceutical formulation, where selectivity of
method was assured from forced degradation of the drug [32]. Degradation pathway for forced degradation behavior of enalapril maleate
was identied in different stress conditions [34] and two degradation
impurities of epirubicin were found in aqueous formulation [35].
14
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
Table 2
Representative chromatographic analytical methods of impurity and forced degradation proling during 20082012.
S.
no.
Name of drug
1.
2.
Methamphetamine
hydrochloride
Almotriptan
malate
Matrix; therapeutic
category
Impurity/degradant
Column/stationary phase
Mobile phase
Detection
API; psychostimulant
29 impurities
Capillary column, 30 m
0.32 mm 1.0 mm
Nitrogen gas
API; antimigraine
3 impurity
Sodium phosphate
buffer (pH 7.6):ACN
(80:20)
ACN:CH3 COOH (25
mM, pH 4.0);
gradient
O-Phosphoric acid
(25 mM, pH 2.5)
and Octane sulfonic
acid (25
mM):n-Propanol
(73:27)
ACN:CH3 COONH4
buffer (pH 4.7; 0.01
M), gradient
ACN: sodium
acetate (0.02 mM,
pH 4.5); gradient
Mass
selective
detector
227 nm
2008 [18]
234 nm
2008 [19]
215 nm
2008 [20]
247 nm
2008 [21]
UV 254 nm;
Fluorescence
336 and 531
nm
PDA-MS
detector
215 nm
2008 [22]
3.
Alprazolam
Tablets; anxiolytic
20 degradant
4.
Atomoxetine
hydrochloride
API; antidepressants
Phenyl
methylamino-propanol
and mandelic acid
5.
Atorvastatin
calcium
Tablets;
anti-hyperlipidemic
6.
Betahistine
9 degradants
7.
API; steroid
2 impurities
8.
Betamethasone
17-valerate
Bicalutamide
9.
Bovine obestatin
2 degradants and 6
process-related impurities
3 impurities
10.
Budesonide
Tablets; steroid
10 impurities
11.
Canine obestatin
API; antibodies
9 impurities
12.
Carvedilol
Tablets;
antihypertensive
5 impurities
13.
API; antibiotic
12 impurities
14.
Clindamycin
palmitate HCl and
clindamycin
Clopidogrel
API; antiplatelet
5-[1-(2-Chlorophenyl)-2methoxy-2-oxoethyl]-6,7dihydrothieno[3,2-c]
pyridin-5-ium
15.
Dexamethasone
Dexamethasone-coated
eluting stents; steroid
16.
API; hepatoprotective
5 degradants
17.
4 impurities of side
reaction and degradation
18.
Econazole nitrate
Cream; antifungal
4-Chlorobenzyl alcohol
and
-(2,4-dichloro-phenyl)
-1H-imidazole-1-ethanol)
ACN:H2 O (60:40)
0.01 M KH2 PO4 (pH
3.0):ACN (50:50)
Eluent A: H2 O (0.1%
formic acid); Eluent
B: ACN (0.1% formic
acid); gradient
ACN:phosphate
buffer (pH 3.2, 28.6
mM) (30:70)
Eluent A: H2 O (0.1%
formic acid); Eluent
B: ACN (0.1% formic
acid); gradient
ACN:phosphate
buffer (pH 2.5; 0.01
M) (40:60)
CH3 COONH4
buffer:MeOH
(15:85)
Eluent A: ACN:
potassium
phosphate buffer
(pH 2.3, 10 mM)
(20:80); Eluent B:
ACN: potassium
phosphate buffer
(pH 2.3; 10 mM)
(80:20); gradient
HCOONH4 (20 mM,
pH 3.8):ACN;
gradient
ACN:H2 O (60:40)
Phosphate buffer (5
mM, pH 3.67):
MeOH; gradient
MeOH: H2 O;
gradient
Year
[Ref.]
2008 [17]
2008 [23]
2008 [24]
2008 [25]
240 nm
2008 [26]
2008 [25]
240 nm
2008 [27]
226 nm;
LC/MS/MS
2008 [28]
2008 [29]
239 nm
2008 [30]
235 nm
2008 [31]
270 nm
2008 [32]
220 nm
2008 [33]
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
15
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
Column/stationary phase
Mobile phase
Detection
Year
[Ref.]
19.
Enalapril maleate
API; antihypertensive
5 degradants
210 nm
2008 [34]
20.
Epirubicin HCl
Injection; antibiotic
3 degradation impurities
254 nm
2008 [35]
21.
Fenobrate
Tablets;
anti-hyperlipidemic;
247 nm
2008 [36]
22.
Fluorapacin
2 related substances
2008 [37]
Gatioxacin
10 related substances
TEA (1%, pH
4.3):ACN (87:13)
200500 nm
2008 [38]
24.
Glimepiride
API; antidiabetic
5 degradants
218 nm
23.
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
2008 [25]
26.
Levothyroxine
8 impurities
223 nm
2008 [40]
27.
Lopinavir
API; anti-HIV
8 related impurities
210 nm
2008 [41]
API; psychostimulant
29 impurities
GC-FID
2008 [42]
API; antiischemic
6 related impurities
Electrospray
interface
detector
2008 [43]
225 nm
2008 [44]
2008 [25]
200500 nm
2008 [45]
2008 [25]
227 nm
2008 [46]
28.
29.
Methamphetamine
Mildronate
30.
Montelukast
sodium
API; antiallergic
4 impurities
31.
Mouse obestatin
API; antibodies
3 impurities
32.
Moxioxacin
API; antibacterial
4 related substances
33.
Ovine obestatin
API; antibodies
5 impurities
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
16
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
Table 2
Continued
S.
no.
Impurity/degradant
Column/stationary phase
Mobile phase
Detection
Year
[Ref.]
API; antiasthamatic
Phenylethanolamine
derivatives
Pipecuronium
Powder for injection;
bromide
steroid
11 impurities
nHexane:gthanol:TEA
(98:2:0.1)
254 nm
2008 [47]
4 impurities
37.
Pridinol mesylate
2 degradant
38.
Primaquine
phosphate
Primaquine
phosphate
Salicylaldehyde
isonicotinoyl
hydrazone
API; antimalarial
2 impurities
API; antimalarial
2 impurities
2 -Hydroxy-acetophenone, Isonicotinoyl
hydrazone, 2 -hydroxy
propiophenone
Isonicotinoylhydrazone
9 process impurities
35.
