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ISSN 1061-9348, Journal of Analytical Chemistry, 2018, Vol. 73, No. 4, pp. 303–316. © Pleiades Publishing, Ltd., 2018.

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Determination of Dipeptidyl Peptidase-4 Inhibitors


by Spectrophotometric and Chromatographic Methods1
P. B. Deshpande* and S. R. Butle
Department of Pharmaceutical Chemistry, School of Pharmacy, Swami Ramanand Teerth Marathwada University,
MH, Nanded-431606 India
*e-mail: padmanabh77@yahoo.co.in
Received September 6, 2016; in final form, September 12, 2017

Abstract⎯Dipeptidyl peptidase-4 (DPP-4) inhibitors are a novel class of oral anti-diabetic agents used in the
treatment of type 2 diabetes mellitus and work to enhance the effect of incretin hormones. There has been
significant research on wide range of analytical techniques that could be useful in the estimation of DPP-4
inhibitors in formulations and biological matrices. Analytical methods such as ultraviolet (UV) spectropho-
tometry, mass spectroscopy, NMR spectroscopy, HPLC, high pressure thin layer chromatography, ultra per-
formance liquid chromatography, liquid chromatography‒mass spectrophotometry and capillary zone elec-
trophoresis have been reported for the estimation of DPP-4 inhibitors in single and/or in combination with
other drugs. This comprehensive review covers most of the spectrophotometric and chromatographic meth-
ods described for the determination of sitagliptin, alogliptin, vildagliptin, linagliptin, saxagliptin and
teneligliptin in pure forms, in different pharmaceutical dosage forms and biological fluids. From the review
it can be deduced that a large number of chromatographic methods have been developed, and HPLC-UV
methods have been commonly used in the detection and evaluation of DPP-4 inhibitors.

Keywords: sitagliptin, alogliptin, vildagliptin, linagliptin, saxagliptin, teneligliptin, analytical methods


DOI: 10.1134/S1061934818040032

In diabetes mellitus, incretin response is dependent Mechanism of action of DPP-4 inhibitors. DPP-4
on the increase DPP-4 enzymatic activity in plasma inhibitors highly selectively inhibit dipeptidylpepti-
and release in visceral adipose tissues. Increase in dase-4 enzyme for the treatment of T2DM. The DPP-
DPP-4 levels correlated with the degree of glycemia or 4 inhibitors are a class of agents that act as like incretin
insulin resistance, that suggesting DPP-4 mediated enhancer. By inhibiting DPP-4 enzyme, they increase
incretin degradation which is responsible for patho- the level of two known active incretin hormones,
genesis of diabetes mellitus. DPP-4 inhibitors are a GLP-1 and glucose dependent insulinotropic poly-
newer class of oral anti-diabetic agents, used world- peptide (GIP). Incretin is a part of endogenous system
wide, due to modest effects on HbA1c, and lack of involved in the physiological regulation of glucose
serious side effects. homeostasis. When blood glucose levels are normal or
elevated, GLP-1 and GIP increase synthesis and
DPP-4 is one of the members of bound glycopro- release of insulin from pancreatic beta cell. GLP-1
tein responsible for the catalytic degradation of incre- also lowers glucagon secretion from pancreatic alpha
tin hormones, glucagon-like peptide-1 (GLP-1) and cell, leading to reduce hepatic glucose production.
glucose dependent insulinotropic polypeptide. DPP-4 This mechanism is unlike the mechanism seen with
is widely distributed in various body parts, such as sulfonylurea, cause insulin release even when glucose
pancreas, kidney, lungs, spleen and prostate gland [1]. level is low, which can lead to sulfonylurea induced
Endothelial, epithelial and immune cells such as hypoglycemia in patients with T2DM and in normal
T cells and macrophages are highly expressed with subjects [6].
DPP-4 enzyme. Disturbance in the expression of Pharmacokinetics. All at once, gliptin shows good
DPP-4 is generally observed in certain disorders such oral bioavailability which is not considerably influ-
as autoimmune diseases, solid tumors, hepatitis-C, enced by intake of food. Adequately prolonged half-
type 2 diabetes (T2DM), and obesity [2‒4]. Chemical life and sustained DPP-4 enzyme inactivation gener-
structures, nomenclatures and molecular weights of ally permit one single oral administration per day for
these drugs are shown in Table 1 [5]. the management of T2DM. The only exception is
VILDA for which a twice-daily administration is rec-
1 The article is published in the original.
ommended because of a shorter half-life. The phar-

303
304 DESHPANDE, BUTLE

Table 1. Chemical structures of studied dpp-4 inhibitors

Drug
Chemical structure Chemical name Mol. wt.
(abbrev.)

