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12 November 2026

70 Pages

UPLC System for the Analysis of Active Substances from Various Biological Materials

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Department of Inorganic Chemistry and Pharmaceutical Analytics, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St, 30-688 Kraków, Poland
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Faculty of Chemistry, University of Opole, 48 Oleska St, 45-052 Opole, Poland
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Author to whom correspondence should be addressed.
Molecules2026, 31(22), 4091;https://doi.org/10.3390/molecules31224091
This article belongs to the Special Issue Recent Advances in Analytical Methods for Drug Analysis
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Abstract

Ultra-performance liquid chromatography (UPLC) is a type of liquid chromatography characterized, compared to other chromatographic methods, by shorter analysis times, resulting from factors such as the use of columns with smaller particle sizes. It has been used in many scientific studies, including pharmaceutical and medical research. This paper compiles information from various publications on the use of UPLC for the determination of compounds in biological materials. The following biological materials of human and animal origin were taken into account: hair, nails, blood (whole blood and plasma), urine, tissues, saliva and gastric fluids, cerebrospinal fluids, feces and seminal plasma. The characteristics of each biological material were discussed, together with the appropriate processing procedures required for subsequent testing. The substances analyzed included compounds from the group of drugs, hormones, biomarkers, proteins, enzymes, metabolites, lipids and toxic substances. In addition, the collected data also included information on the type and parameters of the UPLC column, mobile phase composition, flow rate, detection method, total run time and values of the LOD (Limit of detection) and LOQ (Limit of quantitation) parameters. The collected data can aid analysts in a broad range of laboratory research, enabling the monitoring of active ingredient concentrations in biological materials, which is crucial, especially in the context of therapy and human health.

1. Introduction

UPLC and Ultra-High-Performance Liquid Chromatography (UHPLC) are both liquid chromatography techniques that use columns with particle sizes of less than 2 micrometers in order to achieve high-resolution separation, but there are few differences between them. UHPLC is a more general term for advanced liquid chromatography systems, whereas UPLC is a specific brand developed by Waters Corporation. These techniques differ in terms of system design, column characteristics, separation rate and versatility. The aforementioned liquid chromatography techniques are characterized by short analysis times; specifically, the analysis time for UPLC can be up to 10 times shorter, while for UHPLC it is typically 3 to 5 times shorter, compared to conventional high-performance liquid chromatography (HPLC) techniques. Unlike HPLC, where particles can range in size from 2.5 to 10 μm, UPLC allows the use of particles less than 2 μm (usually 1.7 μm) and 1.7 to 2.5 μm in UHPLC columns [1]. This particle size requires higher pressures, so UPLC system operate in the 6000 to 15,000 psi range [2]. In addition, by using higher temperatures, the viscosity of the mobile phase will decrease and thus the flow rate will increase. In this way, even higher efficiency can also be achieved [3].
These methods use columns with smaller solid grains, which allows analysis to be carried out at lower solvent flows. Thus, the volume of consumed solvent is much lower than with HPLC, helping to reduce the amount of chemical waste generated by the process. UHPLC is characterized by shorter analysis times compared to HPLC. Shorter times mean that the chromatography process is less energy intensive and requires less electricity. In addition, due to the smaller solid grains in UPLC columns, it features higher resolution, leading to better separation of sample components. This greater separation efficiency translates into fewer repeat analyses and reduced waste generated by the process. These factors contribute to a reduction in chemical waste, energy consumption and overall environmental impact [1]. In this publication, most of the analyzed sources are based on UPLC rather than UHPLC; therefore, only the term ‘UPLC’ will be used.
Two separation techniques can be used in UPLC: Hydrophilic Interaction Chromatography (HILIC) and Reversed-Phase Chromatography (RP/RPLC). HILIC is used for the separation of highly polar compounds: amino acids, sugars, small peptides, organic acids and metabolites. RP, on the other hand, is used to separate non-polar, hydrophobic and moderately polar compounds (e.g., most small-molecule drugs, impurities, fat-soluble vitamins). Regardless of the method chosen: HILIC or RP, UPLC technology enables significantly narrower peaks and better separation of multi-component mixtures than traditional HPLC, at higher operating pressure. HILIC in UPLC system, combined with mass spectrometry, delivers satisfactory results in metabolomic analysis. UPLC with an RP column, on the other hand, is the standard for the qualitative and quantitative analysis of pharmaceuticals [4].
Despite its numerous advantages, the UPLC method also has disadvantages that should be considered when selecting a method. The main disadvantage is faster column wear due to the use of higher pressures [1].
Due to its high throughput, UPLC is currently used in many studies, and in combination with tandem mass spectrometry, it is widely used in drug metabolite identification, pharmacokinetics, toxicology, bioanalysis and bioequivalence studies, contributing to the development of medical science [5].
The aim of this narrative review is to collect data on the use of UPLC in the assay of biological active substances obtained from biological material of various origins. Publications were considered eligible if they addressed the application of UPLC or UHPLC for the analysis of biological materials and were relevant to the determination of bioactive compounds, including drugs, hormones, biomarkers, proteins, enzymes, metabolites, lipids, and toxic substances. Priority was given to original research articles providing specific information on analytical procedures and experimental results. Studies describing biological sample preparation, chromatographic conditions, detection techniques, and analytical performance parameters, such as the limit of detection (LOD) and quantification (LOQ), were considered particularly relevant. This review is intended to serve as a general introduction to the analysis of biological samples using UPLC and to facilitate decisions regarding the choice of an analytical method. However, it does not constitute a detailed protocol for conducting a specific analysis but rather provides a basis for selecting the methodology. The selected literature was analyzed narratively, with particular emphasis on biological matrices, sample preparation procedures, chromatographic column characteristics, mobile phase composition, flow rate, detection methods, analysis time, and reported LOD and LOQ values. The collected information was subsequently organized according to the type of biological material to facilitate comparison of the analytical approaches described in the literature. The study provides a comprehensive comparison of analytical strategies used in various biological matrices, encompassing both commonly analyzed samples (plasma, serum, urine) and less frequently described materials such as saliva, hair, nails, and feces. We also emphasized the practical nature of the review, focusing on chromatographic column selection, UPLC conditions, and detection methods, which can be helpful in designing new analytical methods. A prepared analysis of the literature in terms of analytical conditions can provide valuable information to scientists, eliminating the need to re-develop the conditions for determining selected active substances in complex biological material.

