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Chromatographia

, Volume 82, Issue 1, pp 17–48 | Cite as

The History of the Core–Shell Particles and Applications in Active Pharmaceutical Ingredients Via Liquid Chromatography

  • Mehmet Gumustas
  • Przemyslaw Zalewski
  • Sibel A. OzkanEmail author
  • Bengi UsluEmail author
Review
  • 368 Downloads
Part of the following topical collections:
  1. 50th Anniversary Commemorative Issue

Abstract

High performance liquid chromatography (HPLC) and ultrahigh performance liquid chromatography (UHPLC or UPLC) have been the most widely used tools for research and routine quality control of active pharmaceutical ingredients (API). The most important challenge in these techniques is fast and efficient separation. Both techniques are preferred due to their selectivity, high accuracy and remarkable precision. On the other hand, they have some limitations: In some cases, traditional HPLC uses high amounts of organic solvents with longer analysis time, and furthermore UHPLC has high back pressure and frictional heating. To overcome these limitations, scientists have developed new type of column particles. In general, two different silica types of column packing material based on their backbone have been used for HPLC and UHPLC. Stationary phases that have fully porous silica particles comply with the essential criteria of analysis, but these show all the limitations of HPLC. However, in recent years, core–shell silica particles (a combination of solid core and porous shell) have been increasingly used for highly efficient separation with reduced run times. Thus, core–shell technology provides the same efficient separations as the sub 2 µm particles that are used in UHPLC, while eliminating the disadvantages (potentially lower backpressure). The key factors for core–shell particles are size and thickness of porous shell layer, the latter of which can be explained using the Van Deemter equation. The columns packed with core–shell particles have been employed in a wide range of applications for analysis and quality control of pharmaceutical active substances. This review will underline the advantages of core–shell silica particles in the analysis of pharmaceutically active ingredients based on liquid chromatography from the perspective of column properties, system suitability test parameter results and validation steps.

Keywords

HPLC UHPLC UPLC Core–shell Pharmaceutical Validation 

Introduction

Since the implementation of ultrahigh performance liquid chromatography (UHPLC) in 2004, the next significant attainment has been the implementation of core–shell particles. High resolution and fast separation have always been key parameters for high performance liquid chromatography (HPLC). In some cases, to overcome the analytical challenges the column length must be reduced and the flow rate of the mobile phase must be increased since increasing the mobile phase flow rate in fully porous silica packed columns causes a raise in the back pressure. One of the ways to resolve this problem is using superficially porous silica packed columns which generate less back pressure than fully porous particles. The fact is the particle size required to gain the same chromatographic performance is larger with a superficially bead, and so manufacturers have used larger beads, which have a lower back pressure. That is the reason why superficially porous particle generates less back pressure than a fully porous particle.

Core–shell silica particles are composed of a solid core and a porous shell as shown in Fig. 1. For chromatographic uses, they are generally made from the same component, silica, but with a different structure (a porous shell and a solid core). The core and shell could be made from different or the same materials. The core could be a single structure, linkage of group of spheres or even hollow shell filled in with small structures. The shell can be an uninterrupted layer or an aggregation of smaller spheres onto a bigger core sphere or aggregated core spheres. Sometimes core–shell structures are composed of shell and incorporated into smaller spheres or even combined with multiple shells. Both the shell and the core can be made from materials with varied porous properties. The size of the core particle, the shell thickness and the porosity in the shell are key factors determining different types of chromatographic applications. In short, in comparison with totally porous particles with similar diameters, the diffusion path is much shorter because the inner core is solid-fused silica, which is not accessible to the analytes interacting with the particle. While core–shell stationary phases can be successfully used to improve the separation and reduce the analysis time of a wide range of analytes, this review paper aims to underline the advantages of core–shell silica particles in the analysis of active ingredients of the pharmaceuticals based on liquid chromatography from the perspective of column properties, system suitability test parameter results and validation steps.

Fig. 1

Basic structure of core–shell particle; an example

History

Before the core–shell silica particles, several column packing materials were produced. The milestones of these packing materials are illustrated in Table 1 [1].

Table 1

Historical milestones of column development.

Reprinted with permission from the literature [1]

Datea

Column

Description

Company

1967

Pellosil

Pellicular ion exchange (40 µm)

Northgate

1969

Zipax

Porous layer silica (40 µm)

DuPont

1971

MicroPak

Irregular porous silica (5–10 µm)

Varian

1972

Zorbax

Spherical porous silica (7 µm)

DuPont

1972

Permaphase

Silane phase (7 µm)

DuPont

1973

µBondapak C18

Silane phase (10 µm)

Waters

1978

SynChropak GPC100

Gel filtration column

SynChrom

1988

Rx-silica

Type-B silica

DuPont

1989

StableBond

Stable bonded phases

DuPont

1994

Hypercarb

Porous graphitic carbon

Hypersil

1996

ZirChrom PBD

Zirconia particles

Keystoneb

2000

SilicaRod

Monolith

Merck

1999

XTerra

Hybrid particles (3–5 µm)

Waters

2003

Rapid Resolution

Porous silica (1.8 µm)

Agilent

2004

Acquity

Porous silica (1.7 µm)

Waters

2007

Halo

Shell particles (2.7 µm)

Advanced Materials Technology

aDate of commercial introduction

bProduced by Zirchrom, distributed by Keystone Scientific

The idea of core–shell stationary phases was created be Horváth in 1967 [2, 3]. He developed 50 µm particles covered by ion exchange resin, thus creating the first superficially porous packing material. Kirkland observed that such kinds of packing material enable much faster separations than fully porous particles. Thanks to Kirkland, who passed away in 2016, and also his co-workers, this technology reached the mainstream of liquid chromatography [4]. His next step was to reduce the size of the core and the shell and as they predicted a decrease in the size of the particles would result in a drastic increase in the column efficiency and pressure. On the other hand, porous particles can be packed more homogenously than conventional ones. The material developed and reported by Kirkland and co-authors was successfully applied to fast separation of peptides and proteins [5]. Today core–shell stationary phases are available on the market in different internal diameters (5 µm, 2.7 µm, 2.6 µm and 1.7 µm, 1.3 µm, etc.).

The 5 µm Poroshell particles are composed of a 4.5-µm solid core and a 0.25-µm porous silica layer. The 2.7 µm Halo or Ascentis Express and Poroshell-120 particles are composed of a 1.7-µm nonporous core and a 0.5-µm porous silica layer. Kinetex particles are composed of a 1.90-µm or 1.24-µm solid core and a 0.35-µm or 0.23-µm porous shell. Table 1 summarizes stationary phase chemistry and the particle structures of the latest shell packings. According to Gritti and Guichon`s paper, in the case of 2.7 µm Halo fused-core packing (Ascentis Express), the peaks become much broader than expected [6]. This situation is explained by Fekete et al. as resulting from the rough surface of particles causing the mass transfer rate to be reduced through the outer stagnant liquid film [7]. Furthermore, the new 16-nm pore-sized Halo-ES-peptide column, developed for separation mixtures of large molecules, provide markedly better performance than the first generation of Halo 9 nm sized particles [8, 9, 10]. While this benefit is hardly visible with small molecules, the change is more critical with peptides and proteins. The kinetic performance for insulin of the 2.7 µm Halo 16 nm particles appears to be equivalent to that of the recently commercialized 2.6 µm Kinetex 10 nm pore sized particles [8, 9, 10]. The latest core–shell particle, branded Eiroshell by an Irish company (Glantreo Ltd.), has three different structures; 1.7 µm core shell particles (1.0 µm solid core, 0.35 µm shell thickness) (a), 1.2 µm solid core, 0.25 µm shell thickness (b), and 1.4 µm solid core, 0.15 µm shell thickness (c). This company also states that the thickness of the porous layer plays a significant role in governing the porosity of the particles [11].

Manufacturing Methods for Core–Shell Particles

Core–shell particles are generally manufactured by a process involving two or more steps. At the beginning, the core is created and then the shell is applied on the core particle.

Historical Perspective

First protocell particles were prepared by the co-spraying method. The greatest disadvantage of this approach was formation of amounts of totally porous particles. The next disadvantage was a problem of separating these from the suitable ones [12, 13]. Another method was the coacervate approach [5]. In this method, the dense silica cores were covered with a coacervate film. The particles manufactured by this method were sintered to improve particle strength and remove uncorrected micro-pores [5]. A mechanical action was a fundamental of the dry blending method, which was used to locate small particles onto larger ones [14, 15].

Layer by Layer Approach Via Electrostatic Interaction

The most popular method for preparing core–shell particles for chromatographic uses is a layer-by-layer (LbL) method. This technique is based on the electrostatic interaction between both the negatively and positively charged components for the preparation of multiple layers together. The cores are first covered with the excess of polyelectrolyte which is then eliminated by rinsing. After that step, covered cores are immersed in nanoparticles with opposite charges to the organic polyelectrolyte. Each step of synthesis is repeated until the appropriate shell thickness is obtained [16].

Shell Synthesis on Pre-Formed Cores

This method was used to obtain hollow shell structures or capsules. During the procedure, the core polymer particles were separated by washing or thermal treatment [17]. In an alkaline solution, silica core spheres were immersed by the sol–gel process of tetraethoxysilane and n-octadecyltrimethoxysilane. Then the particles were calcined at 550 °C. This process was necessary to remove the porogen. The obtained particles have a surface area as high as 348 m2/g [18]. Fe3O4 nanoparticles were covered by a thin layer of silica, then they were covered by another silica layer and cetrimonium bromide to generate the mesopores [19].

One-Pot Synthesis and Spheres on Sphere Silica Particles

A one-pot synthesis offers potential benefits such as simplicity, facile scale-up, easier quality control, reduction of reaction time and materials costs. Nevertheless, there has been very limited data about the one-pot synthesis of core–shell particles for chromatographic use. For example, one-pot manufacturing of 50 nm particles composed of silver core and a silica shell was developed by subsequent addition of AgNO3 and tetraethoxysilane with sodium hydroxide as a basic catalyst [20].

Droplet Based Microfluidic Approach

During emulsification methods, polydisperse emulsion droplets are produced. In the next step, obtained droplets are converted into round microparticles during the process of consolidation. Finally obtained emulsions can be used to form core–shell structures [21]. The core–shell particles are often produced using a technology based on stabilizing the droplet emulsions by use of small particles. An “inside-out” microfluidic technique was compiled for manufacturing both emulsions stabilized by monodisperse particles and microspheres with nanoparticles [22]. A single emulsion method was used to develop core–shell particle. The scheme of production is presented in Fig. 1. In a first step, a sol obtained from tetraethoxysilane was immersed in a flowing phase containing tetrabutyl titanate. After formation, based on water diffusion the hydrolysis of tetrabutyl titanate takes place on the droplet and finally a thin gel is formed around the droplet. The last step of this approach is full hydrolysis in a solidification bath with continuous fluid. The above mentioned techniques were successfully applied for producing the silica–titania core–shell particles [23] (Fig. 2).

