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Ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS) in practice: analysis of drugs and pharmaceutical formulations

Abstract

Background

UHPLC-MS/MS is connected in various research facilities for the qualitative and quantitative investigation of a pharmaceutical substance, pharmaceutical items, and biological specimen.

Main body

The commence review article is an endeavor to offer pervasive awareness around assorted aspects and details about the UHPLC-MS/MS and related techniques with the aim on practice to an estimation of medicinal active agents in the last 10 years. The article also focused on isolation, separation, and characterization of present impurity in drug and biological samples.

Conclusion

Review article compiles a general overview of medicinally important drugs and their analysis with UHPLC-MS/MS. It gives fundamental thought regarding applications of UHPLC-MS/MS for the study on safety limit. The summary of developed UHPLC-MS/MS methods gives a contribution to the future trend and limitations in this area of research.

Background

Ultra-high performance liquid-chromatography (UHPLC) covers liquid chromatography separations implementing columns enclose particles smaller than the 2.5–5 μm sizes typically used in high-performance liquid chromatography (HPLC) [1]. UHPLC work on the same assumption as that of HPLC [2] and of which governing principle is that, as column packing particle size decrease, efficiency and thus resolution accretion [3]. Separations using column contain smaller particles display enhance efficiency per unit time [1, 2], but the efficiency cannot minimize at superior mobile phase flow rates or linear velocities [4]. After attribute, slighter particles, rapidity, and peak resolution can be absolute to new limits [5].

Since it is extremely well recognized from Van Deemter equations, the efficiency of the chromatographic process is proportional to particle size decrease [6]. Pursuant to his model characterized band broadening, it clarifies by the connection between height equivalent of a theoretical plate (HETP) and linear velocity, is reliant on a diameter of particle packed into the analytical column [4, 6]. These accomplishments show the very considerable increase in resolution, sensitivity, and efficiency with the quicker outcome and a smaller amount expenditure of solvents which lowers the cost and make the technology environment friendly [7].

The hyphenated technique has turned out a precious method for the assessment of pharmaceuticals in various biological samples. The hyphenated technique is an attachment of the chromatographic system linked with the spectroscopic system with the right interface, such as LC-MS/MS [8]. It is well known that the detection profit appreciably from the performance characteristics of the UHPLC technology. As there is reduced in chromatography dispersion with an increased concentration of analyte will encourage improved source ionization efficiency [5].

The hyphenated techniques usually applied for identification as well as quantification of the analyte when it is compared with other analytical methods [8]. At present era, employing of UHPLC gives the full benefits of chromatography applications for the separations using shorter columns, and superior flow rates for augmented rapidity, with greater resolution and sensitivity. The recognition criterion of UHPLC-MS/MS is shown in Table 1 [7]. The current review recapitulates the applications of UHPLC-MS/MS method for assessing drug in pharmaceutical as well as the biological matrix. In literature, there are several methods reported for analysis of drugs using UHPLC-MS/MS, the major categorized such as antidiabetic, anticancer, antibiotics, cardiovascular, antiviral, nonsteroidal anti-inflammatory drug (NSAID), and others.

Table 1 Acceptance criteria for UPLC-MS/MS

Main text

UHPLC columns

The Acquity UHPLC column involved in the front line of liquid chromatography (LC) column development by giving higher quality chromatographic data’s in less time. For use in applying up to 15000 psi (1000 bar), UHPLC columns are designed, certified, and tested [9]. However, different technologies produced distinct nature of columns actuality used in UHPLC is depicted in Fig. 1.

Fig. 1
figure1

Types of UHPLC columns

Charged surface hybrid

Third-generation particle technology was developed by waters, designed to recover sample loadability and peak tailing in uncertain ionic strength mobile phase composition. The charged surface hybrid retains the low level surface charge with 1.7 μm particle size [9]. The basic charged surface hybrid (CSH) C18 column characteristics such as peak shape and increased loading capacity, mainly for basic compounds under low-pH, weak-ionic-strength mobile-phase [10]. The polyaromatic compound selective straight-chain-alkyl is especially used in Acquity UHPLC CSH Phenyl-Hexyl column and also it gives exceptional peak shape under different pH conditions [10]. The Acquity UHPLC CSH Fluoro-Phenyl columns show excellent selectivity for polar compounds, positional isomer, and halogenated compounds. This is due to a dipole-dipole, hydrogen-bonding, aromatic, and hydrophobic interaction [10].