Literature Search and Selection

The literature review was conducted using the bibliographic databases PubMed, Scopus, Web of Science Core Collection, and Google Scholar. Full-text articles were additionally retrieved through publisher platforms including ScienceDirect (Elsevier), SpringerLink, Wiley Online Library, Taylor & Francis Online, MDPI, and ACS Publications.
The search strategy combined keywords related to ultra-performance liquid chromatography and biological matrices using Boolean operators. Representative search strings included:
  • (“UPLC” OR “UHPLC” OR “ultra-performance liquid chromatography” OR “ultra-high-performance liquid chromatography”);
  • AND (“MS/MS” OR “mass spectrometry” OR “tandem mass spectrometry”);
  • AND (“bioanalysis” OR “bioanalytical method” OR “biological matrix”);
  • AND (“plasma” OR “serum” OR “urine” OR “hair” OR “nails” OR “saliva” OR “cerebrospinal fluid” OR “feces” OR “tissue”).
Additional articles were identified through manual screening of the reference lists of relevant publications. Publications from 2005 to 2026 were considered for inclusion, with emphasis placed on studies reporting analytical applications, method development, validation, and recent advances in UPLC/UHPLC techniques. References to current regulatory guidance documents, including FDA M10, ICH M10, and EMA Bioanalytical Method Validation Guideline, were also included where relevant. Publications written in English and available up to early 2026 were considered. Materials unrelated to the subject matter, duplicate entries across databases, studies with imprecise results, and content of low methodological quality were excluded.