Fig. 2

The scheme represents the preparation of silica–titania core–shell particles by the microfluidics approach. The oil phase is tetrabutyl titanate in liquid paraffin with Span 80 (surfactant) and oleic acid. Adapted with permission from (Lan, W., Li, S., Xu, J., Luo, G., 2011. Synthesis of Titania–Silica Core–Shell Microspheres via a Controlled Interface Reaction in a Microfluidic Device. Langmuir 27, 13,242–13,247). Copyright (2016) American Chemical Society [***23]

One of the pioneers on the core–shell particles is Halo, and they have analytical columns that have various chemistries such as C18, C8, HILIC and amide. The satisfactory stability of these stationary phases was reported [16]. The fast (0.7–3.5 min) separation of naphthalene, virginiamycin, pesticides and explosives on Halo C18 columns was described [16]. These columns were successfully applied for separations compounds with higher molecular weights for example proteins [24]. Cavazzini et al. (2007) used Halo C18 columns for the separation of moderate molecular weight peptides. Separation of tryptic digests of myoglobin and bovine serum albumin was also done [6, 25]. The separation of five flavonoids in apple juice on Halo C18 column was done by Ali et al. in 2011. The Halo C8 stationary phase was successful applied for the separation of naphthalene, lorazepam and virginiamycin. Uracil, 4-chloro-1-nitrobenzene, naphthalene and phenol have been separated on Halo C8 stationary phase using a simple mobile phase composed of equal volumes of acetonitrile and water [26]. On the other hand, DeStefano et al. (2008) reported successful separation of virginiamycin on Halo C8 with following mobile phase combined with phosphate buffer and acetonitrile at pH 3.0 (35:65; v/v) [16]. Generally, Halo RP amide columns are a good choice for the separation of freely soluble compounds in water. On the other hand, HILIC is another stationary phase appropriate for the separation of molecules with high polarity properties. For HILIC, organic component in mobile phases increases retention with hydrophilic analytes [27]. This attribute makes this stationary phase ideal for analysis connected with MS detectors. Separation performance of HILIC stationary phases with respect to column efficiency, sample capacity and variation in flow rates by separating basic compounds was described by McCalley in 2008 [28]. HILIC stationary phases were successfully applied for the analysis of acetylcholine, choline and choline-trimethyl-d9 molecules [29]. Kinetex columns were produced by Phenomenex Inc., CA, USA and they also developed columns based on the superficially porous particle technology. Kinetex core shell columns have been available since 2009 with C18, XB-C18, C8, PFP and HILIC stationary phase. These columns join ultra-performance, around 300 000 plates per meter and not more than 40 MPa as back pressure. XB-C18 with its di-isobutyl C18 ligand enable a high selectivity for bases at low pH. C18 and PFP stationary phases give satisfactory RP selectivity while the HILIC phase ensures an alternative selectivity connected with polarity of analytes. C8 gave a less hydrophobic alternative to the Kinetex C18 phase with minimal secondary interactions (owing to greater bonding density), resulting in better peak shapes. Kinetex stationary phases were successfully applied for the identification and quantification of various compounds, i.e., acids, alkaloids, antibiotics, antidepressant, aromatics, dyes, phenols, b-blockers and nucleic acid bases [30, 31]. Ascentis Express columns manufactured by Supelco Analytical (USA) improved stationary phases based on core–shell technology. Ascentis Express Columns are based on C18, C8, RP-amide, HILIC, phenyl-hexyl, peptide ES-C18 and F5 stationary phases. All companies have key properties such as reaching satisfactory level of separation, high resolution and sensitivity. Ascentis Express Columns have been successful applied for the separation and identification of both acidic and basic compounds, aromatics, dyes, hormones, b-blockers, peptides, phenols, anti-depressants, natural products, phenolic, bases, metabolites and polar compounds on these columns [30, 31].

Advantages and Disadvantages of Core–Shell Silica Particles

Initially, the core–shell columns offer faster separations than the traditional columns that are packed with totally porous silica with the same size both for small and large molecules. For comparison, 1.7 µm particle size Kinetex 5 cm long C18 column offers around 50% improvement in plate heights for separation of peptides in confronted with totally porous particles. On the other hand, decreasing the particle size from 2.6 µm to 1.7 µm results in about 20% improvement in plate heights and the optimum linear velocity shifts towards higher values [32].

The Van Deemter equation describes the relationship between HEPT and linear velocity of the mobile phase (Fig. 3). Furthermore, the aforementioned equation below shows the influence of core shell particles on the chromatographic performance.

Fig. 3

Van Deemter equation is a hyperbolic function which indicates that there will be a minimum value of (h) for a particular value of (v). That is a maximum efficiency will be obtained at a particular linear mobile phase velocity

$$H=A+\frac{B}{v}+Cv$$
where H is the reduced plate height, v is the reduced velocity, A is the Eddy diffusion, B is the longitudinal diffusion and C the resistance to mass transfer. A, B and C are straight connected with the parameters of the column.

A Term

The A term is correlated with dimension and distribution of particles inside the column. For packed columns, the particle size has a profound effect on the minimal value of the H of a column and thus the maximum efficiency attainable. The highest efficiency of column would be obtained from columns packed with the smallest particles.

The Eddy diffusion is associated with both of the quality of the packing and the particle size. The size distribution of a core shell particle is much narrower than monolith particle. The space between the particles in the column is reduced and efficiency increases by reducing Eddy diffusion. On the other hand, the packing density into a column causes an increase in the band broadening. There are two important components that influence the ‘A’ term, the first connected with a regular packing structure of particles, and the second based on homogeneity inside the column. The narrow particle distribution resulted in better packing of the spheres (Fig. 4) [9, 15, 33].

Fig. 4

Illustration of the effect on peak performance by the means of difference between wide particle distribution (conventional silica) and narrow particle distribution (core–shell silica)

B Term

The B term describes molecular diffusion in the axial direction during the separation process. For superficially porous particles diffusion of a solute is blocked by the existence of a core, so that a solute diffuses less in a core–shell silica-packed column than in a totally porous silica column. Consequently, the B term in a Van Deemter equation reduces in the core–shell silica column (Fig. 5).

Fig. 5

Illustration of the effect of B term; solid core particles blocking the diffusion while a solute diffuses both through a pore and outside of fully porous material

Another advantage of superficially porous particles is decreasing the dead volume. Conventional silica particles will only occupy about one-third of the column space, whereas the amount of space occupied by the superficially porous particles is significantly increased to over 20% [8, 9, 10]. This decreasing of the accessible volume of the column results in less occurrence of the B term. It is necessary to evaluate the situation of the various zones within the column media that exist, since diffusion within these zones will be different for the modelling of the diffusion in an efficient way. There is an effective diffusion coefficient that can be gauged on a macroscopic level. It will be an average of the diffusion occurring within the bulk media and the porous media where the diffusion occurs. Suitable model development allows for the effect that the porous layer has influent diffusion, and it will also allow for the effective diffusion rate that needs to be calculated. Some models can be found in the Torquato’s study that discussed dispersion within a multiple zoned bed [34]. Using the same formulas derived by Gritti et al. [8, 9, 10, 15] based on the Garnett–Torquato model:
$$B=~\frac{{2\left[ {1+2\left( {1+{\varepsilon _{\text{e}}}} \right)~\beta - 2{\varepsilon _{\text{e}}}{\xi _2}{\beta ^2}]} \right)}}{{{\varepsilon _{\text{e}}}~\left[ {1 - \left( {1 - {\varepsilon _{\text{e}}}} \right)\beta - 2{\varepsilon _{\text{e}}}{\xi _2}{\beta ^2}} \right]}},$$
where
$$~\beta =\frac{{~\left( {1 - {\rho ^3}} \right)/\left( {1+{\rho ^3}/2} \right)\Omega - 1}}{{\left( {1 - {\rho ^3}} \right)/\left( {1 - {\rho ^3}/2} \right)\Omega +2}}$$

and ρ defines the proportion of the core to all of the particle as diameters (if the result is 1, it defines a solid component, 0 is a totally porous component), \({\xi _2}~\) a three-point parameter for random dispersion of spherical inclusion, \({\varepsilon _{\text{e}}}~\) is assumed as 0.4 and it is the definition of external column porosity, Ω indicates the ratio of the effective diffusivity in the porous layer of the particle (while compared with in the bulk), giving an indication of the retention of a molecule in an effective way, with higher values being more feasible to compounds that have more retention. The minimal value for the B term is generated when the particle does not have any porosity and/or limited retention [35] (Fig. 6).

Fig. 6

Schematic representation of the minimal value for longitudinal diffusion.

Reprinted from Hayes et al. 2014

The plot evidently shows the pros that decreasing the volume of the column by increasing the diameter of solid core (ρ) has on the longitudinal diffusion within the column. It is easy to see that there is a decreasing by 500% as B reduces from 7.7, when Ω is 2, and ρ is 0, to 1.4 and Ω is 0, and ρ is 1. There is a considerable modification in the B term when taking a value for Ω of 0.14 [8, 9, 10]. The correction in longitudinal diffusion is significant only in the low flow rate ranges. In most cases, it is not only significant but also has no influence around the optimal linear velocity.

C Term

The last contribution in Van Deemter equations (C) describes all terms connected with mass transfer. It has been reviewed many times since the original publication [36, 37, 38, 39]. Modifications to the parent idea were based on the inclusion of mass transfer effects due to different flow velocities within the mobile phase and not just within the stagnant regions of the pore structure.

Preliminary papers related with the launch of the solid core material found relevant with the benefits of the technology with the decreased mass transfer. However, Gritti revealed that small molecules are not responsible from this phenomenon [33, 40]. The primary influence to the reduction in band broadening is correlated with the reduction of the B and A dispersion processes. Gritti proposed the modified relationship to characterize the influence of the mass transfer for the band broadening process following:
$${h_{{\text{Long}}}}=~\frac{B}{v}=\frac{{2\left( {{\gamma _{\text{e}}}+\left( {1 - {\varepsilon _{\text{e}}}} \right)/{\varepsilon _{\text{e}}}\left( {1 - {\rho ^3}} \right)/\left( {1+{\rho ^3}/2} \right)} \right)}}{v},$$
$${h_{{\text{Liquid}} - {\text{Solid}}}}=Cv=~\frac{1}{{15}}~\frac{{1 - {\rho ^3}}}{{1+({\rho ^3}/2)}}~{\left( {\frac{{{k_1}}}{{1+{k_1}}}} \right)^2}~\left[ {\frac{{1+2\rho +3{\rho ^2} - {\rho ^3} - 5{\rho ^4}}}{{{{\left( {1+\rho +{\rho ^2}} \right)}^2}}}} \right]\frac{1}{{B - 2{\gamma _{\text{e}}}}}v.$$

Simulation of the large and small molecules for the determination of the effect that altering the solid core ratio to the porous layer will have on the overall chromatographic efficiency is possible using this model (Fig. 7).