Ethylene-bridged hybrid

The deficiency of mechanical strength or efficacy is essential to complete the potential speed, sensitivity, and resolution capabilities for primary generation methyl-hybrid particle of xTerra columns. Hence, there is need of a column with a new pressure-tolerant particle needed to create. An innovative, additional hybrid material columns were set that contains an ethylene-bridged hybrid material. It displayed enhanced efficiency, pH range, and strength as compared to first-generation columns [11]. The developed ethylene-bridged hybrid (BEH) columns fixed polar group attached to the silyl functionality with a C6 alkyl and also for UHPLC BEH phenyl columns [7].

High strength silica

High strength silica (HSS) is another type of column used in UHPLC. In UHPLC, high pore volume UHPLC particles do not acquire the mechanical stability necessary to hold up the high pressure innate of UHPLC separations [9]. For that, there is established a novel silica particle and appropriate morphology required to give long and lifetime efficiency UHPLC column at high pressure likely 1000 bars. HSS particle technology is the modern automation; 1.8 μm UHPLC HSS particles are designed and exclusively for separations using UHPLC [12]. To overcome trouble during separation and retention of small water-soluble and polar organic molecules during reversed phase separation, Acquity UHPLC HSS T3 columns were developed. The Acquity UHPLC HSS C18 selectivity for bases (SB) columns is a non-endcapped, low-coverage silica-based C18 chemistry that alternate selectivity for water-soluble compounds influenced by silanophilic interactions. The enhanced silanol activity of the HSS C18 SB column result in greater retention of basic compounds; due to secondary interactions with residual silanols while simultaneously reducing the retention of non-basic analytes due to the low ligand density and ionic repulsion [10].

Peptide separation technology

The separation or isolation of different peptides, the peptide-based peptide separation technology columns, was utilized for analysis of peptides. Developed peptide separation technology (PST) columns are C18 BEH Technology, in PST column particles sizes in the variety of 1.7 μm to 10 μm and the column dimension ranges from 75 μm to 30 mm internal diameter and column length from 50 to 250 mm. The PST columns demonstrate sharp-edged symmetrical peaks [7].

UHPLC, superior technique than HPLC

The UHPLC system is superior to HPLC system because the UHPLC system operates at high pressure up to 1000 bar or more than that, but a conventional HPLC system, compass a pressure up to 400 bars and it suffers problems like mobile phase swallowing and increases the time of analysis. But in UHPLC system, less solvent consumption and less time for analysis are required [13]. This could unlikely outstanding use of slighter particles less than 2.0 mm and also at tolerable flow up to 5 mL/min. The use of the lesser particle size shows better resolution of peaks, perform faster analysis, sharper, and higher peaks [14].

UHPLC-MS/MS detection

To detect and find out the amount of analyte, the mass spectrometry (MS) was widely used because of its selectively (Watson and Sparkman 2007; Chiu and Muddiman 2008). UHPLC-MS/MS method detection is considered as a method of choice for estimation of drugs in bulk and pharmaceutical formulations and their metabolites in biological fluids. In literature, there are several methods reported for analysis of drugs using UHPLC-MS/MS. In all ionization techniques, electrospray ionization (ESI) and atmospheric chemical ionization (APCI) ion source were extensively used [15]. Among all kinds of mass analyzers viz quadrupole, ion trap, and time of flight, the triple quadrupole was the most preferred one. The several mobile phases were used in UHPLC-MS/MS that includes many solvents such as water, ACN or MeOH, acetic acid, 0.1% formic acid, ammonium hydroxide/ammonia solution, and ammonium acetate (10 mM).