2. UPLC Analysis Conditions in Various Biological Materials

2.1. Blood

Blood is a valuable source of information about a patient’s health. UPLC coupled with mass spectrometry allows accurate and precise determination of many compounds present in blood. It is used to optimize treatment conditions, especially long-term ones. Long-term use of medications such as sedatives or analgesics can be associated with a high risk of addiction. To reduce this risk and ensure appropriate therapy, blood drug and metabolite concentrations are measured. In such cases, UPLC is justified due to its high sensitivity and short analysis time [6]. The reduction in the analysis time during the determination of doxazosin in plasma from 15 to 2 min compared to HPLC is an undoubted advantage of UPLC, especially in toxicological analysis [7]. This enables the testing of a larger number of compounds without compromising the quality of the analysis, as demonstrated in a study in which 9 psychoactive substances (amphetamine, methamphetamine, ephedrine, pseudoephedrine, phentermine, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethamphetamine (MDEA), ketamine) were determined in less than 3 min [8]. Monitoring drug concentrations in the body is crucial, especially for drugs requiring precise dosing and administered to children, pregnant women, and the elderly. Patient plasma samples were analyzed to determine the concentrations of cefuroxime, meropenem, and amoxicillin/clavulanic acid [9]. Another antibiotic tested was linezolid, the use of which may cause side effects in the circulatory system. Wang et al. measured plasma concentrations of linezolid and heme using UPLC-MS-MS to determine the hematological toxicity of this drug [10]. There are several detection methods that can be coupled with UPLC, such as mass spectrometry (MS), UV and fluorescence; however, tandem mass spectrometry (MS-MS) detection is the best choice due to its superior sensitivity and selectivity. However, the software and equipment required for MS analysis are significantly more expensive than the other options [11]. Lidocaine and its metabolite concentrations were also analyzed in plasma samples from pregnant women with gestational diabetes, which is extremely important because diabetes can interfere with the metabolism of many drugs [12]. In the pharmacokinetics study of diclofenac sodium, a mixture of acetonitrile and aqueous ammonium hydroxide solution was used as the mobile phase [13]. A UPLC-MS-MS method was developed for the determination of 22 antiepileptic drugs in plasma. It is characterized by a short analysis time (approximately 10 min) and can be used to monitor drug concentrations in blood to optimize pharmacotherapy [14]. Fiorentini et al. used UPLC-MS-MS to characterize the pharmacokinetic properties of givinostat in pediatric patients [15]. UPLC may also be a useful method for determining antituberculosis drugs, as demonstrated by measuring the concentration of rifampicin and its metabolic products in the plasma of infected patients [16]. The UPLC method also proved effective in separating acetylcarnitine, which is important in newborn screening for metabolic diseases. Plasma (approximately 10 μL) and dried blood drops were used as the material [17]. Among biological and forensic samples, blood (whole, plasma or serum) is probably one of the most popular samples for cannabinoid analysis [18]. Various procedures are used to properly prepare samples for UPLC analysis. Erceg et al. used a mixture of methanol and acetonitrile to precipitate protein from plasma prior to analysis. The samples were then frozen, the solvent evaporated, and the dry residue was dissolved in the mobile phase [19]. In the study by Cai et al., 5 mL of collected blood was used, centrifuged to remove plasma, and then acetonitrile was added to precipitate proteins. After centrifugation, the solution was evaporated to dryness and dissolved in a mixture of acetonitrile and water [20]. It is also possible to analyze smaller sample volumes like 100 μL of a rat plasma [21]. An undeniable advantage of UPLC is its ability to analyze samples of just a few microliters in volume, which makes it possible to analyze dried blood spots consisting of just a few drops of blood, as well as samples from newborns [22]. The storage time of collected biological material can affect the results and varies depending on the type of study. Dried blood spots are stored at 4 °C, while plasma is stored at −20 °C [17], or even −70 °C [23] until analysis. [24]. However, despite its many benefits, miniaturization presents analytical challenges due to the limited volume available for repeat measurements and the difficulty in separating interfering compounds at low volumes [25]. It is also worth mentioning that the interfering compounds present in blood may disrupt the analysis process. The main problem is the presence of proteins and phospholipids, which have a significant effect on the chromatographic system and the MS detector. One of the most substantial effects is the attenuation or amplification of the signal through the disruption of the ionization process by phospholipids [26]. Effective reduction in the matrix effect requires a combination of appropriate sample preparation—such as protein precipitation or SPE—and optimization of chromatographic conditions, including adjustments to the gradient, in order to separate the eluting analyte from the main phospholipid peak [27]. Detailed parameters of the methods for determining drugs in blood samples are presented in Table 1.
Table 1. UPLC technique in the analysis of various substances in blood.