F F
F
F N (R)-4-Oxo-4-[3(trifluoromethyl)-5,6 dihydro [1,
Sitagliptin N
N 2, 4]triazolo [4,3a]pyrazin-7(8H)-yl]-1-(2,4,5-tri- 407.31
(SITP) N fluorophenyl)butan-2-amine)
NH2 O
F
F

N
H2 N 2-({6-[(3R)-3-Aminopiperidin-1-yl]-3-methyl-
Alogliptin N N O 2,4-dioxo-3,4-dihydropyrimidin- 339.39
(ALGP)
1(2H)yl}methyl)benzonitrile

C
N

Vildagliptin N (S)-1-[N-(3-Hydroxy-1-adamantyl) glycyl]pyrroli-


N 303.39
(VILDA) OH H dine-2-carbonitrile
O
N

O 8-[(3R)-3-Aminopiperidin-1-yl]-7-(but-2-yn-1-
Linagliptin
N N yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]- 472.54
(LING) N
N 2,3,6,7-tetrahydro-1H-purine-2,6-dione
N N
O N
NH2

O H
(1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricy-
Saxagliptin N H clo[3.3.1.13,7]dec-1-yl) acetyl]- 2-azabicyclohex- 315.41
(SAXG) OH NH2 ane-3-carbonitrile
N

O {(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H pyrazol-
Teneligliptin
5-yl)-1-piperazinyl]-2- pyrrolidinyl}(1,3-thiazo- 426.58
(TENG) N N N lidin-3-yl)methanone
N N
NH S

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DETERMINATION OF DIPEPTIDYL PEPTIDASE-4 INHIBITORS 305

Table 2. Pharmacokinetic properties of DPP-4 inhibitors


Pharmacokinetic
SITP ALGP VILDA LING SAXG TENG
parameter
Administration route Oral Oral Oral Oral Oral Oral
Bioavailability, % 87 100 85 30 67 87
Metabolism Excreted Excreted Hepatic 90% excreted Hepatic Hepatic
unchanged unchanged to LAY151 unchanged CYP3A4/5 CYP3A4
Elimination half life, h 12.4 12.4‒21.4 1.5 >100 2.5 24.2
Plasma protein binding, % 38 20 9.3 70‒80 <10 77‒82
Excretion Faeces Urine Urine Enterohepatic Renal Renal
and urine or urine and hepatic and hepatic

Table 3. Physicochemical properties of studied DPP-4 inhibitors

Drug pKa Solubility λmax, nm

Sitagliptin (SITP) 7.7 Water soluble, slightly soluble in methanol, ethanol, acetone, acetonitrile, insol- 254
uble in isopropanol

Alogliptin (ALGP) 9.5 Soluble in methanol and dimethyl sulfoxide, sparingly soluble in water as well as 222
ethanol

Vildagliptin (VILDA) 14.7 Soluble in methanol, water and dimethyl sulfoxide 217

Linagliptin (LING) 8.6 Soluble in methanol, sparingly soluble in ethanol and slightly soluble in iso-pro- 242
panol and acetone

Saxagliptin (SAXG) 7.9 Sparingly water soluble, soluble in methanol, ethanol, isopropyl 290
alcohol, acetonitrile, acetone and polyethylene glycol

Teneligliptin (TENG) 8.7 Soluble in methanol, DMSO and water 244

macokinetic characteristics of DPP-4 inhibitors sug- Table 4. Solvents used in spectrophotometry


gest that these compounds are not exposed to a high Wavelength
risk of drug-drug interactions and contribute to a good Solvent
of absorption, nm
efficacy/safety ratio in the management of T2DM in
clinical practice [7‒11]. Summary of differences in the
route of administration, bioavailability, metabolism, Water 190
plasma protein binding and excretion between the
Methanol 205
individual compounds is depicted in Table 2. The dif-
ferent physicochemical properties of DPP-4 inhibitors
Ethanol 205
are represented in Table 3.
Selection of solvents in spectrophoptometry. The Acetonitrile 190
solvent which is used in spectrophotometry should not
absorb ultraviolet radiation in the same region as the Chloroform 240
sample whose spectrum is being determined. Gener-
Cyclohexane 195
ally the solvents which do not contain the conjugated
systems are most appropriate for performing spectro-
Carbon tetrachloride 265
photometric analysis even if they vary at the shortest
wavelength at which they remain transparent to ultra- Tetrahydrofuran 220
violet radiation. The most commonly used solvents in

