applying hplc - hilic as method for analysis of ... · use of electrospray-ionization mass...
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Petkova et al. World Journal of Pharmacy and Pharmaceutical Sciences
APPLYING HPLC - HILIC AS METHOD FOR ANALYSIS OF
PHARMACEUTICAL COMPOUNDS
Stefka Ivanova1, Lily Peikova
1, Petya Koleva
2, Dobrinka Tsvetkova
1,
Valentina Petkova1*
1Faculty of Pharmacy, Medical University – Sofia.
2Medical College, Medical University – Plovdiv.
ABSTRACT
HPLC separation method with high sensitivity and selectivity is used
as a detector with a large linear range and good reproducibility. It can
be applied in order to identify and quantify the main ingredient,
"related substances" and impurities. The identity of the target
component validation of HPLC required to prove the necessary
selectivity, while quantifying and determining the LOD and LOQ is
applied for an external certified reference material. Hydrophilic
Interaction Liquid Chromatography (HILIC) is the most successful
approach for the retention and separation of polar compounds. HILIC
has seen a substantial increase in popularity over the last decade,
driven by the increase in the development of polar drugs within the pharmaceutical industry
and also the growing field of metabolomics, which primarily involves the analysis of polar
molecules. This technique has been described as “reversed -reversed phase’” since in HILIC
the stationary phase is polar and the aqueous portion of the mobile phase acts as the stronger
solvent, which is the opposite of conventional reversed phase chromatography. There are
many stationary phases that can be used in a HILIC mode and many phases are generally
described as HILIC, independently of their chemistry.
KEYWORDS: HPLC, HILIC, LOD, LOQ, HILIC-MS/MS.
INTRODUCTION
The HILIC mode of separation is used extensively for separation of some bio
molecules,organic and some inogranic molecules by differences in polarity.
[1, 2] Its utility
has increased due to the simplified sample preparation for biological samples, when
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 5.210
Volume 5, Issue 1, 01-12 Review Article ISSN 2278 – 4357
Article Received on
29 Oct 2015,
Revised on 21 Nov 2015,
Accepted on 14 Dec 2015
*Correspondence for
Author
Prof. Dr. Valentina
Petkova
Faculty of Pharmacy,
Medical University –
Sofia.
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Petkova et al. World Journal of Pharmacy and Pharmaceutical Sciences
analyzing for metabolites, since the metabolic process generally results in the addition of
polar groups to enhance elimination from the cellular tissue. This separation technique is also
particularly suitable for glycosylation analysis and quality assurance of glycoproteines and
glycoforms in biologic medical products.[3]
For the detection of polar compounds with the
use of electrospray-ionization mass spectrometry as a chromatographic detector, HILIC can
offer a tenfold increase in sensitivity over reversed-phase chromatography because the
organic solvent is much more volatile. Raquel de Oliveira Vilhena and collaborators have
developed a new HILIC-MS/MS method for the simultaneous analysis of carbidopa,
levodopa and its metabolites in human plasma. Some samples from patients undergoing
treatment have been analyzed, and the results indicated that this new method is suitable for
therapeutic drug monitoring in Parkinson's disease patients.[4]
A group of scientists ( Eva
Cífková, Michal Holčapeka, ,
, Miroslav Lísa, David Vrána, Bohuslav Melichar, Vladimír
Študent) have made lipidomic differentiation between human kidney tumors and surrounding
normal tissues using HILIC-HPLC/ESI-MS and multivariate date analysis. The
characterization of differences among polar lipid classes in tumors and surrounding normal
tissues of 20 kidney cancer patients has been performed by hydrophilic interaction liquid
chromatography (HILIC) coupled to electrospray ionization mass spectrometry (ESI–MS). A
notable increase of relative abundances of lipids containing four and more double bonds has
been detected in tumor compared to normal tissues.[5]
Mohammed Shahid Ali and fellow
workers used hydrophilic interaction liquid chromatographic (HILIC) procedure for the
simultaneous determination of pseudoephedrine hydrochloride (PSH), diphenhydramine
hydrochloride (DPH) and dextromethorphan hydrobromide (DXH) in cough-cold
formulations. Mobile phase consists of methanol:water (containing 6.0 g of ammonium
acetate and 10 mL of triethylamine per liter, pH adjusted to 5.2 with orthophosphoric acid),
95:5 (v/v). Column containing porous silica particles (Supelcosil LC-Si, 25 cm × 4.6 mm,
5 μm) has been used as stationary phase. Detection is carried out using a variable wavelength
UV–vis detector at 254 nm for PSH and DPH, and at 280 nm for DXH. Solutions were
injected into the chromatograph under isocratic condition at constant flow rate of
1.2 mL/min. Linearity range and percent recoveries for PSH, DPH and DXH were
determined to be 150–600, 62.5–250, 75–300 μg/mL and 100.7%, 100.1% and 100.8%,
respectively. The method’s stability has been determined and it has been established, that the
indicated excipients like saccharin sodium, sodium citrate, savor and sodium benzoate did
not interfere in the analysis.[6]
Tetsuya Nemoto and collaborators identified high-throughput
determination of nonsteroidal anti-inflammatory drugs in human plasma by HILIC-MS/MS.