2.2. Urine

UPLC analysis of biological samples, such as urine, is widely used to analyze a wide range of compounds, including drug metabolites, hormones, toxic substances, and disease biomarkers [190]. Alwis et al. used the UPLC method to quantify 28 metabolites of volatile organic compounds [191]. Determination of exogenously administered steroids that also occur naturally in animals, such as testosterone, is particularly challenging. The UPLC technique combined with mass spectrometry has found application in profiling phase II metabolites. These compounds, thanks to their low volatility and high polarity, can be determined by this method in urine samples [192]. For advanced analysis of biological samples, such as urine, UPLC coupled with MS offers the highest sensitivity and specificity, as well as extensive identification capabilities. It is suitable for metabolic profiling, determination of low drug concentrations, toxicology and identification of unknown substances. However, the cost of the equipment and software required for this technique is very high [1]. A cheaper alternative is UPLC coupled with UV detection. This method enables the determination of known, pre-defined substances (e.g., the measurement of creatinine levels, specific amino acids or metabolites) that are capable of absorbing UV radiation. However, when it comes to determining the concentration of compounds that do not absorb UV light, this method is inadequate. Even in the case of a heavily contaminated sample, the method may produce overestimated results and make interpretation difficult [4]. Urine has one of the most complex matrices among biological materials. It contains sodium, potassium, calcium and ammonium ions, as well as chlorides, organic molecules, mineral salts and proteins, including albumin. These compounds can interfere with the detection of the target analyte by MS, mainly through ion suppression. This can cause distorted results, reduced method sensitivity and an increase in the LOQ value [193]. The presence of early-eluting urine components (e.g., high levels of salt) may distort the chromatograms, causing peaks to overlap. Moreover, high concentrations of salts and insoluble components in urine can lead to rapid fouling of the MS capillaries and then contribute to the degradation of the chromatographic column [194]. In order to minimize the impact of urine constituents on the analysis, it is essential to prepare the sample properly. The sample preparation process involves diluting the urine with water or a buffer in the appropriate proportion, which reduces the concentration of interfering salts [195]. SPE ensures a high degree of sample purification, allowing polar components of the urine to be removed and only the target analytes to be retained on the sorbent bed [196]. Moreover, the use of stable isotope-labeled internal standards of the analyzed compound is one of the most effective methods of matrix effect compensation. The standard behaves the same way as the analyte and exhibits the same suppression [197]. The advantages of the UPLC method were utilized for the simultaneous determination of bisphenol A and its metabolites in urine samples. These substances are classified as endocrine disrupting compounds, and the use of bisphenol A in plastics production raises concerns about its migration into food [198]. A small amount of horse urine was used to analyze samples for the presence of quaternary ammonium compounds, which may be abused prior to equestrian competition [199]. Zhao et al. used UPLC to analyze nucleosides and other cis-diol metabolites, which are potential cancer biomarkers. The goal of the study was to distinguish cancer patients from healthy individuals and compare the results with those obtained by HPLC. The UPLC method proved to be approximately three times faster and more efficient, with improved resolution and sensitivity (HPLC detected 79 files, compared to UPLC 94) [200]. UPLC analysis of urine samples identified as many as 355 acetylcarnitines, a significant achievement compared to the previously reported 43 acetylcarnitines, which may be important biomarkers of various diseases. Urine samples were prepared by SPE, then sequentially decanted and purified by solid-phase extraction. Gradient elution was used with two mobile phases: eluent A: 0.1% formic acid in water, 4% ACN in water, and eluent B: 0.1% formic acid in ACN [201]. Johnson and Plumb compared the performance of two LC-MS methods: monolithic columns and UPLC columns with sub-2 μm particles for the identification and detection of acetaminophen metabolites in urine. The