Fig. 7

Illustration of relationship between B and C terms; reprinted from Hayes et al. 2014

The porous shell has only a slight effect on the overall H value for small compounds but for larger molecules the effect becomes much more significant. The contribution of the B term is inversely proportional to the linear velocity. However, it does not contribute effectively to the band broadening at higher velocities. This despite the fact that there is a variance between the C term for the small molecule while there is varied thickness of porous shell employed (in this case two extremes were chosen of ρ = 0.1 and ρ = 0.9). Consequently, the actual value of related number is quite small and will have minimum influence on the overall dispersion. The difference between the dispersion observed due to mass transfer effects for larger molecules where the diffusion coefficient is much lower and variation in the C terms is correlated significantly to a difference in the overall dispersion seen with a very thin porous layer compared to a virtually fully porous material. To conclude, for large compounds, a very thin porous layer should be employed to decreased the influence of dispersion, while fully porous particles also provide fast HPLC separation with low back pressure, especially for large compounds.

Core–Shell Silica Particles in Liquid Chromatography

Liquid chromatography was defined in the 1903 by the work of the Russian botanist, Mikhail S. Tswett. His pioneering studies focused on separating the pigments of leaves [41]. Furthermore, the acronym of high-performance liquid chromatography as HPLC, given by the Prof. Csaba Horváth for his 1970 Pittcon paper, originally indicated the fact that high pressure was used to generate the flow required for liquid chromatography in packed columns. There are two well-known types of separation modes available on liquid chromatography; reversed phase and normal phase. Apart from these techniques, a rather new separation mode, namely hydrophilic interaction liquid chromatography (HILIC), has been used since the 1970s and later improved by Alpert in the 1990s.

As a column particle material, the first invention was a fully porous particle technology that had spherical-like shapes and structures resembling a sponge. These particles also have high surface areas and because of this the system reaches high plate numbers. Furthermore, the back pressure came into existence as a result of the interaction of mobile phase and stationary phase inside the column. This phenomenon showed some variations depending on the diameter and length of the column, size of the packed particles, temperature and mobile phase. Among the above parameters, the most significant one is particle size. The smaller particles provide increased efficiency as well as the ability to work at increased linear velocity without a loss of efficiency, providing both resolution and speed. However, smaller particles occurred high back pressures and to meet these requirements scientists need systems like UHPLC. The development of UPLC and/or UHPLC using such smaller particles made it possible to maintain the conventional analytical features of HPLC while dramatically improving the column performance. On the one hand, this system has some advantages such as resolution, efficiency and speed as well as requiring smaller amounts of solvents due to the smaller particles. On the other hand, it has some disadvantages such as the high cost instruments and high frequency detectors for rapid data acquisition, more stable hardware connections because of high pressure and expensive consumables. To avoid these disadvantages, superficially porous silica particles (that namely also core–shell, fused core, shell, etc.) started to be used as an alternative technology. The possibility of performing classical HPLC related methods afforded immediate economic advantages over UHPLC systems, for this purpose fused core particles became a real alternative to totally or fully porous silica particles. Figure 8 represents the increasing attention directed towards core–shell particles used as a stationary phase in liquid chromatography over the years [42, 43, 44].

Fig. 8

Increasing number of core–shell-related LC studies from 2001 to 2018 according to the data from Scopus

One of the advantages using core shell columns is their greater efficiency in high speed analysis without the generation of high back pressures, which is typical in UHPLC and requires for special LC equipment as discussed above. Figure 4 illustrates a schematic representation on the expected impact of the particle structure and particle size distribution on the Eddy diffusion. Related to this figure a uniform porous silica layer is grown around a spherical solid silica core. This unique combination of precise particle architecture and sub-2 µm particle size provides significant performance by increasing the mass transfer rate. A shorter diffusion path results in faster mass transfer kinetics and causes sharper peak shapes. However, in some cases, mass transfer kinetics have been found to play minimal role in efficiency. This finding support that core shell materials improve the chromatographic performance not only from one term (A) but also including other two terms (B and C) of the Van Deemter equation as explained in above section [45].

Nowadays, several companies have commercialized columns that have superficially porous silica particles. A list of companies offering core–shell sorbents along with the physical properties of each are tabulated in Table 2. The table describes the pioneers of core–shell particle manufacturers and their places along with the physical properties given from the view point of;

  • Size of the particle

  • Pore size of the material

  • Length and internal diameter of the commercialized column

  • Column chemistries

Table 2

A list of superficially porous silica material column producers and some specifications

Vendor

Brand

City

Country

Chemistry

Particle size(µm)

Length (mm)

I.D. (mm)

Pore size (A)

Advanced Chromatography Technologies

ACE Ultracore

Aberdeen

Scotland

C18, Phenyl Hexyl

2.5, 5.0

20–250

2.1–4.6

95

Advanced Material Technology

Halo

Wilmington

USA

C8, C18, Phenyl Hexyl, PFP, ES-CN, RP Amide, HILIC, Penta HILIC

2.0, 2.7, 5.0

20–250

2.1–4.6

90

Agilent

Poroshell

Palo Alto

USA

C8, C18, Phenyl Hexyl, PFP, EC-CN, HILIC

2.7–4.0

50–250

2.1–5.0

100–120

ChromaNik Technologies

Sunshell

Osaka

Japan

C8, C18, C28, Phenyl Hexyl, PFP, HILIC- Amide

2.6, 5.0

30–250

2.1–4.6

90–160

Fortis Technologies

Speeedcore

Cheshire

UK

C8, C18, Phenyl Hexyl, PFP, Amide, CN

1.7, 2.6, 5.0

30–150

2.1–4.6

80

Knauer

Blushell

Berlin

Germany

C18, HILIC

2.6

50–150

2.0

80

Macherey Nagel

Nucleoshell

Duren

Germany

C8, C18, Phenyl Hexyl, PFP, HILIC

2.7, 5.0

50–250

2.0–4.6

90

Phenomenex

Kinetex

Torrance

USA

C8, C18, Phenyl Hexyl, PFP, Biphenyl, HILIC

1.3, 1.7, 2.6, 5.0

20–250

2.1–50

100

Restek

Raptor

Bellefonte

USA

C18, PFP, Biphenyl

2.7, 5.0

30–150

2.1, 4.6

90

Sielc

Coresep

Wheeling

USA

RP and NP

2.7

10–150

0.25–4.6

90

Supelco Sigma-Aldrich

Ascentis Express

Bellefonte

USA

C8, C18, Phenyl Hexyl, PFP, ES-CN, RP Amide

3.0, 5.0, 10

20–250

1.0–21.2

100–120

Thermo Fischer Scientific

Accucore

Waltham

USA

C8, C18, C30, Phenyl Hexyl, PFP, ES-CN, HILIC

1.5, 2.6, 4.0

30–250

2.1–4.6

80–150

Waters

Cortecs

Milford

USA

C8, C18, T3, Phenyl Hexyl, HILIC

1.6, 2.7

30–150

2.1–4.6

90–120

Welch

Boltimate

Shanghai

China

C18, Phenyl Hexyl, PFP, HILIC

2.7

50

4.6

90

YMC

Meteoric core

Kyoto

Japan

C8, C18

2.7

30–150

2.1–4.6

80–160

Glantreo

Eiroshell

Cork

Ireland

C4, C18

1.7, 2.2, 2.6

91–120

C18 octadecyldimethylsilane, C8 octyldomethylsilane, Phenyl Hexyl phenylhexyldimethylsilane, PFP pentafluorophenylpropylsilane, EC-CN, ES-CN diisopropylcyanopropylsilane, RP-Amide C16 amide, HILIC hydrophilic interaction liquid chromatography, Penta HILIC proprietary penta-hydroxy ligand

Nowadays, core–shell packing materials are available on the market in various particle sizes such as 1.3 µm, 1.6 µm, 1.7 µm as sub 2 microns and 2.0 µm, 2.2 µm, 2.6 µm, 2.7 µm, 3.0 µm, 4.0 µm 5.0 µm as analytical scale. Other preparative scale columns are also commercially available as 10.0 µm and more. On the other hand, different lengths of the columns are available ranging from 20 mm to 250 mm from varied vendors with the internal diameters between 1 and 50 mm that aimed to use in different scales. Companies are also competing with each other to produce columns in several chemistries. For this purpose, C8, C18, phenyl hexyl, pentafluorophenyl (PFP), cyano (CN), amide, HILIC, etc., type of chemistries have been commercialized. They are also improving the existing technology to make them more stable to high and low pH values and temperatures, etc. In addition, core–shell silica particles may have advantages for the chromatographic fingerprinting of plant materials, especially traditional Chinese medicines. Thus, from the view point of improved selectivity and efficient separation capabilities, generally chromatographic finger printing is one of the most used approaches for the quality control of plant materials. It also was used to evaluate stability and quality of the plants used as medicine especially in China. On the other hand, the chemical pattern analysis recognition methods should be taken into consideration. In the literature there are as yet no comparisons of fully porous particles and superficially porous particles. However, core–shell particles may improve the chromatographic fingerprinting.

Reversed Phase HPLC (RP-LC)

Theoretically polarity, electrical charge and molecular size are primary characteristics of chemical compounds that can be used in liquid chromatographic separations. As indicated in above section, based on their polarities, separation modes are divided into two sub-groups—namely reversed phase and normal phase. In reverse phase, the stationary phase is less polar than the mobile phase and the column has the silica particles modified to make them non-polar by attaching long hydrocarbon chains (C8, C18, etc.) to their surfaces. The particle chemistries available as core–shell material and their benefits with the applications are going to be briefly described under this heading.

C8 and C18 are known as octyldimethylsilane and octadecyldimethylsilane, respectively. Both chemistries provided excellent performance for a broad range of active pharmaceutical ingredients (API) with different polarities. They can be used for the separation of uncharged acids, bases and ion pairs. These columns can be useful for compounds that differ according to their aliphatic and/or aromatic grouping.

Phenyl hexyl is known as phenyl hexyl dimethylsilane. It has complementary selectivity to alkyl phases and it enhances the selectivity for aromatic compounds. The main target analytes for this phase are electron poor molecules and aromatic compounds such as ketones, alkenes, etc. This chemistry used for the polar compounds takes place in highly aqueous conditions.