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306 DESHPANDE, BUTLE

spectrophotometry along with their minimum regions uid phase. One disadvantage of supports coated with
of transparency are listed in Table 4. liquid phase is that the developing solvent may gradu-
Chromatographic separations. Chromatographic ally wash off the liquid phase during repeated use. To
separations consist of a variety of separation proce- overcome this problem, bonded phases have been
dures which are commonly based on selective reten- developed where the liquid phase is covalently bonded
tion of analytes on stationary phase and their sequen- to the supporting material which may be silica or sili-
tial release into mobile phase. Chromatographic sepa- cone polymer.
rations are differentiated on the basis of purpose of The decreasing particle size dramatically improves
separation, the format in which stationary phase is the efficiency of HPLC column, especially when the
placed, physical state of mobile phase, scale of opera- column is operated at the optimum velocity. It is seen
tion and separation mechanism. that reduction of particle size from 45 to 6 μm results
Mobile phases used in chromatography. The primary in a ten-fold or more decrease in plate height. Every
constituent of mobile phases in reversed phase chro- time the diameter of particle is halved, the pressure
matography is water. To adjust the polarity of the drop required is raised by approximately a factor of
mobile phase, water miscible solvents such as metha- four. Often, however, the column length can be short-
nol, ethanol, acetonitrile, dioxane, tetrahydrofuran ened significantly. There are no practical operation
and dimethyl formamide are added; sometimes acids, conditions, when particles larger than 5 μm would be
bases, buffers, or ionic surfactants also added. Water desirable from the point of view of achieving high plate
which is to be used as mobile phase needs to be of high number quickly.
quality, either distilled or demineralized. Polarity The plate count can be increased 1.7 times for
modifiers like methanol, acetonitrile, and tetrahydro- packing material of 3 μm relative to a 5 μm packing
furan are most widely used. Methanol and acetonitrile material for a specified column length. Furthermore,
have comparable polarities, but latter is an aprotic sol- in limits, the plate count and the length of the column
vent. Aprotic nature is very important, if hydrogen are proportional, whereas the resolution of two peaks
bonding plays a significant role in the separation. The and the square root of the plate count are also propor-
mobile phase is filtered prior to using inorganic salts tional. Eventually, however, the use of ever finer parti-
and ionic surfactants, since these additives frequently cles or longer columns of the same size particles
contain a significant amount of water-insoluble con- requires pressures that exceed 5000 psi. Commercial
taminants that may harm the column. columns are available with packing materials with par-
Reversed phase mobile phases are generally non- ticle diameters of 3, 5, and 10 μm [14, 15].
flammable due to high water content. In order to Column properties affecting separation. Column
remove the dissolved gases in the solvents it is very length and diameter are important parameters are
important to degas the mobile phases. Normal phase related to several chromatographic characteristics of
mobile phases are generally non-polar. Linear hydro- chromatographic separation. The parameters which
carbons such as pentane, hexane, heptane, and isooc- are affected by column dimensions are (1) resolution
tane are frequently used. Aliphatic halides such as Rs, (2) retention time tR, (3) selectivity factor α,
dichloromethane, dichloroethane, butyl chloride and (4) column efficiency/band broadening.
chloroform are also used. Modifiers such as alcohols, (1) Resolution Rs describes the separation power of
tetrahydrofuran, and acetic acid are common compo- the entire chromatographic system in relation to the
nents of these mobile phases. Generally, dissolved specific components of the mixture. The resolution
gases are not a problem with normal phase solvents. (Rs) between two neighboring peaks is the ratio of the
Since these solvents are less viscous, lower pressures distance between two peak maxima. It is obtained by
are necessary to maintain an adequate flow rate. A dividing difference between the retention times of two
major drawback of some normal phase solvents is their solutes by their average peak width. For baseline sepa-
flammability [12, 13]. ration, the ideal Rs value is 1.5.
Stationary phases (column packing) in chromatogra- (2) Retention time tR is time required for passage of
phy. Three forms of column packing materials are mobile phase through the column is called t0, dead
available based on a rigid solid structure. These are time or retention time of solute which is unretained. A
microporous supports in which the system of micropo- name retention factor formally recognized as capacity
res ramifies all the way through the particles that are factor is generally used to determine the migration rate
generally 5 to 10 μm in diameter; pellicular supports in of an analyte on a column. If retention factor of ana-
which porous particles are layered on-to an inert solid lytes is below one, it is very difficult to determine the
core like a glass bed of about 40 μm in diameter; retention time accurately as elution is faster. Greater
bonded phases where stationary phase is chemically retention factor indicates that compound takes long
bonded onto an inert support. time for elution. Capacity factor is the ratio between
In liquid-liquid partition system, the immobile decreased retention volume and dead volume. The
phase is coated on an inert support. Both microporous ratio of the number of solute molecules in the station-
and pellicular supports are used for supporting the liq- ary phase to the number of molecules in the mobile