36.
39.
40.
Name of drug
Matrix; therapeutic
category
41.
Tamsulosin
42.
Tazarotene
43.
Tenatoprazole
6 degradants
44.
Levooxacin
API; antibacterial
3 process related
impurities and 1 oxidative
degradant
45.
Lotion;
anti-inammatory
46.
Anastrozole
Tablet; anti-cancer
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
52.
Eletriptan
API; antimigraine
1 degradants (oxidative)
53.
Fatty alcohol
ethoxylates
Surfactant
6 impurities
54.
Gentamicin
API; antibiotic
33 related impurities
Hydro-RP, 250 mm
4.6 mm, 5 m
55.
Heparin sodium
API; anticoagulant
6 impurities
AS11-HC, 250 mm 4
mm, 9 m
56.
Ibuprofen
API; analgesic
3-[4-(2ZirChrom-CARB, 150 mm
Methylpropyl)phenyl]propanoic 4.6 mm, 5 m; C18,
acid
150 mm 4.6 mm, 5
m; Zr-PS, 150 mm
4.6 mm, 5 m; C18, 150
mm 3.0 mm, 7 m
2 by-product
2008 [48]
Tetramethylammonium Electrochemical
hydroxide (4.53 g/L,
detection
pH 6.4):ACN (6:4)
220 nm
MeOH:IPA:potassium
phosphate (50 mM,
pH 6.0) (51:9:40)
TFA (0.01%):ACN
265 nm
(75:25)
TFA (0.01%): ACN
265 nm
(75:25)
Phosphate buffer
LCESI-MS
(10 mM + 2 mM
EDTA, pH 6):MeOH
(40:60)
CH3 COONH4 (10
mM):ACN; gradient
Helium gas
2008 [49]
2008 [50]
2008 [50]
2008 [51]
280 nm
2008 [52]
MS detection
2008 [53]
306 nm
2009 [54]
294 nm
2009 [55]
240 nm
2009 [56]
H2 O:ACN; gradient
215 nm
2009 [57]
CH3 COONH4 (1
mM): ACN; gradient
TFA
(0.06%):ACN:IPA
(87:12:1)
NH3 :H2 O:ACN
(0.1:50:50)
THF:phosphoric
acid (0.05M) (44:56)
Acetic acid
(0.10%):ACN (53:
47)
MeOH:H2 O + TEA
(1%) (30:70) (pH
6.52)
Eluent A:
H2 O:MeOH (80:20);
Eluent B: MeOH;
gradient
Eluent A: MTFA
(50m, pH 2); Eluent
B: MeOH; gradient
Eluent A: H2 O;
Eluent B: NaCl (2.5
M + 20 mM Tris,
pH 3); gradient
ACN:phosphate
buffer (25 mM, pH
2.1) (40:60)
220 nm
2009 [58]
220 nm
2009 [59]
225 nm
2009 [60]
220 nm
2009 [61]
254 nm
2009 [62]
225 nm
2009 [63]
ELSD
detector
2009 [64]
ESI/MSn
detection
2009 [65]
215 nm
2009 [66]
2009 [67]
MeOH:acetate
buffer (10 mM, pH
4.5) (55:45)
Eluent A: NaH2 PO4
(25 mM) + 0.5%
TEA (pH 6); EluentB:
MeOH; gradient
Methanesulfonic
acid:ACN (0.05%);
gradient
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
17
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
57.
Icofungipen
API; antifungal
58.
Lamivudine
API; anti-HIV
59.
Lansoprazole
60.
Metformin
Tablet; antidiabetic
Related compound:
1-cyanoguanidine
61.
Moxioxacin HCl
API; antibacterial
4 synthesis-related
impurities
62.
Nevirapine
analogue
API; anti-HIV
3 impurities
63.
Nimodipine
Tablet;
antihypertensive
Tablet; steroid
3 impurities
Column/stationary phase
Mobile phase
Detection
(1R,2S)-2-(Cinnamyl
amino) -4-methylene
cyclopentane carboxylic
acid
5 degradants
C18, 1005 AB
ACN:H2 O (25:75)
2009 [68]
Eluent A: MeOH;
Eluent B:
CH3 COONH4 buffer
(10 mM, pH4);
gradient
Methyl-tert-butyl
ether:ethyl
acetate:ethanol
diethylamine
(60:40:5:0.1)
NH4 H2 PO4
buffer:MeOH
(21:79)`
H2 O + TEA
(2%):ACN 90:10 (pH
6.0)
Eluent A: H2 O
(HCOOH 0.1%);
Eluent B: ACN
(HCOOH 0.1%);
gradient
ACN:H2 O
(67.5:32.5)
MeOH:H2 O (53:47)
277 nm
2009 [69]
310 nm
2009 [70]
232 nm
2009 [71]
290 nm
2009 [72]
ESI/MSn
detection
2009 [73]
236 nm
2009 [74]
ESI/MS
detection
254 nm
2009 [75]
2009 [76]
245 nm
2009 [77]
250 nm
2009 [78]
225 nm
2009 [79]
250 nm
2009 [80]
275 nm
2009 [81]
225 nm
2009 [82]
220 nm
2009 [83]
2009 [84]
2009 [85]
220 nm
2009 [86]
278 nm
2009 [87]
64.
Norethisterone
65.
66.
Phenazopyridine
HCl
Pridinol mesylate
67.
Puerarin
Injection; vasodilator
9 impurities
68.
Rizatriptan
benzoate
API; antimigraine
Rizatriptan-1,2-dimer and
Rizatriptan-2,2-dimer
69.
Ropinirole HCl
API; anti-Parkinsons
4-[2(Dipropylamino)ethyl]1H-indol-2,3-dione
X-BridgeTM , 3 mm 100
mm, 3.5 m
70.
Salidroside
API; antidepressant
3 impurities
71.
Sertraline
API; antidepressant
9 impurities
72.
Taranabant
API; anti-obesity
6 impurities
73.
Tropicamide
API; ophthalmology
3 impurities
74.
Valsartan
API; antihypertensive
5 impurities
75.
Zarlukast
API; antiasthamatic
5 impurities
76.
Zotarolimus
Coated stents;
immunomodulator
3 degradant
API; analgesic
API, tablet, injection,
Patches;
antihypertensive
Year
[Ref.]