PFP is known as pentafluorophenyl propylsilane, and applications for this phase cover basic analytes, stereoisomers, substituted aromatics. Unsaturated compounds that have double or triple bonds and electro-rich compounds are especially targeted to separate. The main benefits for this chemistry include its suitability for use under RP-LC and HILIC modes, the separation of isomers and its complimentary selectivity to alkyl phases.

CN type columns, also known as diisopropylcyanopropylsilane, have complementary selectivity to alkyl phases just like PFP. However, polar analytes retained more than non-polar analytes. The target analytes are highly polar compounds and hydrophobic compounds (retained too much in regular C8 and C18 chemistries). On the other hand, best results can be seen on aromatic molecules that have electron withdrawing groups, such as heterocycles.

Amide can be used for alcohols, acids, phenols, sugars, carbohydrates and catechin-like compounds. Furthermore, acidic and basic analytes, heterocycles, proton donor and acceptors may be separated using this chemistry.

The correlation between performance of the column and various types of core–shell materials was revealed by an investigation of comparative studies. Furthermore, depending on the test samples, reduced plate heights, and high efficiencies obtained using analytical columns that have core–shell particles [5, 16, 46]. Based on above literature Destefano et al. reported fast and high resolution separation of naphthalene, virginiamycin and pesticides. On the other hand, C 18 Kinetex core–shell column was used for the separation of carbapenems [47] and cephalosporins [48, 49, 50, 51, 52, 53] successfully. While it is not discussed and explained in detail under this heading interested readers may find examples relating to the reversed phase in Tables 3 and 4.

Table 3

Optimized conditions for pharmaceutical applications

Compound

Column supplier

Column brand

Column type

Column dimensions (mm × mm)

P.S. (µm)

Mobile phase (v/v)

pH

Tem (°C)

Detector

Refs.

1,2-Distearoyl-sn-glycero-3-phosphocholine

1-Stearoyl-sn-glycero-3-phosphocholine

2-Stearoyl-sn-glycero-3-phosphocholine

Agilent

Poroshell Bonus RP

C18

100 × 4.6

2.7

Gradient

Water (0.1% TFA) (A): MeOH (0.1% TFA) (B)

55

CAD

[54]

Emtricitabine

Tenofovir

Rilpivirine

Phenomenex

Kinetex

C18

150 × 4.6

5.0

Gradient

Buffer (0.1% H3PO4):ACN

7.0

45

DAD

260 nm

[55]

Glutamate

Glutamine

GABA

Macherey-Nagel

Nucleoshell

HILIC

100 × 2.0

2.7

Gradient

23

ESI-MS/MS

[56]

Kirenol

Darutoside

Darutigenol

Welch

Boltimate

C18

100 × 3.0

2.7

Gradient

Phosphate buffer:ACN

35

UV

215 nm

[57]

Formetanate

3-Hydroxyacetanilide

Amitraz

DMPF

DMF

DMA

Chlordimeform

4-Chloro-2-methylaniline

Waters

Cortecs

C18

100 × 4.6

2.7

Gradient

Water (0.1% formic acid) (A):ACN (0.1% formic acid) (B)

30

ESI-MS/MS

[58]

Donepezil

Agilent

Poroshell EC

C18

75 × 4.6

2.7

Phosphate buffer (10 mM):ACN; (75:25, v/v)

2.5

25

FL

EX:325 nm, EM:390 nm

[59]

13 sulphonamides

Phenomenex

Kinetex

C18

75 × 4.6

2.6

Gradient

Acetate buffer (0.02M):MeOH:ACN

4.5

40

DAD

270 nm

[60]

Cannabinoids

Agilent

Poroshell SB

C18

75 × 3.0

2.7

Gradient

Acetate buffer (0.025M):MeOH

4.75

DAD

[61]

Levocetirizine and impurities

Phenomenex

Kinetex

Biphenyl

250 × 4.6

5

Gradient

45

DAD

230 nm

[62]

Ascorbic acid

Rutin

Hesperidin

Phenomenex

Kinetex

C 18

50 × 4.6

5

Water (0.2% formic acid):ACN (80:20; v/v)

7

DAD

260 nm

[63]

Sodium picosulfate

Sodium benzoate

Related substance

Phenomenex

Kinetex

C 18

150 × 3.0

2.6

ACN:Propan-2-ol:Buffer; (43:2:55; v/v/v)

7

40

UV

263 nm

[64]

Ranitidine HCl

Phenomenex

Kinetex

C 18

100 × 2.1

2.6

Water (0.1% formic acid):ACN (90:10; v/v)

30

DAD

313 nm

[65]

14 components in

Shuanghua Baihe tablets

Phenomenex

Kinetex

C 18

100 × 2.1

2.6

Gradient

Water (0.1% formic acid) (A):ACN (B)

30

MS/MS

[66]

Tranylcypromine sulfate and degradation products

Phenomenex

Kinetex

C 18

75 × 4.6

2.6

ACN:o-phosphoric acid (0.1%); (10:90; v/v)

2.3

30

UV

220 nm

[67]

Methotrexate

7-OH-MTX

Agilent

Poroshell 120 EC

C 18

75 × 3.0

2.7

Buffer (acetic acid/sodium acetate):ACN; (88.8:11.2; v/v)

4.0

40

UV

[68]

Dorzolamide

Timolol

IS

Phenomenex

Kinetex XB

C 18

100 × 4.6

2.6

ACN:buffer (45.56 mM phosphate); (18.17:81.83; v/v)

3.76

-

DAD

254 nm and 295 nm

[69]

(+)-Catechin-ethyl-malvidin-3-glucoside diastereoisomers

Phenomenex

Kinetex

C 18

100 × 2.1

2.6

ACN:buffer (0.1% TFA); (21:79; v/v)

UV

205 nm

[70]

13 phytoestrogens and related metabolites

Phenomenex

Kinetex

C 18

150 × 2.1

2.6

Gradient

Water (A):MeOH:ACN (50:50; v/v) (B)

40

MS/MS

[71]

7 sulfa drugs

Restek

Raptor

Biphenyl

150 × 4.6

5.0

MeOH:Buffer (50 mM ammonium acetate); (20:80; v/v)

40

UV

265 nm

[72]

20 relevant polyphenols

Phenomenex

Kinetex

C 18

100 × 3.0

2.6

Gradient

Water (0.1% formic acid):ACN

35

DAD

254 nm

280 nm

320 nm

370 nm

[73]

Indole-3-carbinol and degradation products

Phenomenex

Kinetex XB

C 18

100 × 4.6

5.0

Gradient

ACN:water

50

DAD

270 nm

[74]

Oleuropein

Oleuroside

Phenomenex

Kinetex

C 18

100 × 4.6

2.6

Gradient

Water (0.1% TFA):ACN

40

DAD

232 nm

[75]

Harpagoside

Phenomenex

Kinetex

C 18

100 × 3.0

2.6

Water:MeOH (42:58; v/v)

DAD

278 nm

[76]

Itopride

Ibuprofen

Pantoprazole

Chromanik

Sunshell

C18

150 × 4.6

2.6

Phosphate buffer(10 mM):ACN; (70:30; v/v)

7.0

25

DAD

220 nm

[77]

Cefozopran HCl

Phenomenex

Kinetex

C 18

100 × 2.1

5.0

Water (0.1% formic acid): ACN; (92:8; v/v)

30

UV

270 nm

[51]

Cefpirome sulfate

Phenomenex

Kinetex

C 18

100 × 2.1

5.0

Water (0.1% formic acid): ACN; (90:10; v/v)

30

UV

270 nm

[52]

Cefoselis sulfate

Phenomenex

Kinetex

C 18

100 × 2.1

5.0

Water (0.1% formic acid): ACN; (95:5; v/v)

30

UV

260 nm

[53]

133 traditional Chinese medicine compounds

Shiseido

Capcell core

ADME

150 × 2.1

2.7

Gradient

Buffer (10 mM ammonium formate):ACN (0.1% formic acid)

40

MS/MS

[78]

Tebipenem pivoxyl

Phenomenex

Kinetex

C 18

100 × 2.1

5.0

ACN:0.1% formic acid; (70:30; v/v)

UV

330 nm

[79]

Prednisolone acetate and 8 impurities

Agilent

Poroshell 120 EC

C18

100 × 4.6

2.7

Gradient

ACN:water (10:90; v/v) (A):ACN(B)

60

DAD

250 nm

[80]

Aspirin

Clopidogrel

Phenomenex

Kinetex

Phenyl hexyl

100 × 4.6

2.6

Gradient

Diammonium hydrogen phosphate salt (1.32 g/L), octane − 1 sulphonic sodium salt (2 g/L) (A): ACN:MeOH (50:50; v/v) (B)

2.3

35

DAD 220 nm

[81]

Repaglinide

Phenomenex

Kinetex

C 18

150 × 4.6

5.0

ACN:water (0.05% TFA); (50:50; v/v)

3.0

25

DAD

215 nm

[82]

Antazoline

Tetrahydrozoline

Phenomenex

Kinetex

C 18

150 × 4.6

5.0

ACN:water (0.05% TFA); (63:37; v/v)

3.0

25

DAD

215 nm

[83]

5 anthocyanins

Phenomenex

Kinetex

C 18

250 × 4.6

5.0

Gradient

Water/formic acid (95:5; v/v) (A)

MeOH/formic acid (95:5; v/v) (B)

25

DAD

[84]

18 phthalate metabolites

Phenomenex

Kinetex

Phenyl hexyl

150 × 2.1

2.6

Gradient

Water (0.1% acetic acid):ACN (0.1% acetic acid)

40

MS/MS

[85]

10 analytes (carotenoids, chlorophylls, tocopherol)

Waters

Cortecs

C 18

150 × 2.1

1.6

Gradient

(0.05 M aqueous ammonium acetate) (A): (ACN:MeOH:CHCl3:THF);(70:20:7:3; v/v/v/v) (B)

30

DAD

290, 460, 650 nm

[86]

Phenomenex

Kinetex

C 18

150 × 2.1

1.7

Cefaclor

Phenomenex

Kinetex

PFP

100 × 2.1

2.6

Water (10 mL TEA, 1.0 g sodium pentanosulfonate):MeOH (78:22; v/v)

2.5

30

UV

265 nm

[87]

Tetracyclines

Sigma-Aldrich

Ascentis Express

C 18

150 × 4.6

2.7

Gradient

0.01 M oxalic acid:ACN; (90:10; v/v)

2.0

30

DAD

365 nm

[88]

Stanozolol metabolites

Phenomenex

Kinetex XB

C 18

100 × 4.6

2.6

Gradient

Water (0.1% formic acid):MeOH

2.3

30

MS/MS

[89]