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DETERMINATION OF DIPEPTIDYL PEPTIDASE-4 INHIBITORS 307

phase is defined as capacity factor, k'. The desired Chromatographic methods. High-performance thin
value ranges from 2 to 10. layer chromatography. Deshpande et al. [36] proposed
a selective stability-indicating high performance thin
(3) Selectivity factor α also known as separation layer chromatographic (HPTLC) method for estima-
factor (α) is determined by measuring relative reten- tion of SITP as bulk drug and in tablet dosage form.
tion of two components in a mixture, it is the ratio of HPTLC methods for the simultaneous determination
the capacity factors of both peaks, and the ratio of its of SITP with MET in their combined tablet formula-
attuned retention times. The selectivity denotes the tion have been developed [37‒39]. Sharma et al.
power of separation of particular adsorbent to the mix- [40‒42] suggested HPTLC method for estimation of
ture of particular components. This parameter does alogliptin benzoate as single and in combination with
not depend on the column efficiency but is dependent MET as well as PIO in pure and tablet dosage forms.
on the component nature, type of eluent, eluent com- Stability indicating HPTLC method has been used for
position and adsorbent surface chemistry. When selec- determination of VILDA in tablet dosage form [43].
tivity of two components is equal to 1, it is difficult to Stability-indicating method has been reported for the
separate them by making improvement in the column simultaneous determination of LING and MET in the
efficiency. The ideal value of α is 2.
presence of their degradation products [44]. HPTLC
(4) Column efficiency/band broadening- The method for estimation of TENG in pharmaceutical
number of theoretical plates per meter is measure of preparation has also been reported by Shind et al. [45].
column efficiency (N) which measures band spreading The summary of reported HPTLC-densitometric
of a peak. A good column and system performance is methods for separation and estimation of DPP-4
indicated by similar spreading of band which inhibitors in bulk and pharmaceutical dosage forms is
means higher number of theoretical plates. listed in Table 6.
Moreover, columns having N which ranges from 5000
to 10000 plates/meter represent a good system. High-performance liquid chromatography. There
is a remarkable increase in the utilization of high-per-
Reported analytical methods. Ultraviolet spectropho- formance liquid chromatography for determination of
tometry. Ultraviolet spectrophotometric methods such studied DPP-4 inhibitors. HPLC has been used regu-
as Vierodt’s, derivative, absorption ratio, area under larly in all fields of DPP-4 inhibitors research. The
curve and dual wavelength methods have been reported methods based on use of different stationary
reported for the determination of different DPP-4 phases (silica C8, C18, cyanopropyl), mobile phases
inhibitors in bulk and pharmaceutical dosage forms and using UV, fluorescence or tandem mass spec-
(Table 5). Simple UV spectrophotometric, first order trometry for detection. The various reported HPLC
derivative, absorbance ratio methods were developed methods [46‒127] for quantitative determination of
for the determination of SITP in pharmaceutical dos- DPP-4 inhibitors either as single or in combination
age form [16‒19]. UV spectrophotometric, absor- with other drugs in pure, pharmaceutical dosage forms
bance ratio and Vierodt’s methods were used for the and biological fluids are shown in Table 7.
determination of SITP in combination with simvstatin
(SIM) as well as metformin (MET) in tablets [20‒24]. Liquid chromatography-mass spectrophotometry.
Absorption ratio and simultaneous equation, UV- Pontarolo et al. [128] have demonstrated HPLC-tan-
spectrophotometric methods have been developed for dem mass spectrometry (MS/MS) method that
the determination of ALGP and metformin HCl allows the simultaneous quantification of VILDA,
(MET) in bulk and combined tablet dosage form MET and MET-related compounds (A, B, and C) in
[25‒27]. Derivative spectrophotometry, 1D and 2D tablets. The analysis was performed on an Agilent 1200
along with dual wavelength and area under curve spec- HPLC system equipped with a G1312B binary pump,
trophotometry were used to estimate ALGP in combi- G1379B degasser, and G1316B column oven, coupled
nation with pioglitazone (PIO) in tablets [28, 29]. to an Applied Biosystems MDS Sciex API 3200 Triple
Spectrophotometric and spectrofluorimetric methods Quadrupole Mass Spectrometer equipped with a
for the determination of VILDA and SAXG in bulk syringe pump and electrospray ionization (ESI)
and pharmaceutical preparations based on derivatiza- source. Chromatographic separation was carried out
tion by 1,2-naphthoquinone-4-sulfonic acid sodium using an XBridge C8 (150 × 4.6 mm, 5 μm) column
salt and 4-chloro-7-nitrobenzofurazan has been used maintained at 25°C. The method consisted of acetoni-
[30]. A simple UV-spectrophotometric method for trile: water: formic acid (20 : 80 : 0.1, v/v/v) as mobile
determination of LING alone and in combination phase with flow rate 800 μL/min. The MS ESI source
with VILDA has been developed in bulk and pharma- operated in positive ion mode and analyte quantifica-
ceutical dosage form [31, 32]. UV method for the tion was achieved using multiple reactions monitoring.
determination of SAXG as single and in combination The ion source parameters include curtain gas 10 psi,
with MET and methyl DOPA has been used employ- collision-activated dissociation 6 psi, nebulizer gas
ing simultaneous equation and absorbance ratio 45 psi turbo gas 40 psi, ion spray voltage (IS) 5500 V,
method [33‒35]. and temperature 600°C.

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308 DESHPANDE, BUTLE

Table 5. Spectrophotometric methods for determination of DPP-4 inhibitors


Drug(s) Method λmax, nm Solvent Reference

SITP – 267 Distilled water [12]