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A simple and sensitive method has been developed and validated for the analysis of thirteen
nonsteroidal anti-inflammatory drugs (NSAIDs) in human plasma samples by hydrophilic
interaction liquid chromatography (HILIC)–tandem mass spectrometry (MS/MS). The mass
spectra obtained by HILIC-MS has shown base peak ions due to [M + H]+ for indomethacin,
oxaprozin, ketoprofen, alminoprofen, zaltoprofen, tiaprofenic acid, pranoprofen, and
ketoprofen-d3 and due to [M − H]− for etodolac, ibuprofen, diclofenac, fenoprofen,
loxoprofen, naproxen, and ibuprofen-d3.[7]
A number of methods have been described in
literature and applied for simultaneous determination of atorvastatin calcium and olmesartan
medoxomil in a pharmaceutical formulation. By reversed phase high-performance liquid
chromatography, high-performance thin-layer chromatography, and UV spectrophotometric
methods. Soni H, Kothari C, Khatri D, Mehta P used validated RP-HPLC, HPTLC, and UV
spectrophotometric methods have been developed for the simultaneous determination of
atorvastatin calcium (ATV) and olmesartan medoxomil (OLM) in a pharmaceutical
formulation. The proposed methods were simple, precise, accurate, and applicable for the
simultaneous determination of ATV and OLM in a marketed formulation. The results
obtained by applying the proposed methods were statistically analyzed and were found
satisfactory.[8]
Abdelaleem EA and collaborators analyzed with HPTLC and RP-HPLC methods for
simultaneous determination of Paracetamol and Pamabrom in presence of their potential
impurities. Developed methods have been validated and proved to meet the requirements
delineated by ICH guidelines with respect to linearity, accuracy, precision, specificity and
robustness. The validated methods were successfully applied for determination of the
studied drugs in their pharmaceutical formulation. The results were statistically compared to
those obtained by the reported RPHPLC method where no significant difference was found;
indicating the ability of proposed methods to be used for routine quality control analysis of
these drugs.[9]
HPLC–MS/MS method for the quantitation and pharmacokinetic analysis of 3-
deazaneplanocin A in mice the scientists Cody J.Peer, Mahadev Rao,Shawn
D.Spencer,Shandiz Shahbazi,Patricia S.Steeq,David S.Schrump and William D.Figg found
that 3-Deazaneplanocin A (DZNep) has been shown to have anti-cancer activity in numerous
cancer types and its continued preclinical, and eventual clinical, drug development will
require rapid and sensitive bioanalytical methods in order to quantitate this drug for
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Petkova et al. World Journal of Pharmacy and Pharmaceutical Sciences
pharmacokinetic analyses. The ultra HPLC with positive thermospray tandem mass
spectrometric (LC–MS/MS) detection affords the most sensitive (limit of quantitation
5 ng/mL) and rapid (3 min run time) bioanalytical method to date for DZNep. Due to the
polar nature of this drug and the internal standard (tubercidin), a hydrophilic-interaction
column (HILIC) was used. The method was accurate, with less than 10% deviation from
nominal values, as well as precise, where both within-day and between-day precisions were
less than 15%. A liquid–liquid extraction procedure was able to recover ∼90% of drug from a
small volume (50 μL) of mouse plasma. This method was successfully applied to a
pharmacokinetic study in mice intravenously injected with DZNep.[10]
Literature search reveals a large number of published papers that describe various usage of
the HPLC-HILIC technique in many analytical fields. Hydrophilic interaction
chromatography (HILIC) in the analysis of antibiotics in different sample matrices including
pharmaceutical, plasma, serum, fermentation broths, environmental water, animal origin,
plant origin, etc. Specific applications of HILIC for analysis of aminoglycosides, β-lactams,
tetracyclines and other antibiotics are reviewed. HILIC can be used as a valuable alternative
LC mode for separating small polar compounds. Polar samples usually show good solubility
in the mobile phase containing some water used in HILIC, which overcomes the drawbacks
of the poor solubility often encountered in normal phase LC. HILIC is suitable for analyzing
compounds in complex systems that elute near the void in reversed-phase chromatography.