Rivastigmine hydrogen tartrate

Phenomenex

Kinetex

HILIC

100 × 4.6

2.6

ACN:buffer (10 mM ammonium acetate); (80:20)

5.8

30

DAD

217 nm

[90]

β-Carotene

Apo-12′-carotenal

Apo-10′-carotenal

Apo-8′-carotenal

Apo-4′-carotenal

5,6-Epoxy-carotenal

Phenomenex

Kinetex

C 18

100 × 2.1

1.7

Gradient

50

DAD

[91]

Lumazinic derivatives

Agilent

Poroshell 120

C18

150 × 3.0

2.7

Gradient

0.4 mM phosphoric acid /MeOH (95:5, v/v): MeOH (B)

3.2

25

FL

450mn

[92]

Phenolic compounds

Phenomenex

Kinetex

C 18

100 × 4.6

2.6

Water (0.1% acetic acid):ACN

25

DAD

[93]

Citrulline and metabolically related amino acids

Mac-Mod

Halo

C 18

50 × 2.1

2.7

Gradient

Buffer (25 mM formic acid/ammonium formate):ACN

3.75

25

DAD

260 nm

[94]

Perindopril isomers

Agilent

Poroshell 120

HILIC

150 × 4.6

2.7

ACN:water (0.1% formic acid); (20:80; v/v)

25

UV

230 nm

[49]

Doripenem

Phenomenex

Kinetex

C 18

100 × 2.1

5.0

Water (12 mM ammonium acetate): ACN; (96:4; v/v)

30

UV

298 nm

[47]

2.6

1.7

Water (12 mM ammonium acetate): ACN; (90:10; v/v)

Meropenem

Phenomenex

Kinetex

C 18

100 × 2.1

5.0

Water (12 mM ammonium acetate): ACN; (93:7; v/v)

2.6

1.7

Water (12 mM ammonium acetate): ACN; (90:10; v/v)

Tebipenem

Phenomenex

Kinetex

C 18

100 × 2.1

5.0

Water (12 mM ammonium acetate): ACN; (93:7; v/v)

2.6

Water (12 mM ammonium acetate): ACN; (90:10; v/v)

1.7

Fermentation product

Chromanik

Sunshell

C 18

75 × 4.6

2.6

Buffer (50 mM borate):ACN; (94:6; v/v)

8.9

30

UV

210 nm

[95]

Mycotoxin T-2

Mycotoxin HT-2

Phenomenex

Kinetex XB

C 18

100 × 4.6

2.6

Gradient

Buffer (5 mM ammonium acetate): MeOH

7.0

30

MS/MS

[96]

Ochratoxin A

Phenomenex

Kinetex

C 18

100 × 4.6

2.6

ACN (formic acid 1%):water (formic acid 1%); (50:50; v/v)

40

FL

EX:333 nm, EM:477 nm

[97]

Trimyristine

Tripalmitine

Triolein

Tristearin

Other triglycerides

Agilent

Poroshell 120 EC

C 18

50 × 3.0

2.7

Gradient

MeOH:isopropanol

45

ESI-Q-ToF

[98]

Retinol

α-Tocopherol

Phenomenex

Kinetex

C 18

50 × 4.6

2.6

MeOH

25

FL

[99]

Acetaminophen

Caffeine

Acetylsalicylic acid

Phenomenex

Kinetex

C 18

100 × 2.1

2.6

Water:ethyl lactate:acetic acid; (94.5:2.5:3.0; v/v/v)

40

UV

275 nm

[100]

Protodioscin

Phenomenex

Kinetex

C 8

50 × 3.0

2.6

ACN:water:n-propanol; (24:74.4:1.6; v/v/v)

35

ELSD-UV

205 nm

[101]

Methylparaben

Ethylparaben

Propylparaben

Phenoxyethanol

Thermo Fisher Scientific

Accucore

C 18

100 × 2.1

2.6

ACN:water (0.1% acetic acid); (20:80; v/v)

40

UV

254 nm

[102]

8 corticosteroids

Phenomenex

Kinetex

Phenyl Hexyl

100 × 4.6

2.6

Gradient

Water (5 mM ammonium acetate/0.01% acetic acid): MeOH

5.4

30

MS/MS

[103]

Metronidazole

Ronidazole

Dimetridazole

MNZ-OH

HMNNI

Phenomenex

Kinetex

XB

C 18

100 × 3.0

2.6

Water (0.1% formic acid): MeOH; (88:12; v/v)

2.6

35

MS/MS

[104]

Lincomycin

Phenomenex

Kinetex

XB

C 18

100 × 3.0

2.6

Water (0.1% formic acid): ACN; (93:7; v/v)

2.6

-

MS/MS

[105]

N-(ω)-Hydroxy-nor-l-arginine and metabolites

Phenomenex

Kinetex

C 18

100 × 3.0

2.6

Gradient

Water (0.1% formic acid): MeOH

3.0

50

FL

EX:235 nm

EM:450 nm

[106]

Vitamin D metabolites

Phenomenex

Kinetex

PFP

150 × 4.6

2.6

Gradient

Water (0.5 mM ammonium acetate):MeOH

50

MS/MS

[107]

Amoxicillin

IS

Ampicillin

Thiamphenicol

Oxacillin

Florfenicol

Cloxacillin

Chloramphenicol

Dicloxacillin

Phenomenex

Kinetex

C 18

150 × 4.6

2.6

Gradient

Water (0.5 mM ammonium acetate): MeOH

DAD

226 nm

240 nm

280 nm

[108]

Ibuprofen

IS

Imp C

Phenomenex

Kinetex

XB

C 18

75 × 4.6

2.6

ACN:Water (4 g Chloroacetic acid); (60:40; v/v)

3.0

30

DAD

254 nm

[109]

CB-1 drug candidate and impurities

Sigma-Aldrich

Ascentis Express

C 18

50 × 4.6

2.7

Water (0.1% phosphoric acid): ACN; (40:60; v/v)

40

UV

220 nm

[110]

Sinafloxacin

IS

Mac-Mod

Halo

C 18

50 × 4.6

2.7

ACN: Phosphate buffer; (20:80; v/v)

3.0

25

FL

EX:295

EM:505

[111]

Betamethasone-17-valerate

Betamethasone-E-enolaldehyde

Betamethasone-Z-enolaldehyde

Mac-Mod

Halo

C 18

100 × 4.6

2.7

ACN:Water; (42:58; v/v)

40

UV

240 nm

[112]

Rimonabant

Mac-Mod

Halo

C 18

50 × 2.1

2.7

Gradient

ACN (0.1% formic acid):Water (0.1% formic acid)

40

MS

[113]

PS particle size, TEM temperature, DAD diode array detector, WL wavelength, IS internal standard, TFA trifluoroacetic acid, THF tetrahydrofuran, PFP pentafluorophenyl, TEA triethylamine, FL fluorescence detector, EX excitation, EM emission, ESI-Q-ToF electro spray ionization q time of flight, ELSD evaporative light scattering detector, Imp impurity, CAD charged aerosol detector

Table 4

Validation parameters of optimized conditions

Compound

Column

Analysis time (min)

System suitability parameters

Validation parameters

Ref

Rs

α

N

T or As

Linearity (µg/mL)

LOD (µg/mL)

LOQ (µg/mL)

Precision (RSD %)

Accuracy %

1,2-Distearoyl-sn-glycero-3-phosphocholine

Poroshell Bonus RP (100 × 4.6; 2.7 µm)

13.0

+

+

+

+

0.5–12.5

+

+

0.3–2.8

97.6–103.6

[54]

1-Stearoyl-sn-glycero-3-phosphocholine

2-Stearoyl-sn-glycero-3-phosphocholine

Emtricitabine

Kinetex C18 (150 × 4.6; 5.0 µm)

7.0

24.51

2.14

5214

1.12

1–50

0.27

0.81

0.64

99.7

[55]

Tenofovir

11.74

1.22

51,675

0.83

1–100

0.14

0.42

0.54

103.7

Rilpivirine

60,675

0.94

1–100

0.04

0.12

0.33

105

Glutamate

Nucleoshell HILIC (100 × 2.0; 2.7 µm)

21.1

0.0025–2

0.25

1.25

2.7

12–23

[56]

Glutamine

0.0625–5

1.6

3.15

8.2

GABA

0.0006–0.5

0.45

0.63

10.6

Kirenol

Boltimate C18 (100 × 3.0; 2.7 µm)

8.0

0.098–195

0.030

0.101

0.52

96.7

[57]

Darutoside

0.101–202

0.044

0.148

0.43

101.2

Darutigenol

0.130–103

0.046

0.154

0.87

98.8

Formetanate

Cortecs C18 (100 × 4.6; 2.7 µm)

4

0.0002–1

0.00001–0.00004

0.00003-0.00012

3.7–6.6

81.9–90.4

[58]

3-Hydroxyacetanilide

Amitraz

DMPF

DMF

DMA

Chlordimeform

4-chloro-2-methylaniline

Donepezil

Poroshell 120 EC-C18 (75 × 4.6; 2.7 µm)

5

+

0.0005–0.025

0.00015

0.0005

11%<

96.9-102.8

[59]

13 sulphonamides

Kinetex C18 (75 × 4.6; 2.6 µm)

8

+

+

+

+

0.1–2

0.9–5 µg/kg

2.7–15.1 µg/kg

10.5–14

52.55–82.87

[60]

Cannabinoids

Poroshell 120 SB-C18 (75 × 3.0; 2.7 µm)

9

+

0.25–50

0.0625

0.25

2.5–5.19

80–107

[61]

Levocetirizine

Kinetex Biphenyl (250 × 4.6; 5 µm)

120

+

+

51985

0.98

160–240

0.013–0.017

0.041–0.050

2%<

96.5–106.6

[62]

Impurity 1

49387

0.89

Impurity 2

59171

0.92

Impurity 5

51228

0.96

Impurity 8

44282

0.92

Impurity 3

48514

0.86

Impurity 4

50761

0.92

Impurity 6

Impurity N-oxide

Impurity 7

Ascorbic acid

Kinetex C18 (50 × 4.6; 5 µm)

2.5

625

80–800

1.212

95.88

[63]

Rutin

3.65

 

800

 

20–220

0.931

100.55

1.832

104.19

Hesperidin

5.78

 

1943

 

20–200

Sodium picosulfate

Kinetex C18 (150 × 3; 2.6 µm)

3

+

+

+

+

+

1.25

99.63

[64]

4.12

99.27

Sodium benzoate

0.11

0.36

4.68

97.86

Related substance

Ranitidine HCl

Kinetex C18 (100 × 2.1; 2.6 µm)