Mass spectrophotometer prominently consists of an ion source to construct gas phase ions and mass analyzers to separate these ions according to their mass to charge ratio; further, a detector to count the ions for every m/z ratios. The PC will change over the information from the analyzer and detector to a mass spectrum [16, 17]. The choice of detector is based on the necessary detection sensitivity and it is additionally controlled by other clear necessity; for example, the thermal, chemical, and required stability and the amount of space available. Ideal properties for detectors are high intensification, fast time analysis, low noise, high collection efficiency, minimal effort, narrow distribution of responses, and long life [18]. The MS-MS detectors are more advantageous over the other detectors with respective to the higher sensitivity to detect very small quantity, high selectivity to notify molecules apart in a mixture, and high time resolution and long lifetime. There are different detectors which are used in mass spectrophotometer such as electron multiplier, Faraday cup electrode, and photomultiplier. Electron multiplier is based on that the ion or electrons strikes on the first dynode, resulting in the emission of several electrons. These secondary electrons are then attracted to the second dynode, where every electron creates a few more electrons, and likewise the electrons are produced. The electron multiplier offers several advantages over the other detectors like low noise, high sensitivity, and typical gain of 106 and total life of electron multiplier 1–2 years. Faraday cup electrode is also known as cylinder electrode. The basic principle behind cylinder electrode is that the incident ion strikes the dynode surface which emits electrons and induces a current which is amplified and recorded. The dynode electrons which are used in faraday cup are made up of secondary emitting material like CsSb, GaP, or BeO. The cylinder electrode is very robust and it is generally used to isotope analysis and isotope-ratio mass spectrometry (IRMS). The photomultiplier are currently presumably the most widely recognized in mass spectrophotometer and it’s also known as scintillation counter. The basic principle of scintillation counter or photomultiplier is that the ions at first strike a dynode which outcome in electron emission. These electrons then strike a phosphorous screen which thusly discharges a burst of photons. The photons then pass into the multiplier where amplification occurs in a cascade fashion. The main advantage of using photons is that the multiplier can be kept sealed in a vacuum preventing contamination and greatly extending the lifetime of the detector [16, 19].

Present perspective on UHPLC-MS/MS methods

The magnitude of the topic on a UHPLC-MS/MS can be learnt from the review articles published on the topics; to our knowledge, more than 11 [20,21,22,23,24,25,26,27,28,29,30] review articles on various facets of UHPLC-MS/MS have been published by different authors. The brief summary of review articles published in different journals on the topic “UHPLC-MS/MS” is depicted in Table 2.

Table 2 Present perspective on UHPLC-MS/MS methods

Application of UHPLC-MS/MS

Bio-analytical method/metabolite studies

The sensitivity and selectivity of UHPLC at low detection levels produces precise dependable information that can be utilized for a wide range of purposes, including pharmacokinetics study, toxicity, and bioequivalence studies as the quantification of a medicinally active agent in biological samples is a crucial part of the development program of a bioanalytical method. The sample preparation techniques gained more significance in bioanalytical methods. UHPLC-MS has vital importance in metabolomics and proteomics [31]. A variety of sample preparation techniques have been applied in a bioanalytical method such as protein precipitation, liquid-liquid extraction, and solid-phase extraction [32]. Among these, the most widely used are protein precipitation and liquid-liquid extraction followed by solid-phase extraction which are used in different category such as antibiotic [33,34,35,36,37,38,39,40], anticancer [36, 41,42,43,44,45, 46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62], antiviral [63,64,65,66,67], antifungal [68,69,70,71,72], cardiovascular [73,74,75,76,77,78,79,80,81,82,83,84,85,86], analgesic [87,88,89,90,91,92,93], steroid [94, 95], NSAID [96,97,98,99,100,101,102,103,104,105,106], diabetes [107,108,109,110], antidepressant [111,112,113,114], antiepileptic [115,116,117,118,119], CNS [120, 121], proton pump inhibitor [122], anti-tubercular [123], vitamin [124, 125], immunosuppressant [126,127,128], anticoagulant [129, 130], expectorant [102], and multicomponent analysis of drug [131,132,133,134,135,136,137,138,139,140,141,142,143,144,145]. The simplest is protein precipitation by acetonitrile and centrifugation prior to analysis. The liquid-liquid extraction by ter-butyl methyl ether, chloroform, ethyl acetate, ethyl ether, etc., and solid-phase extraction techniques, disks, or cartridges are used to extract the sample by using methanol, formic acid, water, etc [146]. Bioanalytical studies using UHPLC-MS/MS is summarized in Table 3 and Fig. 2.

Table 3 Bioanalytical/metabolite studies
Fig. 2
figure2

Analysis of different classes of drugs using UHPLC-MS/MS in between 2006-2017

Stability-indicating method using UHPLC-MS/MS

It is performed at the preliminary stage in the process of drug development [7]. The research conditions force the drug compounds to degrade under tremendous conditions such as acid and base hydrolysis, peroxide oxidation, photo-oxidation, and thermal stability to identify the resultant degradation products. Stability indicating method using UHPLC-MS/MS is included in Table 4 [147,148,149,150,151,152,153]

Table 4 Stability-indicating method UHPLC-MS/MS

Impurity profile of drug using UHPLC/MS/MS

For the medicine development and formulation process, profiling, detection, and evaluation of drug substances and their contamination in crude materials and finishing yield testing is an essential part which is summarized in Table 5 [3] [154,155,156,157,158,159,160,161,162,163].