Impurity/degradant
19-Norandrostenedione
3-Phenyl-5-phenylazopyridine-2,6-diamine
3-Piperidino-propiophenone, hydrochloride,
1-(3,3-diphenylprop-2-en1-yl)piperidine
H2 O:ACN (25:75)
Potassium
phosphate buffer
(50 mM, pH
6.4):MeOH:2propanol
(20:69:11)
Formic acid (0.1%):
MeOH; gradient
Ammonium
dihydrogen
ortho-phosphate
(20 mM) + 2 ml
TEA (pH 2): ACN;
gradient
ACN:sodium
heptane sulfonate
(5 mM) (21.6:78.4)
(pH 2)
MeOH:H2 O (13:87)
TFA (0.4%):ACN
(80:20)
H3 PO4 in H2 O
(0.1%):ACN;
gradient
MeOH:H2 O (30:70)
Elunent A:
CH3 COONH4 (10
mM, pH 3.0) Eluent
B: H2 O:ACN (1:4);
gradient
Eluent A: phosphate
buffer + 1-decane
sulfonic acid
sodium (pH 4):
MeOH (85:15);
Eluent B:
ACN:MeOH:H2 O
(85:10:5)
CH3 COONH4 (10
mM, pH 3.8): ACN;
gradient
18
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
Column/stationary phase
Mobile phase
Detection
Year
[Ref.]
API; antiplatelet
2 impurities
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
254 nm
2010 [89]
79.
Acetylspiramycin
API; antibiotics
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
210 nm
2010 [91]
81.
Alizapride
API; antiemetic
2 degradants
225 nm
2010 [92]
82.
Atorvastatin
calcium
API;
anti-hyperlipidemic
4 impurities
246 nm
2010 [93]
83.
Barnidipine
API; antihypertensive
4 degradants
250 nm
2010 [94]
84.
Clopidogrel
bisulfate
5 impurities
240 nm
2010 [96]
85.
CU201(antitumor
peptidic dimer)
API; anticancer
266 nm
2010 [97]
86.
Desloratadine
Tablet; antiallergic
280 nm
2010 [98]
87.
Duloxetine HCl
API; antidepressant
3 related impurities
230 nm
2010 [99]
88.
Enalapril maleate
API; antihypertensive
Several degradation
impurities
215 nm
2010
[100]
89.
Eprosartan
API; antihypertensive
234 nm
2010
[101]
90.
Escitalopram
API; antidepressant
3 process-related
impurities
240 nm
2010
[102]
91.
Ezetimibe
Process-related impurity
Felbamate
232 nm
92.
API;
anti-hyperlipidemic
API and tablets;
antiepileptic
2010
[103]
2010
[104]
77.
210 nm
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
19
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
Column/stationary phase
Mobile phase
Detection
93.
Fentanyl
API; analgesic
16 impurities
215 nm
2010
[105]
94.
Filgrastim
API; hematopoietic
stimulator
5 impurities
215 nm
2010
[106]
95.
GW876008
(corticotropinrelease factor 1
antagonist)
API; antidepressant
4 impurities
220 nm
2010
[107]
96.
l-Aspartic acid
and l-alanine
CAD
detection
2010
[108]
97.
Omeprazole
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
210 nm
2010
[110]
99.
Oxytocin
220 nm
2010
[111]
100.
Pentoxifylline
API; antidiabetic
3 degradants
274 nm
2010
[112]
101.
Piracetam
4 impurities
Pregabalin
205 nm
102.
API; neurovascular
enhancer
API and tablet;
antipsychotic
2010
[113]
2010
[114]
103.
Rabeprazole
sodium
Methylthio impurity of
rabeprazole
104.
Raltegravir
API; anti-HIV
5 impurities
105.
API; anti-HIV
9 impurities
106.
RG7128 (HCV
polymerase
inhibitor)
Rifaximin
API; antibiotic
1 impurity
107.
Ritonavir
API; anti-HIV
21 degradants
108.
Sertraline
API; antidepressant
3 non-chiral related
impurities
109.
Valsartan
API; antihypertensive
7 degradants
110.
Vestipitant
API; antiemetic
3 biphenyl impurities
111.
Abacavir
API; anti-HIV
8 degradants
112.
ALB 109564
API; anticancer
4 impurities
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
Year
[Ref.]
284 nm
2010
[115]
2010
[116]
2010
[117]
276 nm
2010
[118]
2010
[119]
2010
[120]
210 nm
220 nm
225 nm
2010
[121]
254 nm
2010
[122]
220 nm
2011
[123]
2011
[124]
20
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
Column/stationary phase
Mobile phase
Detection
113.
Anastrozole
API; anticancer
3 degradant
Artemisinin
API; antimalarial
115.
Atazanavir sulfate
API; anti-HIV
Artemisitene,
9-epi-artimisinin
13 process impurities and
degradants
116.
Auraptene
API; immunomodulator
5 impurities
HCOONH4 (10
mM):ACN (60:40)
ACN:H2 O (60:40) +
0.1% formic acid
Eluent A: H2 O:0.025
M CH3 COONH4 ;
Eluent B: ACN;
gradient
H2 O:ACN; gradient
215 nm
114.
117.
Boron
phenylalanine
API; anticancer
4 impurities
118.
Candesartan
cilexetil
Carbamazepine
API; antibiotics
API; antiepileptic
7 impurities
120.
Casopitant
mesylate
De-uorinated casopitant
mesylate analogue
121.
Ciclesonide
4 degradants
122.
Colistin
(Polymyxin E)
35 impurities
123.
Entacapone
API; anti-Parkinsons
4 forced degradants
124.
Etimicin sulfate
API; antibiotic
6 impurities
125.
Ezetimibe
API;
anti-hyperlipidemic
5 degradation and
process-related impurities
126.
Febuxostat
API; anti-gout
4 impurities
127.
Fesoterodine
API; antispasmodic
5 degradants
128.
API; antidiabetic
4 related impurities
129.
G004
(hypo-glycaemic
agent)
Gentamicin
API; antibiotic
5 impurities
130.
Lactic acid
11 impurities
131.
Larotaxel
Sugarcane juice;
humectants
API; anticancer
132.
Lincomycin and
spectinomycin
119.
API; antibiotic
5 Related impurities
Lincomycin related
impurities: 4 and
spectino-mycin related
impurities: 5
DAD/MS
250 nm
324 nm
Year
[Ref.]