SITP First Order Derivative 267.4 Distilled water [13]
SITP – 267 0.1 M HCl [14]
SITP Absorption ratio 267 Distilled water [15]
Area under curve 261‒270
SITP, SIM – 267 Buffer‒methanol (25 : 75, v/v) [16]
SITP, MET Absorbance maxima 266, 232 Distilled water [17]
Area under curve 244‒279
222‒240
SITP, SIM Absorption ratio 250, 237 Methanol‒water (60 : 40, v/v) [18]
SITP, SIM Vierodt’s 267, 238 Methanol‒water (90 : 10, v/v) [19]
SITP, MET Vierodt’s 267, 231 Distilled water [20]
ALGP, MET Vierodt’s 277, 232 Methanol‒water [21]
Absorption ratio 250, 277
ALGP, MET Vierodt’s 224, 237 Methanol [22]
Absorption ratio 224, 251
ALGP, MET Q-absorbance ratio 251, 232 — [23]
Area under curve 272‒282
227‒237
ALGP, PIO First order derivative 275, 268.2 Methanol [24]
Dual wavelength 270.2, 265
280, 271
ALGP, PIO Second order derivative 276, 226 Methanol [25]
Area under curve 271‒281
221‒231
VILDA, SAXG Derivatization by 1,2-naphthoqui- 470, 475 Water‒methanol [26]
none-4-sulfonic acid sodium salt
and 4-chloro-7-nitrobenzofurazan
LING — 241 Methanol‒water (50 : 50, v/v) [27]
LING, VILDA — 294 Distilled water [28]
SAXG — 208 Methanol [29]
SAXG, MET Vierodt’s 274, 231 Distilled water [30]
SAXG, DOPA Simultaneous equation 211, 280 Distilled water [31]
Absorbance ratio 240, 280
204‒241
Area under curve 265‒314
276, 291
Dual wavelength 208, 216

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DETERMINATION OF DIPEPTIDYL PEPTIDASE-4 INHIBITORS 309

Table 6. Thin layer chromatography-densitometric methods for determination of the DPP-4 inhibitors (stationary phase
silica gel 60 F254)
Detection
Drug(s) Mobile phase Reference
wavelength, nm

SITP Toluene‒methanol (8 : 2, v/v) 265 [32]

SITP with MET Butanol‒water‒glacial acetic acid (6 : 2 : 2, v/v/v) 227 [33]

SITP with MET Methanol‒ammonia‒glacial acetic acid (9.4 : 0.4 : 0.2, v/v/v) 214 [34]

SITP with MET 1% (w/v) ammonium acetate in methanol 257 [35]

ALGP Acetonitrile‒1% ammonium acetate in methanol (4.5 : 5.5, v/v) 277 [36]

ALGP with PIO Acetonitrile‒1% ammonium acetate in methanol (4.5 : 5.5, v/v) 254 [37]

ALGP with MET Acetonitrile‒1% ammonium acetate in methanol (4.5 : 5.5, v/v) 253 [38]

VILDA Ethyl acetate‒methanol (8.5 : 1.5, v/v) 217 [39]

LING with MET Acetone‒methanol‒toluene‒formic acid (4 : 3 : 2 : 1, v/v/v/v) 259 [40]

TENG Toluene‒chloroform‒ethanol‒diethylamine (4 : 4 : 1 : 1, v/v/v/v) 254 [41]

Liquid chromatography-tandem mass spectrome- pharmacokinetic and protein binding characteristics


try (LC-MS/MS) method has been described for the of TENG in rats. Sample preparation was done
determination of linagliptin in human plasma. Telmis- through a protein precipitation procedure using SITP
artan was used as internal standard. Separation was as internal standard. Chromatographic separation was
carried out on Waters X-Bridge C18 column. The performed using Poroshell 120 EC-C18 column
mobile phase containing acetonitrile: formic acid (100 × 3.0 mm, 2.7 μm). The method consisted of
(0.1%) (90 : 10, v/v) at a flow rate of 0.6 mL/min was 10 mM ammonium formate and acetonitrile as mobile
used. ESI-MS was kept in the positive mode and the phase at a flow rate of 0.45 mL/min. Detection was
operating parameters were: ion spray voltage 5500 kV, carried out in selective ion monitoring mode using
drying gas temperature 500°C, nebulizer gas pressure positive ion electrospray ionization high resolution
35 psi, auxillary gas pressure 40 psi, de-clustering accurate mass spectrometry.
potential 71 kJ for LING and 65 kJ for internal stan-
dard. The retention times were 1.45 and 1.20 min for
LING and internal standard respectively [129]. ***
LC-MS/MS method was reported by Chunduri A comprehensive review on different spectropho-
et al. [126] for quantification of TENG in human tometric and chromatographic methods reported for
plasma using repaglinide as internal standard. The the detrmination of six DPP-4 inhibitors namely,
analytes and internal standard were extracted by liq- Sitagliptin, Alogliptin, Vildagliptin, Linagliptin,
uid-liquid extraction technique using methyl tert- Saxagliptin and Teneligliptin in bulk, different phar-
butyl ether. Separation was carried out on a Hypersil maceutical dosage forms and biological matrices has
Gold C18 column using 0.1% formic acid in Milli-Q been presented. Some LC-MS/MS methods offering
water and 0.1% formic acid in acetonitrile as mobile high sensitivity and short analysis time have also been
phase. The quantification was performed in a positive developed and validated for quantification of DPP-4
electro-spray ionization mode and multiple reactions inhibitors in human plasma. The study of the available
monitoring. Nitrogen gas was used as both cone gas data revealed that HPLC was comprehensively used
and desolvation gas. The authors have productively for the quantitative estimation of DPP-4 inhibitors
applied the proposed method to evaluate TENG con- since specificity of HPLC method is excellent and suf-
centrations in human plasma samples for pharmacoki- ficient precision is also attainable. However it has to be
netic/bioequivalence studies. confirmed that the astonishing specificity, precision
Ultra high performance liquid chromatography- and accuracy are attainable only if wide-ranging sys-
quadrupole time-of-flight mass spectrometry study tem suitability tests are carried out before the HPLC
was reported by Shantikumar et al. [131] to investigate analysis. We recommend the HPLC–MS/MS