Ion-pair reagents are not required in HILIC which makes it convenient to couple with MS
hence its increased popularity in recent years. In this review, the retention mechanism in
HILIC is briefly discussed and a list of important applications is provided including main
experimental conditions and a brief summary of the results. The references provide a
comprehensive overview and insight into the application of HILIC in antibiotics analysis.[11]
According to Donald S. Rislev and colleagues this method can be applied for analyzing
magnesium from magnesium stearate in pharmaceutical tablets using hydrophilic interaction
liquid chromatography with nano quantity analyte detection. Common validation parameters
were evaluated to assess the methods quantitative potential for magnesium (from magnesium
stearate) including: linearity, accuracy, specificity, solution stability, repeatability, and
intermediate precision. Overall, the method described in this report proved to be very robust
and represents a novel technique to conveniently separate and detect magnesium from
magnesium stearate in pharmaceutical preparations both quickly and accurately.[12]
A group
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of scientists (Tijana Rakić, Biljana Jančić Stojanović, Anđelija Malenović, Darko
Ivanović, Mirjana Medenica ) have found improved chromatographic response function in
HILIC analysis mixture of antidepressants. As a model mixture six antidepressants were
chosen: selegiline, mianserine, sertraline, moclobemide, fluoxetine and maprotiline. Due to
complexity of retention mechanisms in HILIC system, detailed examination of experimental
space assessing the influence of important factors (acetonitrile content in the mobile phase,
buffer concentration and pH of the mobile phase) and their interactions was done by applying
3 3 experimental design. N CRF * is developed and designed to be the only output of the
system which simultaneously measures the separation of all the examined substances, the
chromatographic run duration and the quality of the obtained peaks shape. It allowed
objective estimation of overall chromatogram quality and excluded the arbitrary judgment in
ambiguous situations. The applied function highlighted the influence of investigated factors
on entire mixture and enabled identification of experimental regions where the
chromatographic behavior was satisfactory. Applied experimental design strategy combined
with N CRF * proved to be valuable assistance in HILIC separation of complex mixtures.[13]
M. Gratacós-Cubarsí and collaborators are developed analysis of vitamin B1 in dry-cured
sausages by hydrophilic interaction liquid chromatography (HILIC) and diode array
detection. A method based on hydrophilic interaction liquid chromatography (HILIC) and
diode array detection (DAD) was developed to quantify thiamine (vitamin B1) concentration
in Spanish dry-cured sausages (“chorizo,” “fuet,” and “salchichón”). Samples were extracted
with diluted acid (HCl 0.1 M) followed by an enzymatic hydrolysis to release vitamin B1
vitamers from food matrix. Crude extracts were purified on a weak cation exchange SPE
cartridge and total thiamine concentration was determined by LC-HILIC-DAD with a limit of
detection better than 0.01 mg/100 g. The proposed conditions, that do not require the
derivatization of the extracts nor the use of fluorescence or MS detectors, are suitable to
provide chromatographic separation and identification of vitamin B1 within 8 min.
Selectivity, repeatability and accuracy of the method were evaluated with both spiked
samples and the reference material Pig Liver BCR®
487. Quantification of vitamin B1 was
also carried out for different kinds of commercial samples of Spanish dry-cured products.[15]
L. Matysová, L. Havlíková, , R. Hájková, A. Krivda, P. Solich used application of HILIC
stationary phase to determination of dimethinden emaleate in topical gel. A novel high
performance liquid chromatography method for the determination of dimethindene maleate in
pharmaceutical gel using hydrophilic interaction liquid chromatography (HILIC) with UV
detection was developed and validated.Following optimal conditions for the analysis of
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dimethindene maleate were used: analytical column SeQuant ZIC®–HILIC
(50 mm × 2.1 mm, 5 μm), and mobile phase consisted of a mixture of acetonitrile and
aqueous solution of acetic acid (25 mM) and ammonium acetate (2.5 mM) (87.5:12.5, v:v).