2011
[125]
2011
[126]
2011
[127]
2011
[128]
2011
[129]
Eluent A:TFA:H2 O:
MeOH (0.1:85:15);
Eluent B: MeOH;
gradient
TFA (pH 3):ACN;
gradient
THF:CH3 OH:H2 O
(3:12:85)
Eluent A: H2 O +
0.2% NH4 OH; Eluent
B: ACN + 0.2%
NH4 OH; gradient
Ethanol:H2 O
(70:30)
242 nm
2011
[133]
ACN:sodium sulfate
(4.46 mM, pH 2.3)
(20:80) + 10%
phosphoric acid;
gradient
Potassium
phosphate buffer
(30 mM, pH
2.75):MeOH (50:50)
Eluent A: H2 O:NH3
(25%):CH3 COOH
(96:3.6:0.4); Eluent
B: MeOH; gradient
Eluent A: TFA
(0.05%):MeOH
(49:51); Eluent B:
ACN:Eluent A (3:1);
gradeint
Eluent A:
CH3 COONH4 (10 m
M, pH 3.5); Eluent
B: ACN; gradient
215 nm
2011
[134]
310 nm
2011
[135]
ELSD
2011
[136]
2011
[137]
315 nm
2011
[138]
210 nm
230 nm
LC/MS/MS
208 nm
ACN:MeOH:CH3 COONH4
(30 mM, pH 3.8)
(30:15:55)
Acetic acid (0.1%) +
233 nm
TEA (0.1%):MeOH
(20:80)
Eluent A: TFA (0.1%
ESI/MSn
detection
pH 2.5); Eluent B:
TFA (0.1% pH 2.5 +
TEA Eluent C: ACN;
gradient
NH4 H2 PO4 (20 mM,
210 nm
pH 2.2)
230 nm
H2 O:ACN; gradient
TFA (0.05%, pH
3.0):ACN (90:10)
ESI/MSn
detection
2011
[130]
2011
[131]
2011
[132]
2011
[139]
2011
[140]
2011
[141]
2011
[142]
2011
[143]
2011
[141]
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
21
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
Column/stationary phase
Mobile phase
Detection
133.
Lornoxicam
API; analgesic
Degradants
MS detector
2011
[144]
134.
Memantine
Tablets; anticancer
Maillard reaction
impurities
CAD
detection
2011
[145]
135.
Meprobamate
API; antipsychotic
200 nm
2011
[146]
136.
Mometasone
furoate
Mometasone
furoate
API; steroid
Carbamic acid-2carbamoyloxymethyl-2methyl-pent-3-enyl
ester
8 impurities
H2 O:ACN; gradient
245 nm
API; steroid
8 impurities
245 nm
2011
[147]
2011
[147]
138.
Naproxen
API; analgesic
2011
[148]
Olanzapine
220 nm
2011
[149]
140.
Olanzapine
8 degradants
250 nm
2011
[150]
141.
Olaquindox
API; anti-amoebic
12 degradants
200400 nm
142.
Palonosetron HCl
API; antiemetic
9 degradants
2011
[151]
2011
[152]
143.
Perindopril
tert-butylamine
API; antihypertensive
4 impurities
144.
Phosphorothioate
oligonucleotides
5 synthesis impurities
145.
Polymyxin B
API; antibiotic
38 impurities
146.
Streptomycin
sulfate
Sulindac
API; antibiotic
21 impurities
API; analgesic
5 related impurities
API; antihypertensive
2 photodegradant
254 nm
139.
2-(6-Methoxynaphthalen-2-yl)acrylic
acid
8 impurities
137.
147.
148.
149.
Ursodeoxycholic
acid
Valsartan
210 nm
Year
[Ref.]
215 nm
2011
[153]
LCMS/MS
2011
[154]
215 nm
2011
[134]
CAD/MS
Detection
340 nm
2011
[155]
2011
[156]
RI detection
2011
[157]
2011
[158]
226 nm
22
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
Column/stationary phase
Mobile phase
Detection
150.
Zarlukast
API; antiasthamatic
8 impurities
220 nm
2011
[159]
151.
Rapamycin
API; immunomodulator
9 degradant
Diol-120-NP, 250 mm
4.6 mm, 5 m
2012
[160]
152.
4-Methyl
thioamphetamine
API; psychostimulant
22 impurities
Capillary, 30 m 0.25
mm, 0.25 m
Eluent A: phosphate
buffer + 1-decane
sulfonic acid
sodium (pH 4):
MeOH (85:15);
Eluent B:
ACN:MeOH:H2 O
(85:10:5); gradient
Hexanes:2propanol;
gradient
Helium
2012
[161]
153.
Halobetasol
propionate
Artemisinin
API; steroids
Acetamide and
arylsulfonate
Extract residue impurities
ACN:H2 O; gradient
Eluent A: phosphate
buffer (pH 5.4);
Eluent B: ACN:THF
(90:10); gradient
Eluent A: KH2 PO4
(15
mM):ACN:MeOH
(8:1:1) Eluent B:
ACN; gradient
ACN:H2 O (60:40) +
0.1% formic acid
NH4 H2 PO4 (1.2%,
pH 4.5):ACN (80:20)
Mass
selective
detector
230, 220 and
205 nm
192, 200,
205, 210 and
215 nm
220 nm
220 nm
2012
[165]
318 nm
2012
[166]
2012
[167]
2012
[168]
154.
Artemisia annua
extracts; antimalarial
155.
Atorvastatin
calcium
API;
anti-hyperlipidemic
7 impurities
156.
Azelnidipine
Solution;
anti-hypertensive
4 degradants
157.
Benzopyridooxathiazepine
Bupropion
hydrochloride
Caffeine
API; anticancer
10 degradants
Alkaline degradates,
3-chlorobenzoic acid
4 impurities
158.
159.
160.
Cefditoren pivoxil
161.
Clocortolone
pivalate
Cloperastine
fendizoate
162.
1 degradants
3 impurities
Methyl p-toluene
sulfonate and 2-chloro
ethyl p-toluene sulfonate
163.
Deferasirox
2-[3,5-Bis(2-hydroxyphenyl)-[1,2,4]-triazol-1yl]-benzoic
acid
164.
Desvenlafaxine
1 degradants (acid)
165.
Diltiazem HCl
6 related substances
166.
Dipyridamole
2 impurities
167.