results showed that the UPLC system had three times higher sensitivity and detected a greater number of metabolites [202]. UPLC-Q-TOF-MS has been used to profile endogenous metabolites in urine to elucidate metabolic differences between normal-weight and obese individuals with hyperlipidemia. Urine samples were centrifuged at 14,000 rpm for 10 min. In total, 2 μL of the supernatant was used for analysis. Analytes were eluted from the column with a gradient where A was water and B was ACN, with the initial composition of B being 2% and increasing to 20% after 5 min, 35% after 2 min, 70% after 2 min, and 100% after another 1.5 min, and then re-equilibrated to the initial conditions after 10 min. Each cycle lasted 20.5 min, and the flow rate was 300 μL/min [202]. The UPLC-ESI-MS method was also used to evaluate the effect of repeated nicotine treatment on nicotinic and muscarinic receptors located in the urinary bladder by determining the nicotine concentration in the urine of rats [203]. Sugar is a significant energy component of the diet, but when consumed in excess, it can lead to metabolic disorders and obesity. Currently, the food industry is striving to reduce sugar content in products or replace it with so-called sweeteners, but an effective method for measuring exposure to these substances is needed. Therefore, Diepeveen-de Bruin et al. validated and applied a UPLC-MS-MS method to quantify sugars and other sweeteners in human urine [204]. The study of plant substances in urine using UPLC has a wide range of applications, including the evaluation of the effects of dietary supplements, herbs, or herbal medicines on the body. In addition, it can be used to assess the bioavailability and metabolism of substances of plant origin, and to study interactions between various plant components and other substances in the body. The research team of Wang et al. using UPLC quantified 17 ginseng-derived glycoside saponins, ginsenosides, in rat urine. Collected samples were centrifuged for 10 min at 3500 rpm, and sequentially stored at −20 °C until analysis [205]. The use of UPLC-MS-MS has also proven to be a sensitive, accurate and precise method for the quantification of hesperitin and its enantiomers in urine samples [206]. UPLC was also used for metabolic profiling of urine samples to detect potential biomarkers of chronic renal failure. Urine samples from rats were stored at −80 °C and then thawed, centrifuged, the supernatant diluted with distilled water, and then filtered through a 0.22 µm membrane filter. Radiant elution was performed using a mobile phase composed of: A was 0.1% formic acid, and B was ACN with 0.1% formic acid and 10 mmol/L ammonium acetate) [207]. Alwis et al. performed the analysis of human urine by ESI-MS-MS technique of a mixture of acrolein, acrylamide, acrylonitrile, benzene, 1-bromopropane, 1,3-butadiene, carbondisulfide, crotonaldehyde, cyanide, N,N-dimethylformamide, ethylbenzene, ethylene oxide, propylene oxide, styrene, tetrachloroethylene, toluene, trichloroethylene, vinyl chloride, xylene using the HSST3 column (150 × 2.1 mm, 1.8 µm) and a gradient mobile phase: A—ammonium acetate, B—ACN), obtaining LOD values in the range of 0.5–20 ng/mL [191]. Data on the analysis of urine samples are summarized in Table 2.
UPLC also allows for the determination of substances in both plasma and urine. This is particularly helpful in identifying patterns in the metabolic pathways of various compounds. Colchicine, an alkaloid extracted from the seeds and bulbs of the colchicum plant, has potent anti-inflammatory properties, but its dosing regimen is unclear, as there are no clear boundaries between therapeutic, toxic, and lethal doses. UPLC-MS-MS has proven to be a suitable, rapid, and economical method for the determination of colchicine in human urine and whole blood [186]. Mao et al. used UPLC-MS-MS to determine paraquat and diquat (quaternary ammonium herbicides with high toxicity) in urine and plasma of patients hospitalized for poisoning, obtaining rapid and reliable results [187]. UPLC-MS-MS analysis of morphine-3-O-sulfate (M3S) and morphine-6-O-sulfate (M6S) in human blood and urine was performed using HSS T3 (100 × 2.1 mm, 1.8 µm) and HSS T3 (5 × 2.1 mm, 1.8 µm) columns with M-d3 Morphine-d3 as the Internal Standard. The mobile phase was a mixture of: A—formic acid, B—methanol (gradient). The obtained LOD values [ng/mL] were: in urine M3S 6, M6S 4, and in blood M3S 0.6 and M6S 0.3, respectively [208]. Udenafil and its active metabolite DA-8164 were determined in human urine and blood by UPLC-MS-MS on a BEH C18 column (50 × 2.1 mm, 