The analysis time was less than 3 min at a flow rate of 0.3 ml min−1
. UV detection was
performed at 258 nm. The method was validated and system suitability parameters were
evaluated. The method is suitable for application for routine determination of dimethindene
maleate in topical pharmaceutical preparation.[16]
Scientists (Romain Simon, Quentin
Enjalbert, Jordane Biarc, Jérôme Lemoine, Arnaud Salvador) made evaluation of hydrophilic
interaction chromatography (HILIC) versus C18 reversed-phase chromatography for targeted
quantification of peptides by mass spectrometry. Hydrophilic-interaction liquid
chromatography (HILIC) is a widely used technique for small polar molecule analysis and
offers the advantage of improved sensitivity in mass spectrometry. Although HILIC is today
frequently employed as an orthogonal fractionation method for peptides during the proteomic
discovery phase, it is still seldom considered for quantification. In this study, the
performances in terms of peak capacity and sensitivity of 3 HILIC columns were compared to
traditional reversed phase liquid C18 column in the context of targeted quantification of
proteotypic peptides using selected reaction monitoring mode (SRM). The results showed
that the maximum sensitivity in HILIC chromatography was achieved by using an amide
column without salt buffer and that the signal increased compared to classic reversed phase
chromatography. However, the intensity improvement is quite low compared to the one
obtained for small molecules.[26-30]
This is due on one hand to a higher matrix effect in HILIC
and on the other hand to a change of charge states of peptides in organic solvent (doubly
charged to monocharged).[31-36]
The doubly charged ions can be more readily dissociated than
singly charged ions, making them ideal for SRM peptide quantification. As a result
“supercharging” reagents are added to the mobile phase to shift from predominant singly
charged ions to the more favorable doubly charged species.[14]
Using such optimized
conditions, peptide signal is improved by a factor of between two and ten for 88% of the
peptides of the 81 peptides investigated.[17-20]
The sensitivity of evaporative universal
detectors and LC/MS in the HILIC and the reversed-phase HPLC modes can be compared.
Scientists (Clifford R. Mitchell , Ye Bao, Nancy J. Benz, Shuhong Zhang ) developed and
offered the idea that HILIC mobile phases are mostly composed of polar organic solvent and
are more volatile than reversed-phase mobile phases. Therefore the more easily evaporated
HILIC mobile phases should produce greater sensitivity for those detectors that remove
mobile phase by evaporation.[37-42]
The responses of 12 compounds were measured in the
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reversed-phase mode and the HILIC mode with three detectors: evaporative light scattering
detector (ELSD), corona charged aerosol detector (cCAD), and electrospray mass
spectrometry (ESI-MS). The compounds studied were very polar compounds that were
retained in the HILIC mode. Generally, the HILIC mode was able to achieve greater
sensitivity than the reversed-phase mode for these compounds.[18-25]
Alpert, A.J. and collaborators studied hydrophilic-interaction chromatography of complex
carbohydrates. Some carbohydrates exhibited anomer separation, which made it possible to
determine the orientation of the reducing end relative to the stationary phase. Amide sugars
were consistently good contact regions. Relative to amide sugars, sialic acids and neutral
hexoses were better contact regions at lower levels of organic solvents than at higher levels.
Both asialo- and sialylated glycans could be resolved using the same set of conditions. With
derivatized carbohydrates, detection was possible at the picomole level by UV detection or
on-line electrospray mass spectrometry. Selectivity compared favorably with that of other
modes of HPLC. HILIC is promising for a variety of analytical and preparative
applications.[43-46]
CONCLUTION
Hydrophilic interaction chromatography (HILIC) is a liquid chromatography technique when
a polar stationary phases - silica or polar bonded phases and aqueous mobile phase containing
amount of a less polar solvent (often acetonitrile) is applied. HILIC is important for the
separation of highly polar substances including biologically active compounds, such as drugs,
amino acids, peptides, proteins, nucleosides, neurotransmitters, etc. HILIC is also appropriate
method for analysis of plant extract polar components such as carbohydrates, amino acids,
peptides, phenolic acids, flavonoids and some alkaloids. Plant extracts are usually
multicomponent mixtures of compounds of wide polarity range, which often cannot be
analyzed by use of a single separation and detection method because of the high chemical
diversity. Good results are obtained by use of coupled method, e.g., reversed-phase liquid
chromatography (RP-LC) and HILIC mode separation. The elution order in HILIC is usually
opposite to that in RP separations. This orthogonality determines one of the advantages of
HILIC - the possibility of creating multidimensional separations. An important feature of
HILIC is the improved sensitivity with electrospray mass spectrometry. This is significant for
the analysis of components existing in small concentration in multicomponent mixtures. The
high acetonitrile content also gives additional advantage of HILIC - faster separations due to
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the lower viscosity of HILIC eluents compared to standard RP ones. The presented review
deals with the optimization of HILIC separations and application of the method for analysis
of plant extracts components.
ACKNOWLEDGEMENT
Project DP-13/2015 Medical university – Plovdiv.
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