Eslicarbazepine
acetate
API; antiepileptic
15 impurities
ACN:H2 O:MeOH
(50:30:20)
210 nm
275 nm
THF:ACN:CH3 COONH4
(pH 4.5) (40:50:10)
ACN:H2 O (50:50)
218 nm
ACN:H2 O (70:30)
254 nm
Phosphate buffer
(10 mM, pH
3.0):MeOH with
10% ACN (45:55)
Eluent A:H2 O:TFA
(100:0.05); Eluent
A: ACN:MeOH:TFA
(50:50:0.05)
gradient
TEA (0.2%)
+ CH3 COONH4 (50
mM, pH 6.5):MeOH
(40:60)
TEA (0.2%):ACN;
gradient
Eluent A: KH2 PO4
buffer (10 mM, pH
7.0):MeOH (50:50);
Eluent B:
MeOH:KH2 PO4 (10
mM) buffer; (95:5);
gradeint
Eluent A: KH2 PO4
(10 mM, pH 5): ACN
(95:5); Eluent B:
ACN:H2 O (80:20);
gradient
227 nm
Year
[Ref.]
2012
[162]
2012
[163]
2012
[164]
2012
[169]
2012
[170]
2012
[171]
LCESI-QT/
MS/MS
2012
[172]
228 nm
2012
[173]
240 nm
2012
[174]
2012
[175]
295 nm
215 nm
2012
[176]
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
23
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
Column/stationary phase
Mobile phase
Detection
Eluent A: glycine
buffer (40 mM, pH
9); Eluent B:
ACN:H2 O (90:10);
gradient
Eluent A: H2 O:NH3
(25%):CH3 COOH
(96:3.6:0.2); Eluent
B: MeOH; gradient
Eluent A: 1-octane
sulfonic acid
sodium (10 mM) +
CH3 COONH4 (10
mM) + 0.1% TEA
(pH 4):MeOH
(95:5); Eluent B:
MeOH; gradient
Eluent A: H2 O (0.1%
formic acid); Eluent
B: ACN (0.1% formic
acid); gradient
Eluent A: NH4 H2 PO4
(20 mM) +
1-heptane sulfonic
acid sodium salt
buffer (1%) (pH
2.6):ACN:MeOH
(95:4:1); Eluent
B:ACN NH4 H2 PO4
(20 mM) +
1-heptane sulfonic
acid sodium salt
buffer (1.0%) (pH
9.5) (6:4); gradient
Eluent A:
CH3 COONH4 (50
mM, pH 9.5); Eluent
B: ACN:MeOH
(40:60); gradient
Eluent A: H2 O (0.1%
formic acid); Eluent
B: ACN (0.1% formic
acid); gradient
Eluent A: NH4 OH
(100 mM): H2 O
(1:9); Eluent B:
NH4 OH (100 mM):
ACN (1:9); gradient
CH3 COONH4 (20
mM, pH 4.5):ACN
(60:40)
Eluent A: formic
acid buffer (100
mM, pH 3.5):H2 O
(1:9); Eluent B:
formic acid buffer
(100 mM, pH
3.5):ACN (1:9);
gradient
ACN:ethanol:nbutyl amine:TFA
(96:4:0.10:0.16)
MeOH:H2 O (80:20)
305 nm
2012
[177]
ESI/MSn
detection
2012
[178]
2012
[179]
190400 nm
2012
[180]
222 nm
2012
[181]
237 nm
2012
[182]
ESI/MSn
detection
2012
[183]
ESI/MSn
detection
2012
[183]
ESI/MSn
detection
2012
[183]
ESI/MSn
detection
2012
[183]
254 nm
2012
[184]
296 nm
2012
[185]
2012
[186]
168.
Esomeprazole
magnesium
7 impurities
169.
Etimicin sulfate
API; antibiotic
26 impurities
170.
Fampridine
Isoniacin, niacin,
Isonico-tinamide,
3-aminopyridine, 2-amino
pyridine,
famp-ridine-N-oxide,
3-hydr-oxy-4-amino
pyridine
171.
Glucocorticoids
API; steroid
4-Dimethyl aminopyridine
C18, 50 mm 2 mm, 3
m
172.
Guaifenesin,
terbutaline sulfate
and ambroxol HCl
13 related substances
173.
Imatinib mesylate
Capsules; anticancer
8 impurities
174.
l-Alanyl-lglutamine
5 impurities
175.
l-Alanyl-lglutamine
9 impurities
Polysulfoethyl A, 150
mm 4.6 mm, 5 m
176.
l-Alanyl-lglutamine
7 impurities
QN-AX, 150 mm 4
mm, 5 m
177.
l-Alanyl-lglutamine
7 impurities
QN-AX, 150 mm 4
mm 5 m
178.
Linezolid
API; antibiotic
6 impurities
179.
Luliconazole
6 degradants
180.
Methamphetamine
20 impurities
Helium gas
Mass
selective
detector
Year
[Ref.]
24
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
Table 2
Continued
S.
no.
Name of drug
Matrix; therapeutic
category
Impurity/degradant
Column/stationary phase
Mobile phase
Detection
181.
Moxonidine
Tablet; antihpertensive
5 impurities
255 nm
2012
[187]
182.
Nevirapine
API; anti-HIV
2 impurities
220 nm
2012
[188]
183.
Niacinamide
API; vitamin
254 nm
2012
[189]
184.
API; antihypertensive
185.
Nonpeptide
(angiotensin AT1
receptor
antagonist)
Pantoprazole
Niacin, isonicotinamide,
picolinamide,
3-cyano-pyridine,
niacinamide N-oxide
4 impurities
MeOH:potassium
phosphate buffer
(50 mM), (15:85)
(pH 3.5)
Ammonium
phosphate buffer
(50 mM, pH
4.5):ACN (7:3)
CH3 COONH4 (20
mM, pH 5):ACN
(97:3)
186.
Plazomicin
API; antibiotic
187.
Praziquantel
188.
Rivastigmine
tartrate
API andTablet;
Anthelmintic
API; anti-Alzheimer
11 impurities
189.
Ropinirole
API; anti-Parkinsons
5 degradants
190.
Nanoemulsion;
antiprotozoal
API; antioxidant
2 degradants
192.
SCD: chalcone
derivative
Sodium
tanshinone IIA
sulfonate
Telmisartan
API; antihypertensive
193.
Thiocolchicoside
Methyl
4 ,4 -dibromometh-yl
biphenyl-2-carboxylate
6 degradants
194.
Trandolapril
API; antihypertensive
16 degradants
195.