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310 DESHPANDE, BUTLE

Table 7. Reversed phase HPLC methods for determination of the studied DPP-4 inhibitors
Analytical
Drug(s) Column Mobile phase Reference
wavelength, nm
SITP Phenomenex C18 Triethylamine (0.5%, v/v)‒acetonitrile 267 [42]
(250 × 4.6 mm, 5 μm) (77 : 23, v/v)
SITP Zorbax Eclipse XDB C18 0.01 M potassium dihydrogen phosphate 267 [43]
(150 × 4.6 mm, 5 μm) (pH 2.5)‒methanol (50 : 50, v/v)
SITP with MET Xterra Symmetry C8 Methanol‒acetonitrile‒phosphate buffer 254 [44]
(100 × 4.6 mm, 5 μm) (pH 8) ( 20 : 35 : 45, v/v/v )
SITP with MET Phenomenex C18 0.02 M potassium dihydrogen phosphate 252 [45]
(250 × 4.6 mm, 5 μm) (pH 4.3)‒acetonitrile (55 : 45, v/v)
SITP with MET Waters C18 0.1 M dipotassium phosphate buffer 223 [46]
(250 × 4.6 mm, 5 μm) (pH 7)‒acetonitrile (70 : 30, v/v)
SITP with MET Hypersil BDS C18 Potassium dihydrogen orthophosphate 215 [47]
(100 × 4.6 mm, 5 μm) (pH 8.5)‒methanol (50 : 50, v/v)
SITP with MET Inertsil ODS C18 Ammonium dihydrogen phosphate buffer 246 [48]
(250 × 4.6 mm, 5 μm) (pH 4.3)‒acetonitrile (74 : 26, v/v)
SITP with MET Lichrosphere-100 C18 Methanol‒potassium dihydrogen phosphate 266 [49]
(250 × 4.6 mm, 5 μm) buffer (70 : 30, v/v)
SITP with MET Symmetry C18 Methanol‒phosphate buffer (60 : 40, v/v) 258 [50]
SITP with MET Hypersil BDS C18 Potassium dihydrogen orthophosphate 260 [51]
(150 × 4.6 mm, 5 μ) (pH 4)‒methanol (50 : 50, v/v)
SITP with MET HiQSil C18 Acetonitrile‒methanol‒phosphate buffer 266 [52]
(250 × 4.6 mm, 5 μm) (pH 4) (20 : 30 : 50, v/v/v)
SITP with SIM Cosmosil C18 Methanol‒water (90 : 10, v/v) 252 [53]
SITP with MET Inertsil-ODS C18 Ammonium acetate buffer‒ acetonitrile 256 [54]
(50 : 50)
SITP with SIM Agilent C8 Methanol‒water (25 : 75, v/v) 266 [55]
SITP with MET Supelco Acetonitrile‒0.01 M ammonium acetate 245 [56]
(stability study) (25 × 4.6 mm, 5 μm) buffer (pH 4.5) (70 : 30, v/v)
SITP with SIM Qualisil BDS C8 Methanol‒water (70 : 30, v/v) with 0.2% 236 [57]
(stability study) (250 × 4.6 mm, 5 μm) of n-heptane sulfonic acid adjusted
to pH 3.0 with ortho phosphoric acid
ALGP Angilent Zobax SB-CN Solvent A: water‒acetonitrile‒trifluoroacetic 278 [58]
acid (1900 : 100 : 1, v/v/v).
Solvent B: acetonitrile‒water‒trifluoroacetic
acid (1900 : 100 : 1, v/v/v)
ALGP Symmetry cyanide Potassium dihydrogen phosphate buffer 215 [59]
pH (4.6)‒acetonitrile (20 : 80, v/v)
ALGP Lux cellulose 2 Ethanol‒diethyl amine (100 : 0.5, v/v) 230 [60]
ALGP Finepaksil C18 Methanol‒double distilled water (80 : 20) 222 [61]
ALGP with MET Agilent C18 Buffer‒methanol (30 : 70, v/v) 254 [62]
ALGP with MET XTerra Potassium dihydrogen phosphate buffer 235 [63]
(250 × 4.6 mm, 5 μm) (pH 4.0)‒acetonitrile (70 : 30, v/v)
ALGP with PIO Enable C18 Phosphate buffer (pH 3.6)‒acetonitrile 268 [64]
(250 × 4.6 mm, 5 μm) (35 : 65, v/v)
ALGP with MET Aglient C18 Water‒methanol 242 [65]
ALGP with MET X Bridge C18 Buffer‒methanol‒acetonitrile 290 [66]
(20 : 60 : 20, v/v/v)