1.7 µm) using an isocratic elution mixture (ACN/formic acid (75:25, v/v) with a detection limit of 1 ng/mL [207]. Taspoglutide was determined by UPLC-MS-MS in human urine and plasma using BEH C18 (50 × 2.1 mm, 1.7 µm) and HILIC Si (50 × 2.1 mm, 3 µm) columns, in a gradient mobile phase: A1: water–methanol–aqueous ammonium formate–formic acid (50:50:12.5:5, v/v/v/v); B1: water–acetonitrile–methanol–ammonium formate–formic acid (50:700:250:12.5:5, v/v/v/v/v); A2: water–ammonium bicarbonate with ammonium hydroxide (985:15, v/v); A3: water–acetonitrile–ammonium bicarbonate (735:250:15, v/v/v); B3: water–acetonitrile–methanol (10:45:45, v/v/v) obtaining a limit of quantification of 4 pg/mL for plasma and 10 pg/mL for urine [209,210]. NG,NG-dimethyl-l-arginine (ADMA), symmetric dimethylarginine (SDMA), NG-monomethyl-l-arginine (NMMA), L-homo-arginine (H-Arg), citrulline (Cit) and citrulline butyl esters were analyzed by UPLC-MS-MS in human plasma, serum or urine. A BEH C18 column (50 × 2.1 mm, 1.7 µm) and a mobile phase composed of: A—water with 0,1% formic acid, B—methanol with 0,1% formic acid (gradient) were used, obtaining LOD values of 0.01 µM and LOQ: 0.05—0.5 µM [211]. Human whole blood and urine samples were analyzed for gamma-hydroxybutyrate, beta-hydroxybutyrate, pregabalin, 1,4-butanediol, and gamma-butyrolactone using UPLC-MS-MS. The mobile phase was an HSS T3 column (100 × 2.1 mm, 1.7 µm), and the mobile phase was a mixture of A—0,2% formic acid and B—methanol (gradient elution). LOD values were set at 0.65, 0.004, 0.23, and 1.1 µg/mL, while LOQ values were set at 1.3, 0.008, 0.37, and 2.15 µg/mL [212]. Chemical profile of Epimedium brevicornum Maxim. (epimedoside A, epimedin A, eEpimedin B, epimedin C, icariin, 2′′-O-rhamnosoyl icaride, icariside II, icaritin, icaritin-3-O-α-L-rhamnopyranosyl-7-O-β-D-glucopyranuronoside) analyzed by UPLC-MS system in rat urine and blood samples. A BEH C18 column (50 × 2.1 mm, 1.7 µm) and an eluent of the following composition were used: A: 0.1% formic acid in water and B: 0.1% formic acid in acetonitrile with a flow rate of 0.25 mL/min [213]. Lévèques et al. determined hesperetin and its enantiomers in human plasma and urine samples using a UPLC-MS-MS system. The mobile phase used was a mixture of: A—water with 0.1% formic acid, B—ACN with formic acid (gradient elution) and columns: UPLC HSS T3 (100 × 2.1 mm, 1.8 µm) and Chiralpak IA-3 (150 × 2 mm, 3 µm) [206]. Glechoma longituba metabolites were analyzed in rat plasma and urine by UPLC-QTOF-MS system with BEH C18 (100 × 2.1 mm, 1.7 µm) column and gradient elution (A—water, formic acid, B—ACN) [214]. Onoue et al. analyzed quantity of nicotine, cotinine and antipyrine in human plasma, urine and tissues (bladder, salivary gland, heart and cortex) by UPLC-ESI-MS system with BEH C 18 (50 × 2.1 mm, 1.7 µm) and A—ACN, B—ammonium acetate (gradient elution), obtaining LOD and LOQ values of 5 and 2.5 ng/mL [203]. Rat urine, bile, feces, and plasma were analyzed for the content of mosapride, mosapride N-oxide, and morpholine ring-opened mosapride using an BEH C18 column (100 × 2.1 mm, 1.7 µm), gradient elution (A–formic acid, B—ACN), and MS-MS detection. The obtained LOD values were in the range of 10—25 ng/mL [45]. Phosphorus and sulfur metabolites were analyzed by UPLC-MS system in rat liver, plasma, urine, bile. BEH C18 (100 × 2.1 mm, 1.7 µm) stationary phase, and eluent containing: A—water with formic acid, B—methanol with formic acid (for the organic/aqueous tissue extracts and plasma extracts), A1—ammonium acetate with formic acid, B1—methanol with formic acid (for bile and urine) (gradient) were used. The determined LOQ values were within the range 0.15–0.25 ng [215]. Human urine and whole blood are the materials in which the content of narcotic analgesics (buprenorphine, O-desmethyltramadol, fentanyl, norbuprenorphine, norfentanyl, pethidine, piritramide, tilidine, tramadol) was determined. An C18 column (50 × 2.1 mm, 1.7 µm) and an eluent gradient with the following composition: A: water with ammonium bicarbonate and ammonium hydroxide B: methanol and an MS-MS detector were used. The LOQ values for the determined compounds were in the range 0.025—1.25 ng/mL [216]. Waterval et al. determined underivatized amino acids in human plasma and urine by UPLC-MS-MS system. An BEH C18 column (100 × 2.1 mm, 1.7 µm) and a mobile phase gradient, A—tridecafluoroheptanoic acid, B—trifluoroacetic acid/ACN, with a flow rate of 650 µL/min were used, obtaining LOQ values in the range 40–287 μmol/L [217].
Table 2. UPLC technique in the analysis of various substances in urine.