Wogonin
API; anxiolytic
2 degradants
196.
Zolmitriptan
API; antimigraine
6 impurities
Phenyl, 100 mm 3
mm, 2.7 m
197.
Bortezomib
API; anticancer
3 impurities
191.
2-Chloromethyl-3,4dimethoxy pyridine
HCl
3 impurities
2 impurities
8 impurities
2.1.2. 2009
2.1.2.1. Impurity proling Both techniques of LCMS, ion trap mass
spectrometry and time of ight mass spectrometry were used
for characterization of impurities in chloroquine and hydroxychloroquine bulk drug samples [59]. 1-(1,1-Bis(4-uorophenyl)1,3-dihydroisobenzofuran-5-yl)-4-(dimethylamino) butan-1-one hydrobromide as an impurity of citalopram was isolated by semipreparative HPLC and structure was established by using Q-TOF
mass analyzer, NMR and IR spectroscopy. Overlaid FT-IR spectra
Year
[Ref.]
210 nm
2012
[190]
210 nm
2012
[191]
NH4 OH (25
mM):ACN; gradient
ACN:CH3 COONH4
(25 mM) (40:60)
Eluent A: KH2 PO4
(10 mM, pH
7.6):ACN (90:10);
Eluent B:
ACN:MeOH (60:40);
gradient
Toluene:ethyl
acetate:NH3 (6 M)
(5:6:0.5)
MeOH:H2 O (70:30)
(pH 5,TFA)
CH3 COONH4
(0.2%):MeOH
(35:65)
KH2 PO4 +
sodium-1-pentane
sulfonate (pH 3)
Ammonium
formate buffer (10
mM; pH 3):ACN;
gradient
Ammonium
hydrogen carbonate
(10 mM, pH
8.14):ACN (68:32)
MeOH:CH3 COONH4
buffer (5 mM)
(75:25)
KH2 PO4 (20 mM) +
sodium 1-hexan
sulfonate (5 mM, pH
2):ACN; gradient
Eluent A:
HCOOH:ACN:H2 O
(1:300:700); Eluent
B: HCOOH:ACN:H2 O
(800:200:1);
gradient
210 nm
2012
[192]
2012
[193]
2012
[194]
210 nm
210 nm
2012
[195]
330 nm
2012
[196]
2012
[197]
271 nm
230 nm
2012
[198]
MS/MS
Detection
2012
[199]
2012
[200]
275 nm
2012
[201]
220 nm
2012
[202]
270 nm
2012
[203]
this agent in Neoral capsules and its generic versions were determined [61]. Two monoacylated diacerein impurities of diacerein with
same molecular weight (MW = 326) but different position of acetyl
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
Fig. 3. Overlaid FT-IR spectra of (a) citalopram and (b) citalopram impurity-II. (Reuse
with the permission of Elsevier Limited, The Boulevard, Langford Lane, Kidlington,
Oxford OX5 1GB, UK.)
group was conrmed by NMR spectroscopy, which were characterized as 5-acetoxy-4-hydroxy-9,10-dioxo-9,10-dihydroanthracene-2carboxylic acid (1.14%) and 4-acetoxy-5-hydroxy-9,10-dioxo-9,10dihydroanthracene-2-carboxylic acid (1.24%) [62]. Polyethylene glycol (PEG) present as impurity in fatty alcohol ethoxylates (FAEs) which
are used as surfactants. Gradient elution favor the separation of PEG
and FAEs as these have dramatic difference in hydrophobicity of
PEG and FAEs, while evaporative light scattering detection (ELSD)
is not compactable with gradient elution, so both isocratic and gradient elution were used to study the same [64]. Atmospheric pressure chemical ionization (APCI) of mass spectroscopy was applied for
identication of gentamicin impurities, where no suppression in ionization was observed at high TFA concentration [65]. Over sulfated
chondroitin sulfate (OSCS) and dermatan sulfate were estimated in
heparin API by using a polymer-based strong anion exchange (SAX)
column with gradient elution form, which were present due to over
sulfating and incomplete purication, respectively [66]. As zirconiabased stationary phase coated with graphitized carbon offers wide
pH and temperatures range for separation, was applied to analyze 3[4-(2-methylpropyl)phenyl]propanoic acid as an impurity of ibuprofen [67]. Salidroside is phenolic glycoside of genus Rhodiola, used for
treatment of cardiovascular and cerebrovascular diseases. The biosynthetic pathways for impurities icariside D2, 4-hydroxyphenacyl-dglucopyranoside and picein were proposed [81]. Column packed with
dimethyl beta-cyclodextrin used as chiral stationary phases, was used
to determine related enantiomeric impurities of sertraline as it minimizes chiral hydrogen bonding and establishes weak dipole effect for
high selectivity of separation [82]. Off-line HPLCFT-IR coupling was
used for identication of tropicamide along with its major impurity
(apotropicamide) in raw material [84].
2.1.2.2. Forced degradation proling Forced degradation of tenatoprazole (novel proton pump inhibitor) was carried out to establish intrinsic stability, and found susceptible in acidic, oxidative and
photolytic condition [54], while with levooxacin only oxidative
degradant was identied [55]. As beta-lactam antibiotics are sensitive towards acidic/alkaline degradation, in this sequence, impurities in biapenem aqueous solution were identied as two dimmers
and three hydrolytic degradants and the degradation pathway was
also discussed [58]. Forced degradation study of zotarolimus and zotarolimus coated stents has revealed that coated stunt should protect
from moisture and heat, as these produce different type of degradants
[87].
25
26
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
Fig. 4. Schematic diagram showing Maillard reaction between lactose and memantine. (Reuse with the permission of Elsevier Limited, The Boulevard, Langford Lane,
Kidlington, Oxford OX5 1GB, UK.)
and spectinomycin in the presence of their impurities in pharmaceutical formulation [141]. Carboxylic acid impurities as pyruvic,
oxalic, formic, succinic, itaconic, aconitic, acrylic, citric, propionic and
fumaric acids were quantify in lactic acid prepared from fermentation of sugarcane juice and compared to commercial samples while
acetic, malic and butyric acids were not observed in any of sample
[142]. Four Maillard reaction (reaction between amino compounds
and reducing sugar, Fig. 4) impurities without chromophore were
determined as memantine-lactose, memantinedimethylamino
glycine, memantinegalactose and memantineglucose adducts
by HPLC using charged aerosol detection. Heptauorobuturic acid
was introduced in mobile phase to improve resolution and peak
shapes of the impurities [145]. No mutagenic potential of 2-(6methoxynaphthalen-2-yl) acrylic acid as unknown polar impurity of
naproxen was found by Ames test (biological assay method) using
Salmonella typhimurium [148]. MELC offers UV detection near 200
nm, proteins solubilization in complex matrices and fast analysis
time. Impurities in streptomycin sulfate was determined by reversed
phase ion-pair HPLC method using charged aerosol detection at the
level of 4.6% and 16.0%, which offers straightforward quantication
of all impurities [155]. Refractive index detection technique was used
to determine impurities of ursodeoxycholic acid which is used for
treatment of gallstones, billiary cirrhosis, viral hepatitis and cystic
brsosis [157].