1.5

+

+

+

+

0.02–0.24

0.0048

0.0147

0.15–0.38

99.62–100.12

[65]

Ferulic acid

Kinetex C18 (100 × 2.1; 2.6 µm)

9.0

10–1000

0.51

1.60

1.82

102.9

[66]

Isoferulic acid

10–1000

0.59

1.82

2.62

100.8

Corynoline

1.0–100

0.16

0.53

3.17

102.6

Acetylcorynoline

2.0–200

0.23

0.82

2.84

100.5

Protopine

1.0–100

0.12

0.40

3.05

101.5

Adenosine

20–2000

2.03

6.91

2.16

101.8

Caffeic acid

10–1000

1.17

3.52

1.49

100.5

Vanillic acid

10–1000

0.51

1.78

2.38

102.8

Rutin

10–1000

0.55

1.84

1.73

100.3

Orientin

10–1000

1.03

3.41

2.58

99.2

Isoorientin

10–1000

1.28

5.02

1.81

100.9

Asarinin

20–2000

2.10

7.09

2.58

101.6

Acteoside

10–1000

1.17

3.73

1.92

99.8

Cholalic acid

10–1000

0.50

1.89

2.09

101.6

Degradant a

Kinetex C18 (75 × 4.6; 2.6 µm)

8.0

2.39

1.95

2150

1.17

3–150

0.164

0.498

0.20

100.58

[67]

Degradant b

2.33

1.42

2698

1.20

Tranylcypromines

3315

0.63

Methotrexate

Poroshell 120 EC-C18(75 × 3.0; 2.7 µm)

4.0

0.10–6.0 µm

0.10

0.72–13.4

88–109.2

[68]

7-OH-MTX

Dorzolamide

Kinetex XB C18 (100 × 4.6; 2.6 µm)

3.5

7.41

1.53

55005

1.02

0.0009–0.05

0.0003

0.0009

1.26–1.81

98.7–101

[69]

IS

20.93

2.17

62331

1.04

0.0015–0.05

0.0005

0.0014

1.46–1.97

98.5–100

Timolol

(+)-Catechin-ethyl-malvidin-3-glucoside diastereoisomers

Kinetex C18 (100 × 2.1; 2.6 µm)

20

1848–2342

[70]

Daidzein

Kinetex C18 (150 × 2.1; 2.6 µm)

10

0.0002–0.5

1.4

108

[71]

Dihydrodaidzein

1.0

35

3.5

60

Glycitein

0.1

107

Biochanin

1.3

75

Enterodiol

2.2

73

52

Enterolactone

0.7

63

Coumestrol

1.5

75

Naringenin

1.6

77

Dihydrogenistein

0.4

84

O-DMA

0.6

111

Matairesinol

1.5

105

Equol

1.3

Genistein

Sulfisoxazole

Raptor Biphenyl (150 × 4.6; 5.0 µm

40

+

+

+

+

1–10

0.017

0.057

0.057

66–71

[72]

Sulfadiazine

0.059

0.197

0.197

77–81

Sulfamethoxazole

0.045

0.149

0.149

74–79

Sulfamonomethoxine

0.035

0.115

0.115

72–81

Sulfamerazine

0.068

0.227

0.226

69–100

Sulfamethoxypyridazine

0.016

0.054

0.054

68–74

Sulfadimidine

0.056

0.186

0.187

62–81

Gallic acid

Kinetex C18 (100 × 3.0; 2.6 µm)

20

+

+

+

+

0.5–25

0.08

0.26

0.27

92.4

[73]

(−)-Gallocatechin

0.5–10

0.10

0.33

1.09

85.2

OH-Tyrosol

0.5–25

0.09

0.30

1.21

77.9

Caftaric acid

1–25

0.15

0.5

1.70

89.8

Tyrosol

0.5–25

0.11

0.36

1.61

82.1

(−)-Epigallocatechin

1–25

0.27

0.90

1.05

93.4

(+)-Catechin

1–100

0.26

0.86

1.08

110.8

Caffeic acid

0.5–25

0.12

0.40

1.99

102.6

Syringic acid

0.5–25

0.10

0.33

1.18

108.3

(−)-Epicatechin

0.5–50

0.13

0.43

1.04

109.3

p-Coumaric acid

0.5–25

0.09

0.30

0.99

90.6

(−)-Gallocatechin gallate

0.5–10

0.12

0.40

2.81

72.3

Ferulic acid

0.5–25

0.07

0.23

1.02

89.5

Polydatin

0.5–25

0.07

0.23

0.78

112.3

Piceatannol

0.5–10

0.11

0.36

1.42

108.6

Quercetin-3-glucoside

0.5–10

0.12

0.40

0.55

76.8

Kaempferol-3-glucoside

0.5–10

0.10

0.33

0.96

80.2

trans-Resveratrol

0.5–25

0.08

0.26

1.42

114.9

Cinnamic acid

0.5–25

0.14

0.46

0.78

95.9

Quercetin

0.5–25

0.33

1.10

2.56

75.6

Indole-3-carbinol

Kinetex XB C18 (100 × 4.6; 5.0 µm)

6.0

+

+

+

1.32

5–500

0.03

0.10

0.2–0.8

100–104

[74]

IS

1.28

CP1

CP2

CP3

Oleuropein

Kinetex XB C18 (100 × 4.6; 2.6 µm)

12

3.1

 

290726

0.9

500–1528

5.0

0.5

99.9

[75]

Oleuroside

335016

0.9

Harpagoside

Kinetex C18 (100 × 3.0; 2.6 µm)

4.0

15–45

15

1.14

103.6–105

[76]

Itopride

Sunshell C18 (150 × 4.6; 2.6 µm)

6.0

[77]

Ibuprofen

5.0

1.41

Pantoprazole

12.14

1.65

133 traditional Chinese medicine compounds

Capcell core ADME (150 × 2.1 ;2.7 µm)

28

0.05–0.1

0.05<

+

0.83–12.8

74–140

[78]

Tebipenem pivoxyl

Kinetex C18 (100 × 2.1; 5.0 µm)

3.0

0.02–0.24

0.02–0.24

0.11–0.31

98.9–102.9

[79]

Prednisolone acetate and 8 impurities

Poroshell 120 EC C18 (100 × 4.6; 2.7 µm)

33

> 1.5

+

+

+

0.1–4.0

0.002–0.005

0.007–0.018

0.5–1.6

92.5–114.9

[80]

Aspirin

Kinetex Phenyl hexyl (100 × 4.6; 2.6 µm)

8.0

6306

1.1

0.2

100.2−–100.5

[81]

Clopidogrel

30881

1.0

IS

Kinetex C18 (150 × 4.6; 5.0 µm)

4.0

3801

0.8

0.2–300

0.012

0.035

0.99–1.25

100.7

[82]

Repaglinide

7.08

2.04

5509

1.1

Tetrahydrozoline

Kinetex C18 (150 × 4.6; 5.0 µm)

3.5

3369

0.5–200

0.068

0.206

0.39–0.92

101.57

[83]

IS

7.33

1.58

5053

Antazoline

2.19

1.12

6525

0.078

0.238

102.87

cya-xyl-glc-gal

Kinetex C18 (250 × 4.6; 5.0 µm)

37

> 1.6

0.46–57.73

0.35–1.20 ng

1.05–3.63 ng

1.79–3.29

95.5–101

[84]

cya-xyl-gal

cya-xyl-glc-gal sinapoyl cya 3-O-glc

cya-xyl-glc-gal feruloyl cya-xyl-glc-gal p-coumaroyl

18 phthalate metabolites

Kinetex Phenyl hexyl (150 × 2.1; 2.6 µm)

16

0.0003–0.0014

+

+

+

+

[85]

Neoxanthin

Kinetex C18 (150 × 2.1; 1.7 µm)

7.34

1.0–25.0

0.1–1.6

0.4–3.2

8.56

[86]

Violaxanthin

8.07

0.82

Lutein epoxide

20.53

4.66

Lutein

22.28

0.29

β-Carotene

17.44

1.52

Chl-a

dw

-

Chl-a′

22.50

11.79

Chl-b

3.24

0.82

Chl-b′

6.36

4.45

Γ-Tocopherol

2.88

17.18

 

Cortecs C18 (150 × 2.1; 1.6 µm)

7.60

3.33

6.92

9.64

13.87

dw

4.50

0.71

5.52

2.14

Cefaclor

Kinetex PFP (100 × 2.1; 2.6 µm)

9.0

40–60

0.46–1.90

70–75.9

[87]

Oxytetracycline

Ascentis Express C18 (150 × 4.6; 2.7 µm)

20.0

5 µg/kg

17 µg/kg

4.1–10.6

70–71.4

[88]

Tetracycline

5 µg/kg

17 µg/kg

6.6–15.2

70.8–80

Chlorotetracycline

10 µg/kg

33 µg/kg

6.8–18.6

57–60.4

Doxycyclines

5 µg/kg

17 µg/kg

9.9–16.1

52–52.8

16-OH-STN

Kinetex XB C 18 (100 × 4.6; 2.6 µm)

11.0

0.0005–0.008

0.05 µg/kg

0.17 µg/kg

5.6–24.1

85.4-106.2

[89]

3-OH-STN

0.05 µg/kg

0.33 µg/kg

4-OH-STN

0.15 µg/kg

0.50 µg/kg

Rivastigmine hydrogen tartrate

Kinetex HILIC (100 × 4.6; 2.6 µm)

5.0

6528

1.34

1–30

0.56

1.89

4.0<

> 95.0

[90]

β-Carotene

Kinetex C18 (100 × 2.1; 1.7 µm)

5.5

1.0–5.0

0.231

0.741

4.1<

101.6

[91]

Apo-12′-carotenal

0.25–5.0

0.025

0.075

74.4

Apo-10′-carotenal

0.25–5.0

0.017

0.052

94.6

0.25–5.0

0.030

0.087

84.5

Apo-8′-carotenal

1.0–5.0

0.293

0.889

84.1

1.0–5.05

0.221

0.640

65.8

Apo-4′-carotenal

5,6-Epoxy-carotenal

Lumazinic derivatives

Poroshell 120 C18 (150 × 3.0; 2.7 µm)

25

[92]

9.79

 

1480

0.01–0.6

0.00031

0.001

2.9

GS

13.04

 

1984

0.004–0.12

0.00005

0.00002

4.5

Gly

4.0

 

2052

0.004–0.125

0.00008

0.00003

3.6

3-DG

6

 

27283

0.004–0.04

0.00002

0.000007

4.5

MGly

1.58

 

47071

0.004–0.03

0.00003

0.00001

6.0

DIA

11.68

 

81245

0.004–0.15

0.00009

0.00003

3.9

2,3-Pen (1)