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DETERMINATION OF DIPEPTIDYL PEPTIDASE-4 INHIBITORS 311

Table 7. (Contd.)
Analytical
Drug(s) Column Mobile phase Reference
wavelength, nm
ALGP with MET XTerra Potassium dihydrogen phosphate buffer 235 [67]
(stability study) (250 × 4.6 mm, 5 μm) (pH 4.0)‒acetonitrile (70 : 30, v/v)
ALGP with PIO Hypersil BDS C18 Phosphate buffer‒acetonitrile (45 : 55, v/v) 215 [68]
(stability study)
ALGP with MET X-Terra C18 Sodium dihydrogen ortho phosphate 235 [69]
(stability study) (150 × 4.6 mm, 3.5 μm) (pH 4.0)‒acetonitrile (70 : 30 , v/v)
VILDA XBridge Shield C18 Solvent A: 50 mM ammonium bicarbonate 210 [70]
(pH 7.8). Solvent B: acetonitrile
VILDA Shimpack VP-ODS 0.02 M phosphate buffer (pH 4.6)‒acetonitrile 210 [71]
(80 : 20, v/v)
VILDA Xterra Waters C18 Aqueous phase (25% ammonium hydroxide 210 [72]
in 1000 mL of water, pH adjusted
to 9.5)‒organic phase (methanol) (60 : 40, v/v)
VILDA C18 Buffer‒acetonitrile (50 : 50, v/v) 220 [73]
VILDA Altima C18 Dilute ortho phosphoric acid pH 2.6 ± 0.5 266 [74]
as buffer‒acetonitrile (72 : 28, v/v)
VILDA Symmetry C18 Methanol‒10 mM ammonium acetate buffer 220 [75]
(30 : 70, v/v)
VILDA Shimpack VP-ODS C18 0.01 M phosphate buffer (pH 5.3)‒acetonitrile 210 [76]
(30 : 70, v/v)
VILDA with MET Thermo hypersil ODS 0.1 M potassium hydro phosphate‒acetonitrile 263 [77]
C18 (60 : 40, v/v)
VILDA with MET Kromosil C18 Phosphate buffer (pH 5.8)‒acetonitrile 215 [78]
(80 : 20, v/v)
VILDA with MET Kromosil C18 0.1 M dipotassium mono hydro phos- 250 [79]
phate‒acetonitrile (70 : 30, v/v)
VILDA with MET Waters C18 Phosphate buffer (pH 7)‒ acetonitrile 263 [80]
(70 : 30)
VILDA with MET Monolithic Acetonitrile‒sodium dihydrogen phosphate 208 [81]
(10 mM) and sodium dodecyl sulfate with
pH 4.5 ± 0.2 (30 : 70, v/v)
VILDA with MET Phenomenax C18 Phosphate buffer (pH 6.0)‒methanol 255 [82]
(65 : 35, v/v)
VILDA with MET Phenomex Phosphate buffer‒acetonitrile (75 : 25, v/v) 260 [83]
VILDA with MET ZODIAC Disodium hydrogen phosphate buffer 200 [84]
(pH 3.5)‒methanol (73.5 : 26.5, v/v)
VILDA with MET Lichrocart C18 0.05 M potassium dihydrogen phosphate 215 [85]
( pH 3.5)‒acetonitrile (70 : 30, v/v)
VILDA with Inertsil C18 A: 0.1% ortho phosphoric acid. 217 [86]
MET, SITP, B: acetonitrile‒methanol (95 : 5, v/v)
SAXG
VILDA with MET Sunfire BDS C8 Disodium hydrogen phosphate buffer 263 [87]
(stability study) (pH 7 ± 0.5)‒acetonitrile (60 : 40, v/v)
VILDA (UPLC) Phenomenex C18 Potassium dihydrogen phosphate 220 [88]
with MET (pH 4)‒acetonitrile (70 : 30, v/v)
LING Symmetry C18 Methanol‒water (83 : 17, v/v) 241 [89]