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
photolysis conditions [133]. Intrinsic stability of fesoterodine was established according to ICH guidelines by forced degradation [139]
and 1-(4-(2-(2-bromobenzenesulfonamino)ethyl)phenylsuphonyl)3-(trans-4-methyl cyclohexyl) urea was characterized as impurity
of G004, a sulfonylurea derivative potential hypoglycaemic agent
[140]. Major forced degradation product of lornoxicam was formed
due to amide hydrolysis and oxygen addition across the enolic double bond [144]. Anti-HIV drugs, abacavir sulfate and atazanavir sulfate and anti-cancer drug anastrozole were studied to understand
the forced degradation behavior under different stressed conditions
[147,149]. Olanzapine and its degradation products were determined
in API and pharmaceutical dosage forms [150], while its oxidative
degradation impurities were characterized as hydroxymethylidene
thione and acetoxymethylidene thione [149]. Different forced degraded samples of olaquindox were studied by HPLC combined with
hybrid ion trap/time-of-ight mass spectrometry and especially its
degradation products were correlated with its phototoxicity and
photoallergic reaction [151]. Two photo-degraded products of valsartan were characterized as: N-[2 -(1H-tetrazol-5-yl)-biphenyl-4ylmethyl]-N-isobutylpentanamide formed by decarboxylation and N(diazirino[1,3-f] phenanthridin-4-ylmethyl)-N-isobutylpentanamide
resulted from additional loss of nitrogen from tetrazole followed by
cyclization [158].
27
2-chloroethyl p-toluenesulfonate) as genotoxic impurities in cloperastine fendizoate were determined by two different chromatographic methods, GCMS and HPLC-DAD, respectively, due to different physical and chemical properties of these impurities. Fendizoate was removed by strong anion-exchange (SAX)-SPE before GCMS analysis, as a step of sample purication [171]. Although, six impurities were reported in deferasirox, but a new impurity was characterized as 2-[3,5-bis(2-hydroxy-phenyl)-[1,2,4]-triazol-1-yl]-benzoic
acid, which can be minimized by controlling the concentration of
2-hydrazino-benzoic acid in 4-hydrazinobenzoic acid [172]. Cross
examination by liquidliquid extraction and solid-phase microextraction [186] and common synthetic impurities identication [161]
were reported for impurity proling in methamphetamine and 4methylthioamphetamine, respectively. Chloromethyl-3,4-dimethoxy
pyridine hydrochloride, is generally used as counter-ions to form salt
or protecting group appears as genotoxic impurity in APIs. Ammonium acetate was used to improve detection sensitivity of this genotoxic impurity by LC/MS/MS technique, where it increases ionization
[191]. High pH mobile phase (pH > 11) with XBridge C18 column was
employed for analysis of aminoglycoside plazomicin and its impurities, which allows higher loadings of drug and its impurities. Thus,
higher pH of mobile phase compensates lower UV absorption of the
drug [192]. Methyl 4 ,4 -dibromo methyl biphenyl-2-carboxylate was
identied as principle synthetic route impurity in telmisartan based
on spectral data deriving from 2D-NMR and MS [198]. Zolmitriptandimer was characterized as impurity in zolmitriptan by means of LC
MS and NMR studies which was identied as by-product of its last
step Fischer indole synthesis [202]. When a uid has temperature
and pressure are higher than corresponding critical values, known
as supercritical uid [206] and it is used in supercritical uid chromatography (SFC) for impurity proling of pharmaceutical products.
The elution prole in SFC is generally orthogonal to RPLC data, which
were very useful in assessing purity of APIs. SFC method is more
complex than RPLC due to difcult to understand solute (complex
molecule)-stationary phase interactions [207].
2.1.5.3. Impurity and forced degradation proling HPLC and spectrophotometric methods were applied to determine bupropion hydrochloride, its alkaline degradates and 3-chlorobenzoic acid as impurity [167]. Preparative HPLC, LCMS/MS, UPLC-TOF-MS, NMR and
FT-IR spectroscopy were employed to study forced degradation of
28
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
dipyridamole product and two additional impurities were also characterized [175]. Total 15 impurities and eslicarbazepine were determined by stability indicating RP-HPLCUV method and characterized by LC/ESI-IT/MS/MSn . Acridine-9-carboxylic acid was identied as degraded impurity, while (10S)-10-hydroxy-10,11-dihydro5H-dibenzo[b,f]azepine-5-carbox-amide was found as both degraded
as well as process impurity and remaining all were process related
impurities [176]. 26 impurities were detected in commercial samples of etimicin sulfate, a semi-synthetic aminoglycoside antibiotic
with less chronic nephro- and ototoxicity, by liquid chromatography ion-trap mass spectrometry by using C18 column with an alkaline aqueous mobile phase. The source of impurities were identied as starting material for synthesis and its residual impurities, intermediates, synthetic by-products and degradation products [178].