12.06

 

72407

0.004–0.15

0.00008

0.00003

2.3

2,3-Pen (2)

1.68

 

27549

0.004–0.06

0.00016

0.00005

4.7

PhGly (1)

17.63

 

24488

0.004–0.06

0.00007

0.00002

5.7

PhGly (2)

2.08

  

Ferulic acid

Kinetex HILIC (100 × 4.6; 2.6 µm)

22

0.007–500

0.007

2.8

98.7

[93]

Catechin

0.033–1000

0.033

3.4

99.3

Procyanidin B2

0.030–1000

0.030

3.9

98.9

Other 17 compounds

Citrulline and metabolically related amino acids

Halo C18 (50 × 2.1; 2.7 µm)

30

0–126.4 µm

5–11

 

[94]

Perindopril isomer I

Poroshell 120 HILIC (150 × 4.6; 2.7 µm)

2.0

1.68

34693

1.83

0.40–1.40

0.15

0.46

1.04–1.71

95.6–96.3

[49]

28716

1.51

0.40–2.40

0.04

0.11

1.20–1.80

97.1–97.9

Perindopril isomer II

Doripenem

Kinetex

C 18 (100 × 2.1; 5.0 µm)

0.82

0.97

0.05−3.0

0.01

0.03

0.6

105

[47]

Kinetex

C 18 (100 × 2.1; 2.6 µm)

0.87

1.03

0.25–3.0

0.03

0.09

1.2

95

Kinetex

C 18 (100 × 2.1; 1.7 µm)

0.67

1.38

0.5–3.0

0.12

0.34

0.6

102

Meropenem

Kinetex

C 18 (100 × 2.1; 5.0 µm)

0.68

0.92

0.05–3.0

0.01

0.02

0.2

81

Kinetex

C 18 (100 × 2.1; 2.6 µm)

0.79

1.12

0.25–3.0

0.03

0.09

2.3

101

Kinetex

C 18 (100 × 2.1; 1.7 µm)

0.58

1.39

0.5–3.0

0.14

0.43

1.2

102

Tebipenem

Kinetex

C 18 (100 × 2.1; 5.0 µm)

0.87

1.14

0.05–3.0

0.01

0.03

0.2

95

 

Kinetex

C 18 (100 × 2.1; 2.6 µm)

0.53

1.12

0.05–3.0

0.01

0.02

1.5

100.5

 

Kinetex

C 18 (100 × 2.1; 1.7 µm)

1.16

0.76

0.5–3.0

0.01

0.03

0.2

99

Fermentation product

Sunshell C18

(75 × 4.6; 2.6 µm)

8.0

9975

1.20

[95]

Mycotoxin T-2

Kinetex XB C18

(100 × 4.6; 2.6 µm)

16

6.25−50.0 µg/kg

0.5 µg/kg

1.7 µg/kg

2.7

98.3

[96]

Mycotoxin HT-2

1.5 µg/kg

5.0 µg/kg

8.7

97.9

Ochratoxin A

Kinetex C18

(100 × 4.6; 2.6 µm)

5.0

29000

0.5–50

0.0025

0.0083

-

81.3–83.2

[97]

Trimyristine

Poroshell 120 EC (50 × 3.0; 2.7 µm)

25

34965

0.1–2.4 µg/g

0.03 µg/g

0.11 µg/g

0.19–0.31

[98]

Tripalmitine

 

53099

0.03 µg/g

0.09 µg/g

Triolein

1.6

 

40987

0.03 µg/g

0.08 µg/g

Tristearin

 

160170

0.04 µg/g

0.13 µg/g

Other triglycerides

Retinol

Kinetex C18 (50 × 4.6; 2.6 µm)

1.22

9.41

44500

1.092

2.3 nm

6.4 nm

[99]

α-Tocopherol

98580

1.161

7.7 nm

21.4 nM

Acetaminophen

Kinetex C18 (50 × 2.1; 2.6 µm)

3.0

97.1

[100]

Caffeine

99.5

Acetylsalicylic acid

101

Methylparaben

Accucore C18 (100 × 2.1; 2.6 µm)

8.0

25900

1.7

0.5–20

0.015

0.050

1.3–4.6

98–98.4

[102]

Ethylparaben

9.1

 

75825

1.4

0.022

0.073

0.043

0.142

Propylparaben

16.8

 

145511

1.1

Prednisolone

Kinetex

Phenyl Hexyl (100 × 4.6; 2.6 µm)

24.5

0.25–2.0

0.03 µg/kg

0.10 µg/kg

6.5–14.6

95–114

[103]

Prednisone

0.03 µg/kg

0.10 µg/kg

6.0-15.5

97–113

Dexamethasone

0.02 µg/kg

0.07 µg/kg

6.7–12.5

95–96

Betamethasone

0.01 µg/kg

0.03 µg/kg

2.5–16.7

102–119

Methylprednisolone

0.02 µg/kg

0.07 µg/kg

5.1–11.1

94–99

0.02 µg/kg

0.07 µg/kg

6.3–12.4

90–98

Methylprednisone

0.01 µg/kg

0.03 µg/kg

3.4–6.6

105–110

0.10 µg/kg

0.33 µg/kg

4.0–11.1

94–101

Flumethasone

Triamcinolone acetonide

Metronidazole

Kinetex XB C 18 (100 × 3.0; 2.6 µm)

3.0

1.5–9.0 µg/kg

0.05–0.1 µg/kg

0.17–0.33 µg/kg

1.4–2.5

88.0–97.2

[104]

MNZ-OH

5.6–8.4

68.9–91.1

Ronidazole

1.4–2.7

99.7–105

1.6–3.0

86.8–92.8

HMNNI

7.8–14.6

90.7–96.4

Dimetridazole

Lincomycin

Kinetex XB C 18 (100 × 3.0; 2.6 µm)

3.5

5–250 µg/kg

0.05 µg/kg

0.17–1.7 µg/kg

3.7–28.7

94.2–125

[105]

Nor-NOHA

Kinetex C 18 (100 × 3.0; 2.6 µm)

10

> 1.5

0.01–2 mm

0.005 mm

11<

90–110

[106]

Arginine

0.005–1 mm

IS

25OH-D3

Kinetex PFP (150 × 4.6; 2.6 µm)

10

4.0–265 nm

4.0 nm

5<

[107]

25OH-D2

3.9–184 nm

3.9 nm

3-epi-25OH-D3

2.0–134 nm

2.0 nm

24R,25(OH)2-D3

2.8–130 nm

2.8 nm

Amoxicillin

Kinetex C 18 (150 × 4.6; 2.6 µm)

17

3600

1.0

0.5–20

25.9 ng

4.3

99.6-110.3

[108]

IS

3.6

0.69

13626

1.5

Ampicillin

6.3

1.34

25659

1.0

14.1 ng

2.9

Thiamphenicol

7.7

1.69

38722

1.5

41.6 ng

3.4

Oxacillin

9.1

2.36

75698

1.0

9.6 ng

2.2

Florfenicol

3.1

2.49

84568

0.75

23.5 ng

2.8

Cloxacillin

1.9

2.56

89328

1.0

26.7 ng

3.2

Chloramphenicol

8.2

2.71

56096

1.5

23.5 ng

3.6

Dicloxacillin

1.8

3.00

122277

1.0

42.3 ng

1.4

Ibuprofen

Kinetex XB C 18 (75 × 4.6; 2.6 µm)

2.5

1.82

[109]

IS

4.79

1.02

Imp C

4.68

1.01

Void

Ascentis Express C 18 (50 × 4.6; 2.7 µm)

2.0

[110]

CB-1

Trans

1.91

1.34

Cis

3.75

1.11

Sinafloxacin

Halo C18 (50 × 4.6; 2.7 µm)

3.0

0.005–0.5

0.002

0.005

5.8<

100.3–103.5

[111]

Betamethasone-17-valerate

Halo C 18 100 × 4.6; 2.7 µm

9.0

20000

100–500

0.97

[112]

Betamethasone-E-enolaldehyde

1.60

1.06

 

0.8-4.0

Betamethasone-Z-enolaldehyde

IS internal standard, PFP pentafluorophenyl, STN stanozolol, Imp impurity

Hydrophilic Interaction Liquid Chromatography (HILIC)

This technique proposed by Alpert in 1990 has been applied for the analysis of many hydrophilic compounds. Amide, diol, polyol, bare silica, ion exchange and zwitterion phases have been used as a hydrophilic stationary phase along with an organic solvent rich mobile phase for HILIC. It is somehow defined a combination of normal phase, reversed phase and the ion chromatography (Fig. 9). The HILIC has similarities with traditional NP-LC, but the key difference is that HILIC employs semi-aqueous mobile phases. As indicated in the above section, reversed phase needs a polar stationary phase and apolar mobile phase. In addition, highly polar analytes cannot be retained in such conditions. It is well known that separation in HILIC is achieved by partition between a mobile phase and a water rich layer on the stationary phase. Therefore, it is important for HILIC that a stable water rich layer can be formed on the stationary phase.

Fig. 9

Hydrophilic interaction liquid chromatography combines the characteristics of RP-LC, normal phase LC (NP-LC) and ion exchange chromatography

The mechanism on silica can be explained by a combination of mechanisms outlined below:

  • Polar analyte partitions into and out of adsorbed water layer

  • Charged polar analyte can undergo cation exchange with charged silanol groups

If either of the above are missing one, it is not possible to talk about retention of the polar species [27, 114, 115]. Nearly all of the core–shell silica particle manufacturers have HILIC-based (HILIC and penta-hydroxy ligand of HILIC) columns. One of the key parameters about polarity is log P values. In this technique, polar analytes with log P values near or less than zero can be separated well. Apart from retention of highly polar analytes, this technique has some more benefits such as complementary selectivity to reversed phase and enhanced sensitivity in mass spectrometry (high organic mobile phase promotes enhanced electrospray ionization mass spectrometry response). One important aspect of superficially porous columns for HILIC separation is that column efficiency is not influenced at high flow rates, which implies that shorter analysis times could be achieved at higher flow rates while generating acceptable pressure levels. There are many application areas for HILIC mechanism such as purines, pyrimidines, carbohydrates, peptides, nucleotides, aliphatic amino acids, quaternary amines, flavonoids, etc. For example, a Halo Penta-HILIC column was successfully applied for fast separation of nucleosides and bases in less than 9 min [46] and for the analysis of cocaine, meperidine, methamphetamine and its metabolites. The core–shell particles used in HILIC techniques offered a faster separation, but simultaneously generated 30% lower efficiency than fully porous particles [116]. On the other hand, Poroshell 120 HILIC has 2.7 µm particle size, used for the determination of cetirizine dihydrochloride in bulk substance and in pharmaceutical dosage form with high efficiency, repeatability, and sensitivity [117]. Within the frame of this review, more applications of core–shell packed HILIC columns are also summarized in Tables 3 and 4 [90, 93, 117].