2.3. Tissues

UPLC tissue analysis can provide precise information about their chemical composition, which can be useful in scientific research, medical diagnostics, and the evaluation of treatment efficacy. UPLC enables accurate determination of drug and metabolite concentrations in various tissues, allowing for precise monitoring, testing, and optimization of drug therapies, as well as understanding the pharmacokinetic and pharmacodynamic processes occurring in the patient’s body. This leads to increased treatment efficacy and minimized adverse effects. Biological tissues are among the most complex matrices in UPLC analysis. The presence of proteins, lipids and salts has a significant impact on the determination of compounds and, consequently, on the reliability of the results. Furthermore, the direct introduction of unfractionated tissue lysates leads to contamination of the chromatographic column and the ion source in MS detection. Sample preparation is the most important step in minimizing the matrix effect when analyzing compounds in tissue samples. This process involves SPE, which allows for the selective removal of proteins and lipids (including phospholipids) from tissue homogenates, leaving a pure extract. It is also possible to precipitate proteins; however, the extract obtained using this technique is less pure than that obtained by SPE [270,271]. Ackermans et al. developed a method for determining thyroid hormones and their metabolites in various tissue samples obtained from male Wistar rats, including liver, heart, and hypothalamus. Because the thyroid gland in rats is significantly small, human thyroid tissues obtained during surgery for a benign multinodular tumor were also used. Solid-phase liquid chromatography with tandem mass spectrometry (SPE LC-MS-MS) was used in this study. The mobile phase consisted of eluent: A—5% ACN in water containing 0.1% acetic acid, and B—95% ACN in water containing 0.1% acetic acid. The use of UPLC instead of HPLC lowered the detection limits, allowing for the use of smaller tissue sample volumes [272]. Drug abuse in animals has a number of serious consequences for humans, ranging from growing drug resistance to increasing environmental pollution, which is why it is extremely important to have appropriate methods for determining drugs in animal tissues. Chan et al. developed a screening method for the analysis of antiviral drugs (amantadine, zanamivir, oseltamivir, acyclovir) in poultry tissues. Collected tissues were extracted with a mixture of ACN, water, and acetic acid. After purification of the sample using a cation exchange column, the eluate was divided into two fractions, which were evaporated to dryness. The first fraction was dissolved in a mixture of methanol and water, and the second in a mixture of ACN, methanol, and water. These fractions were analyzed by UPLC-MS-MS [273]. A similar method was used to quantify 13 aminoglycoside antibiotics in pork, fish and veal livers and kidneys [274]. UPLC-MS-MS was applied for monitoring the use of growth promoters in animals. Thirteen synthetic growth promoters were identified, confirmed, and assayed, including dexamethasone, methylboldenone, and dienestrol. The analysis was conducted on 5 g of beef muscle, which, after appropriate preparation, was analyzed by UPLC-MS-MS using electrospray ionization (ESI), in both positive and negative polarities. The total analysis time was 14 min. The use of UPLC allowed for faster analysis, which is crucial for meat quality and safety control in the food market [275]. Examining brain tissue with UPLC can help diagnose and study neurological disorders such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. It allows the identification of biomarkers and pathological changes in brain tissue. Using LC-MS-MS QTOF, 18 phospholipids were identified which can be used to identify brain areas enriched in neurons and glial [276]. Ma et al. used UPLC-MS to quantify the mass of radiotracers extracted from rat tissues. The results were very close to those obtained with the traditional method of measuring radiotracers, demonstrating the accuracy and utility of this technique. The use of UPLC in positron emission tomography (PET)) studies can significantly speed up the process of developing new probes for molecular imaging and makes it possible to accurately quantify substances in tissues [277]. UPLC-MS-MS is also a useful method for quantitative determination of trans-ferulic acid-4-β-glucoside (FAG) in rat liver and plasma. FAG can increase thermogenesis in brown adipose tissue, which is a promising feature in treatment of cold injury [188]. Sigma-1 receptors are nonopioid receptor proteins involved in modulation of pain. 3-(2-(azepan-1-yl)ethyl)-6-benzylbenzo[d]thiazol-2-(3H)-one hydrochloride (MCI-77) is a selective sigma-1 receptor ligand, which may have potential in the treatment of neuropathic pain and nerve injury. Popa et al. used UPLC-MS-MS to quantify MCI-77 and determine its pharmacokinetic parameters in mouse plasma and brain homogenate and obtained satisfactory results [189]. Details of drug determination methods in tissue samples are summarized in Table 3.
Table 3. UPLC technique in the analysis of various substances in tissues.