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312 DESHPANDE, BUTLE

Table 7. (Contd.)
Analytical
Drug(s) Column Mobile phase Reference
wavelength, nm
LING X Bridge C18 Phosphate buffer (pH 3.4)‒acetonitrile 240 [90]
(70 : 30, v/v)
LING Symmetry Chromosil Acetonitrile‒water‒methanol (25 : 50 : 25) 238 [91]
C18
LING Khromosil C18 0.02 M potassium dihydrogen phosphate 226 [92]
(pH 5.0)‒acetonitrile (70 : 30, v/v)
LING (stability) C18 Methanol‒phosphate buffer (70 : 30, v/v) 218 [93]
LING with MET C8 Acetonitrile‒water‒methanol to pH 4.1 243 [94]
(stability study) with 0.1% ortho phosphoric acid
(25 : 50 : 25, v/v/v)
LING with MET Hypersil C18 Phosphate buffer (pH 5.6)‒methanol‒ 233 [95]
acetonitrile (40 : 5 : 55, v/v/v)
LING with MET Grace vyadyec genesis Acetonitrile‒0.01 M dipotassium hydrogen 237 [96]
CN phosphate buffer (75 : 25, v/v)
LING with MET Phenomex Luna RP C18 Phosphate buffer‒methanol‒acetonitrile 231 [97]
(65 : 10 : 25, v/v/v)
LING with MET Hypersil BDS C18 Potassium dihydrogen phosphate‒acetonitrile 250 [98]
(40 : 60, v/v)
LING with MET Agilent Zorbax SB C18 Potassium dihydrogen phosphate‒acetonitrile 236 [99]
(stability study) (40 : 60, v/v)
LING with MET Inertsil ODS 3V C18 Phosphate buffer (pH 4.5)‒acetonitrile 280 [100]
(stability study) (60 : 40 , v/v)
LING with MET Symmetry Waters C18 Potassium dihydrogen phosphate buffer 260 [101]
(pH 4.6)‒methanol (30 : 70, v/v)
LING with MET Water’s X-Bridge C18, Acetonitrile‒0.02 M phosphate buffer 225 [102]
(150 × 4.6 mm, 5 μm) (pH 5.0) (35 : 65, v/v)
LING with MET C18 Methanol‒0.05 M KH2PO4 (pH 4.6) 267 [103]
(70 : 30, v/v)
SAXG Hypersil C18 Acetonitrile‒0.02 M potassium dihydrogen 220 [104]
(stability study) (250 × 4.6 mm, 5 μm) phosphate (30 : 70, v/v)
SAXG Waters XBridge C18 0.1% phosphoric acid ( pH 3.0)‒methanol 225 [105]
(stability study) (250 × 4.6 mm, 5 μm) (70 : 30, v/v)
SAXG Inertsil C8 0.02 M sodium dihydrogen phosphate 210 [106]
(stability study) (250 × 4.6 mm, 5 μm) in water (pH 5.0)‒acetonitrile
SAXG with MET C18 Phosphate buffer (pH 5.0)‒acetonitrile‒ 225 [107]
(25 × 4.6 mm, 5 μm) methanol (75 : 15 : 10, v/v/v)
SAXG with MET Phenomenex C18 0.02 M potassium dihydrogen phosphate 240 [108]
(250 × 4.6 mm, 5 μm) (pH 4.3)‒acetonitrile‒methanol
(50 : 25 : 25, v/v/v)
SAXG with MET Inspire C18 Buffer‒methanol (55 : 45, v/v) 208 [109]
(250 × 4.6 mm, 5.0 μm)
SAXG with Inertsil® CN-3 Potassium dihydrogen phosphate buffer 208 [110]
VILDA (250 × 4.6 mm, 5 μm) (pH 4.6)‒acetonitrile (15 : 85, v/v)
SAXG with PIO Inertsil C18 Acetonitrile‒phosphate buffer (pH 7.0) 260 [111]
(150 × 4.6 mm, 5 μm) (60 : 40, v/v)
SAXG with MET Enable C18 G 0.05 M KH2PO4 buffer (pH 4.5)‒ 220 [112]
(250 × 4.6 mm, 5 μm) methanol‒acetonitrile (60 : 20 : 20, v/v/v)

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DETERMINATION OF DIPEPTIDYL PEPTIDASE-4 INHIBITORS 313

Table 7. (Contd.)
Analytical
Drug(s) Column Mobile phase Reference
wavelength, nm
SAXG C18 Phosphate buffer (pH 2.70)‒acetonitrile 210 [113]
(250 × 4.6 mm, 5 μm) (80 : 20, v/v)
SAXG with MET Inertsil C8 Buffer (pH 2.5)‒acetonitrile (70 : 30, v/v) 229 [114]
(150 × 4.6 mm, 5 μm)
SAXG with MET Phenomenex C18 Phosphate buffer‒acetonitrile (60 : 40, v/v) 242 [115]
SAXG with MET Zodiac C18 Phosphate buffer (pH 6.8)‒acetonitrile 248 [116]
(150 × 4.6 mm, 5 μm) (94 : 6, v/v)
SAXG Eclipse XDB C18 Potassium dihydrogen ortho phosphate 213 [117]
(stability study) (150 × 4.6 mm, 5 μm) (pH 3.4)‒acetonitrile (800 : 200, v/v)
SAXG with MET Thermo hypersil BDS C8 Water (pH 3.0) adjusted with ortho phosphoric 241 [118]
(stability study) (250 × 4.6 mm × 5 μm) acid‒methanol (70 : 30, v/v)
SAXG with MET Hypersil ODS C18 Phosphate buffer (pH 5.0)‒acetonitrile‒meth- 211 [119]
(stability study) (250 × 4.6 mm, 5 μm) anol (25 : 50 : 25, v/v/v)
SAXG with MET Zorbax C18 Potassium dihydrogen phosphate‒methanol 248 [120]
(stability study) (250 × 4.6 mm, 5 μm) (60 : 40, v/v)
TENG Shisedo C18 Acetonitrile‒methanol‒water 246 [121]
(stability study) (250 × 4.6 mm, 5μm) (30 : 40 : 30, v/v/v)
TENG Kromasil 100-5-C8 Methanol‒0.025 M phosphate buffer (pH 3) 254 [122]
(stability study) with ortho phosphoric acid (60 : 40, v/v)
TENG Kromasil 100 5-C18 Phosphate buffer (pH 6.0)‒acetonitrile 246 [123]
(stability study) (250 × 4.6 mm, 5 μm) (60 : 40, v/v)

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