Chiral Liquid Chromatography

Chiral molecules are divided into sub groups such as diastereomers and enantiomers. One of the most important types of chiral molecules is called enantiomers. Enantiomers are the two-mirror image form of a chiral molecule which is identical from the view point of both physical and chemical properties. However, the biological profiles can be differed from each other. Due to the biological, toxicological and pharmacological differences, these compounds have a significant place in the pharmaceutical industry. For this reason, separation of the enantiomers becomes much more important. One of the main points for this phenomenon is that there is no theory that would allow for prediction of a result regarding the separation order based on analyte structure, mobile phase composition and chiral selector on the stationary phase [118]. For this reason, an understanding of natural forces is essential based on the binding of one enantiomer to the chiral stationary phase over the other. Therewithal, reversal of enantiomer elution order has significant outcomes on the determination of enantiomeric purity. If the impurity, eluted before the main peak, it can be determined with better accuracy and precision [118, 119, 120, 121, 122, 123, 124, 125]. For the most part, research in this field has been done using five different types of chiral stationary phases as follows; polymer-based, pirkle or brush type, cyclodextrin based, chirobiotic phases and protein based. The mostly preferred and universal ones are polymers such as polysaccharides (amylose, cellulose) as a chiral selector on fully porous particles. The use of core–shell silica materials in chiral chromatography is a rather new technique in the literature and there are not many investigations in this field. However, Chankvetadze and his group reached superfast and second scale separations using superficially porous materials. The advantages of core–shell silica over totally porous silica for chiral and achiral liquid phase chromatographic separations have been documented in the literature survey and will be summarized in applications section [2, 8, 9, 10, 15, 33, 42, 43, 112, 120, 124, 126, 127, 128, 129, 130]. On the other hand, a very recent study by Bezhitashvili et al. demonstrates practical HPLC separation of enantiomers on a chiral stationary phase prepared by covalent immobilization of a polysaccharide derivative, namely cellulose (3,5-dichlorophenylcarbamate), onto the surface of superficially porous silica. As a result of their study, baseline separation was achieved for several compounds included chiral sulfoxides, etc., and thanks to the core–shell particles, separation was completed in less than 30 s [131].

Nanoliquid Chromatography

Miniaturization techniques have become much more important to achieve highly sensitive chromatographic results. For this reason, the columns that are used in these types of applications are better for diluting the samples. Nanoscaled chromatography provides higher efficiency and sensitivity than conventional liquid chromatography systems with less amounts of sample and minimized dead volume of the columns [70, 122, 132].

The type of the columns in liquid chromatography can be listed as follows;

  • Semi-preparative columns have 10–200 mm I.D., 5–50 cm length with a flow rate of 10–1000 mL min−1 and the sample injection volume in the range from 1 to 10 mL

  • Conventional LC columns have the dimensions of 5–25 cm length with the 4–5 mm I.D. with the maximum flow rate of 2 mL min−1. In conventional chromatography, analytes can be injected as 5–50 µL

  • Narrow bore and microbore LC columns that have the lengths of 1–2 mm I.D. and 5–25 cm length with the 0.01–0.3 mL min−1

  • Nano LC or open tubular LC columns are varied 50–100 µm I.D. The length of this columns varied 1–25 cm and the flow rates are between 100 and 300 nL min−1 with the 1–3 nL injection volume.

And related to the flow rates miniaturized liquid chromatography techniques are divided into subcategories: As indicated above micro LC has a flow rate of 10 µL min−1, while capillary LC and nano LC covers the use of flow rates 1–10 µL min−1 and below 1 µL min−1 respectively. The columns that have 1 and/or 2 mm I.D. are used in traditional LC systems, but the instrument itself needs to be modified to decrease the dead volume (t0). The dead volume creates more problems when touching the capillary columns. To overcome this problem, some instrumental modifications are required, for example, pumps should be adopted to accommodate low flow rates, and injection and detection should be performed directly on the capillary. On the occasion of packing effects, the efficiency between analytical and narrow bore columns is similar to each other [133, 134]. Thus, different packing methods have been applied such as dry packing [135], high pressure slurry packing [136], and centripetal force packing [137] to overcome some of the issues. The main advantages of nano LC are that it initially reduces the solvent consumption and subsequent waste production. Based on the decreasing of internal diameter, the sensitivity increases while the necessity for sample analyses reduces. Furthermore, narrow column bead size provides sharp signals with the better efficiency. On the other hand, many of the published studies have been realized using conventional 3.0–5.0 µm fully porous silica particles. However, chromatographic performance improved in parallel with decreasing particle size to less than 2.0 µm, but consequently this phenomenon come with the high backpressure problems [138]. Based on this situation, core–shell particles generally improve the efficiency of the separation with the rapid elution without using sub 2.0 micron particles in conventional HPLC system [139, 140, 141]. The main application areas of nano LC can be found in proteomics discovery workflows in the literature. On the other hand, this method is used for the determination and the quantification of peptides in complex matrices. However, within the frame of this review, some examples of nano LC will be given in Sect. 5.5 below.

Applications of Core–Shell Based Columns in High Performance Liquid Chromatography

The key advantages of core–shell particle packed columns have been discussed in the sections above. Due to the described benefits, improved efficiency has been widely exploited in recent years. These columns are not only used in pharmaceutical applications as a quality control method, but they have also been used in various fields such as biological compounds (determination of metabolites and biomacromolecules, in the analysis of peptides and proteins), environmental samples such as pesticides and polycyclic aromatic hydrocarbons, and in the food industry where they have been used to determine the presence of antioxidants and food contaminants (bisphenols, mycotoxins, etc.) [46, 127, 142, 143, 144, 145, 146, 147, 148].

The frame of this review covers the application of superficially based particles as a column material in liquid chromatography. Based on surveys conducted between 2010 and 2018, it is clear that there is a rising interest on core–shell particles in this field. For this reason, some selected papers were reviewed from the view point of vendors, chemistry, dimension, and particle size of the columns. Furthermore, analysis parameters such as pH, temperature and detector wavelength are represented in Table 3. On the other hand, Table 4 illustrates the total analysis time with system suitability parameter results (resolution factor, selectivity, efficiency, tailing and/or asymmetry) as well as the validation results such as linearity range, LOD and LOQ, precision and accuracy.

Apart from the tables some other techniques that are discussed above are used in pharmaceutical applications. There are some comparative studies to be found in the literature that determine the efficiency of 2.1 mm internal diameter, narrow bore core–shell columns with monolithic and fully porous traditional columns. In the study of Marhol et al., the analysis performed by core–shell silica particles demonstrated sharper peaks and better efficiency when compared to monolithic columns. However, monolithic columns have advantages, especially when performed with lower back pressures at higher linear velocities where they offer higher permeability [149]. Omamogho and Glennon indicated in their study that the performance of the fully porous particles was significantly negated by the extra-column band broadening, especially in narrow bore columns [11]. Gritti and Guiochon used varied types of core–shell silica particles on various columns that have different internal diameters for the investigation of the effect of internal diameter on efficiency. As a result of their work, depending on the examined silica type, 2.1 mm and 4.6 mm I.D. columns had comparable efficiencies. However, particle size was found to be the dominant factor effecting column efficiency with decreasing particle sizes range from 4.6 to 1.3 µm [150].

Lomsadze et al. report comparative high-performance liquid chromatographic separations of enantiomers with chiral stationary phases prepared by coating cellulose tris(4-chloro-3-methylphenylcarbamate) on totally porous and on superficially porous silica of comparable particle diameters. Optimized method was successfully applied for the separation of enantiomers of trans-stilbene oxide, benzoin and 2,2′-dihydroxyl-6,6′-dimethylbiphenyl. As a result of their study, the advantage of chiral stationary phases prepared with core–shell silica is obvious from the viewpoint of plate numbers and resolution as well as the analysis time [124].

In another study performed by Wu et al., chiral core–shell silica microspheres with trans-(1R,2R)-diaminocyclohexane (DACH) bridged in the mesoporous shell was used for rapid chiral separation and demonstrated better performance than the column packed with the functionalized periodic mesoporous organosilicas. In proposed work, R/S-1,1-bi-2,2-naphthol, R/S-6,6-dibromo-1,1-bi-2-naphthol and R/S-1,1-bi-2,2-phenanthrol were successfully separated rapidly on the column packed with the DACH core–shell silica particles. Moreover, the column packed with core–shell particles exhibited better performance than the column packed with the DACH functionalized periodic mesoporous organosilicas [128].

Regarding the application of miniaturized techniques, currently there are fewer studies published on the application of core–shell particles in capillary column. Fanali et al. used 100 µm I.D. capillary packed with 2.6 µm core–shell Kinetex C18 particles for the analysis of different brands of green and black tea constituents. Shorter analysis time and sharper peaks in the chromatogram were observed, compared to sub-2 µm C18 particles [139]. The same group was shown the application of phenyl-hexyl core–shell particles that were packed into capillary columns with 25, 50, 75, 100 and 150 µm I.D. to be used to separate five aromatic hydrocarbons. As a result of this study, a higher plate number per meter was achieved while decreasing capillary diameter without significant loss of efficiency. These results indicated that the extra band broadening observed with narrow bore columns were almost excluded in capillary columns [141].

Conclusion

High performance liquid chromatography provides simple, accurate, precise, sensitive and reproducible quantitative method for routine analysis of active pharmaceutical ingredients from bulk form, commercial preparations as well as the biological media. In the literature, most of the published reports show that the fully porous articles chosen for the analysis of pharmaceuticals more than the core–shell type silica particles. However, in recent times, over a hundred technical publications have represented the performance of superficially porous particles comparing them to fully porous particles in different fields such as environmental, food and biomolecule applications. In addition, recent developments in chromatographic technology have resulted in core–shell stationary phases becoming more popular. Based on a wide range usage of this technique, scientists have continued to see performance gains and benefits such as efficiency, higher sample throughput, better sensitivity, and increased resolution by novel advancements in core–shell silica particle technology. The general consensus in the literature is that the positive characteristics of core–shell particles are extremely beneficial, with future advancements promising even higher operational pressures will be reached, in particular using sub 2 micrometer columns in UHPLC instruments.

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Forensic Toxicology, Institute of Forensic SciencesAnkara UniversityAnkaraTurkey
  2. 2.Department of Pharmacognosy, Faculty of PharmacyPoznan University of Medical SciencesPoznanPoland
  3. 3.Department of Analytical Chemistry, Faculty of PharmacyAnkara UniversityAnkaraTurkey

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