Table 5 Impurity profile of drug using UHPLC-MS/MS

UHPLC in separation of isomers

Chirality may influence biological activity; so, there is a necessity for the enantioseparation or diasterioseparation of these compounds. Therefore, sequentially to further examine the mechanisms of action of the enantiomers or diastereomers, it is necessary to understand which compounds are present at the site of action. Therefore, there is an increased demand for sensitive analytical methods to quantify and evaluate the chirality of metabolites present in biological fluids [96]. UHPLC is an incredible tool for the present rehearsing chromatographer, as it can essentially expand the output of a chromatographic separation. What is more, the more extensive scope of usable stream rates makes rapid partitions conceivable. Up till now, various UHPLC columns were employed for separation of structural analogs or for separation of isomers. These UHPLC columns are flexible column with excellent chemical durability and are suitable for quick analysis of samples containing hydrophobic compounds that are strongly retained in columns or samples containing compounds with large differences in hydrophobicity. In addition, its high bonding density consent for excellent separation of compounds with minute structural differences. Furthermore, these UHPLC columns are used for a wide range of application areas such as measuring the optical purity wand purification of chiral materials [164]. The separations of isomers using UHPLC are summarized in Table 6.

Table 6 Separation of isomers studies using UHPLC

Future direction

In the last decade, literature survey shows that several drugs and metabolites were separated, from their impurities and degradation product by implementing UHPLC-MS/MS technique. For separation or extraction of analytes or drugs and metabolites from the biological fluid with the help of organic solvents, but there are many problems associated with those organic solvents such as toxic nature, injurious to the environment, and dangerous. To overcome these problems, the green solvents are the choice for extraction of analytes. In the future, the more prominent result is also obtained with the help of green solvents because advantage green solvents are their high viscosity, high thermal stability, and low vapor pressure. They are also highly reusable and therefore considered efficient compared to organic solvents. In this survey, the column generally used is BEH C18. The green solvents with the help of increases; high-throughput, sensitivity, and resolution of drugs analysis and identify structures of compounds. Nonetheless, steady up gradation of UHPLC-MS/MS techniques besides data-handling routines are still obligatory for data preprocessing, statistical analysis, biomarker recognition impurity, and degrades products.

Discussion and conclusion

The presented review article gives a perspective on UHPLC-MS/MS in drug substance and medicine product. The current review article collects a simplified, fast, and selective UHPLC-MS/MS methods which were developed for the determination of drug in bulk and also in plasma. UHPLC-MS/MS technique holds out a very promising system for isolation, characterization, and identification of degradation products and impurities. This knowledge can create abundant information about drugs and guidance for its storage, increasing tools for quality control, and safer treatments.

Availability of data and materials

Not applicable.

Abbreviations

BEH:

Ethylene-bridged hybrid

CSH:

Charged surface hybrid

HETP:

Height equivalent of theoretical plate

HILIC:

Hydrophilic interaction chromatography

HPLC:

High-performance liquid chromatography

HSS:

High strength silica

IRMS:

Isotope-ratio mass spectrometry

LC:

Liquid chromatography

LLE:

Liquid-liquid extraction

MPa:

Megapascal

MS:

Mass spectroscopy

NSAID:

Nonsteroidal anti-inflammatory drug

PP:

Protein precipitation

Psi:

Per square inch

PST:

Peptide separation technology

QuEChERS:

Quick, easy, cheap, effective, rugged, and safe

RP:

Reverse phase

SB:

Selectivity for bases

SPE:

Solid-phase extraction

UHPLC:

Ultra high-performance liquid chromatography

UPLC-MS/MS:

Ultra performance liquid chromatography-mass spectroscopy

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Acknowledgement

The authors are thankful to Principal of R.C. Patel Institute of Pharmaceutical Education and Research Shirpur, Dist: Dhule (MS) 425 405 for providing necessary library facilities.

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RHR and ASP carried out literature review on applications of UHPLC-MS/MS in drug analysis. AAS and SRC organized a preliminary draft of the article. All authors read and approved the final manuscript.

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Correspondence to Atul A. Shirkhedkar.

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Rathod, R.H., Chaudhari, S.R., Patil, A.S. et al. Ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS) in practice: analysis of drugs and pharmaceutical formulations. Futur J Pharm Sci 5, 6 (2019). https://doi.org/10.1186/s43094-019-0007-8

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Key words

  • UHPLC-MS/MS
  • UHPLC
  • Pharmaceutical analysis
  • Impurity
  • Bio-analytical