Seven potential impurities (isoniacin, niacin, isonicotinamide, 3aminopyridine, 2-aminopyridine, fampridine n-oxide and 3-hydroxy4-aminopyridine) of fampridine were determined by using C18 stationary phase in gradient mode and ultraviolet dual wavelength detection technique. Fampridine is used to improve walking in patients
with multiple sclerosis and its major oxidative degradation product was also determined as fampridine n-oxide [179]. About 24 analytes including guaifenesin, terbutaline sulfate, ambroxol HCl, their
related compounds and degradation product were determined by
stability-indicating LC method [181]. In similar way, niacinamide and
potential impurities (niacinamide n-oxide, isonicotinic acid, niacin,
isonicotinamide, picolinamide, 3-cyanopyridine) were also analyzed
where niacinamide n-oxide was identied as oxidative degradation
product [189]. In addition to six known impurities, three impurities
were identied as rivastigmine N-oxide, rivastigmine p-isomer and
rivastigmine o-isomer. Rivastigmine N-oxide was also identied as
oxidative degradant of the drug [194]. Sodium tanshinone IIA sulfonate is used in China for treating cardiovascular disease is isolated
from roots of Salvia miltiorrhiza. Starting material, synthetic byproducts and degradation were identied as main sources the impurities
[197]. Process related impurity (6-chloro-5,7-dihydroxy-8-methoxy2-phenyl-4H-chromen-4-one) and degradation product of alkaline
condition (5,7-dihydroxy-6-methoxy-2-phenyl-4H-chromen-4-one)
of synthetic wogonin crude drug were characterized by HPLCQ-TOF
MS/MS technique [201].
Fig. 5. General outline of the impurity fate mapping framework. (Reuse with the permission of Elsevier Limited, The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB,
UK.)
and analytical search for potential impurities in the starting materials, intermediates and drug substance, and experimental studies to
track their fate through the manufacturing process in order to understand the process capability for rejecting such impurities. Comprehensive IFM provide elements of control strategies for impurities [95]. The regression coefcient plots of resolution between peak
pairs were included in the experimental design to optimize separation of oxytocin and its related substances [117]. Multiobjective
optimization technique was employed to optimize microemulsion
liquid chromatographic (MELC) method through Derringers desirability function for separation of perindopril tert-butylamine and its
four impurities, where central composite design was used to study
different factors responsible for the separation [153].
Analysis time for sulindac and its related impurities (E-sulindac,
sulindac sulfone and sulindac sulde) was reduced using Platinum
C18 Rocket column (53 mm 7 mm, 1.5 m particle size) and experimental design, which was processed by software R version 2.7.2.
Four factors were taken into consideration for optimization of the
method, which were: duration of initial isocratic step, percentage
of organic modier at beginning of gradient, percentage of organic
modier at end of gradient and gradient time. Fig. 6 shows the probability surfaces in different directions of the space around the optimal solution (for each graph, two factors were xed at their optimal
values) [156]. Experimental design as tool was applied for analysis
of genotoxic impurity 4-dimethylaminopyridine in glucocorticoids,
where quadratic model, central composite face was employed to optimize the method [180]. Full factorial design and surface response
curve were used to study forced degradation proling of luliconazole
[185]. For optimization of LC method, which was used for analysis
of moxonidine and its impurities in tablet, both central composite
design technique and response surface method were applied by using variable factors as buffer pH value, column temperature, methanol
content [187]. Response surface methodologies, such as Box-Behnken
and Central Composite Design (Fig. 7) were used to optimize compositional parameters and evaluate interaction effects for validation of
stability-indicating HPTLC method which was applied to degradation
kinetic proling of ropinirole [195].
As above we have discussed trends in analytical perspective on impurity and forced degradation proling of pharmaceuticals including
different techniques used in impurity proling, experimental design,
different conditions of analysis (mobile phase, column, types of elution and detection wavelength) and therapeutic category of API. Statistical tools have been applied to analyze above various parameters
of impurity and forced degradation proling and these parameters
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
29
Fig. 8. Different columns used for impurity and forced degradation proling during
20082012.
Fig. 6. Surface of probability to reach S > 0. The design space is surrounded by black
lines for an expected probability to have well-separated peaks is 0.9. Factors optimal
values are placed between parentheses. (Reuse with the permission of Elsevier Limited,
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK.)
combination of hydrophilic stationary phases and hydrophobic mobile phases and generally effective for separation of low-molecular
weight polar compounds. Different columns (cyano, amino, silica and
sulfobetaine) with variation in pore size, particle size and dimension
were used for the study [43].
Chiral chromatography is a tool for analytical determination of
enantiomeric purity as well as isolation of pure enantiomers. In
this context, enantioselective and chemoselective HPLC method was
employed to determine (R)-( + )- and (S)-()-lansoprazole enantiomers and its reported impurities using Chiralpak IA with mixture of mobile phase consisting of methyl-tert-butyl ether:ethyl acetate:ethanol:diethylamine [70]. BEH (bridged ethylene hybrid) C18
column one of the newer technology in column chemistry, where
surface hybrid groups reduce surface silanol concentration, internal
bridging groups provide high interconnectivity and internal hybrid
groups provide hydrophobicity. These characteristics of BEH column
enables strength of column (withstand higher pressure), great peak
shape, wider pH range and shorten run time. Ultra performance liquid chromatography (UPLC) equipped with BEH column was used
for determination of atorvastatin, fenobrate and their impurities in
tablets, which offers high optimum velocities and low minimum plate
heights for well-retained compounds with very small run time [21].
Maximum work on active pharmaceutical ingredient (API) for impurity and degradation proling, which was totalled to 73% during
20082012 (Fig. 9). Maximum of 14% of total work was on tablet
doasge form and followed by capsules, creams and injections. Although, other dosage forms were also subjected to perform this study,
such as coated eluting stents [30,87], powder for injection [48], lotion
[56], soft gelatin capsules [61], patches [77], nasal solution [91], plant
extracts [163], syrup [181], and nanoemulsion [196].
30
D. Jain, P.K. Basniwal / Journal of Pharmaceutical and Biomedical Analysis 86 (2013) 1135
3. Conclusion
The present review describes comprehensive update on recent
trends in analytical perspectives of degradation and impurities proling of pharmaceuticals including active pharmaceutical ingredient
(API) as well as drug products during 20082012, which may serve
and ample view to all the interest group.
Acknowledgements
Fig. 9. Different matrix used for impurity and forced degradation proling during
20082012.
Fig. 10. Types of elution performed in LC analysis for impurity and forced degradation
proling during 20082012.
Fig. 11. Drug categories of different matrix used for impurity and forced degradation
proling during 20082012.
2.6.Therapeutic categories
Although, most of all therapeutic categories have been taken
into consideration for impurity and forced degradation proling, but
drug candidate belongs to chemotherapeutic category were maximum used for this study as 18% (Fig. 11) and followed by drugs acting on cardiovascular system (16%), central nervous system (15%),
immunomodulator (6%), GIT (6%), antineoplastics (6%), psychopharmacological agents (4%), etc. Recently, ten impurities of antihyperlipidemic drug (simvastatin) were summarized by Basniwal and
Jain [208].
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