2.4. Hair

Various substances both external (e.g., drugs) and internal (e.g., biological amines) have the ability to accumulate in both the hair bulb and hair shaft [314]. An unquestionable advantage of hair analysis is the ability to assess long-term exposure, spanning several years. Analyses of other biological materials, e.g., urine or blood, do not offer such possibilities. Hair is a very good sample for forensic and clinical research due to its high durability, stability and often higher content of tested substances in comparison with blood or urine. Previous hair analysis techniques have been characterized by time-consuming compound separation processes using gas chromatography or HPLC. The ability to omit derivatization during analysis is undoubtedly a significant advantage [315]. Hair, due to its ease of collection, transportation and maintenance, is a convenient sample for analysis. Ease of downloading is a notable advantage for children and elderly. In drug abusers, substances such as cocaine, codeine, benzodiazepines, morphine and 6-monoacetylmorphine can be detected in hair samples [316]. Separation of ketamine and norketamine, the main metabolite of ketamine by a combination of micro-powder extraction and UPLC-MS is possible within 2 min [317]. Another study shows that UPLC-MS-MS can be a useful method for detecting ethyl glucuronide (EtG) in hair. EtG is a biomarker of long-term alcohol abuse and can be tested more reliably in hair than blood [318]. There is also a need to determine endogenous compounds that perform important functions in the organism. Blanco-Ces et al. used UPLC-MS-MS to separate and detect gamma-hydroxybutyrate (GHB) in hair samples with satisfactory results [319]. Hair consists mainly of proteins, primarily keratin, as well as lipids, melanin and minerals. During extraction, these natural components leach into the solution and may cause a matrix effect by ion suppression, which can reduce the sensitivity and accuracy of the method [320]. Proper preparation of the hair sample plays a key role in ensuring the analysis is carried out correctly. Preliminary decontamination is carried out, which involves thoroughly washing and degreasing the hair using alcohol or other organic solvents. SPE is then performed to remove interfering substances, primarily proteins [321]. Míguez-Framil et al. used human hair samples washed with a diluted soap solution, followed by cleaning with water and drying (40 °C, 30 min). They pulverized the hair to obtain an average particle size of about 50 µm [315]. Yao et al. used a different pretreatment method, washing the hair with dichloromethane, water, and methanol. After air-drying, the hair was cut into small pieces and further analysis was performed [321]. Human hair was used as a screening material for the analysis of alprazolam, amitriptyline, amphetamine, benzoylecgonine, bromazepam, buprenorphine, chlordiazepoxide, chlorprothixene, citalopram, clonazepam, aminoclonazepam, clozapine, cocaine, codeine, diazepam, flunitrazepam, aminoflunitrazepam, fluoxetine, ketamine, ketobemidone, lamotrigine, levomepromazine, lidocaine, lorazepam, 6-MAM, MDA, MDEA, MDMA, methamphetamine, methadone, metoclopramide, metoprolol, mianserin, mirtazapine, morphine, nitrazepam, aminonitrazepam, norfluoxetine, dibenzepine, nortriptyline, orphenadrine, oxazepam, oxycodone, paroxetine, promethazine, quetiapine, sertraline, tramadol, triazolam, venlafaxine, zaleplon, zolpidem and zopiclone by UPLC-TOF-MS on a C18 column (100 × 2.1 mm, 1.8 μm) and using the mobile phase: A—0.05% formic acid B—100% methanol, satisfactory results were obtained, with LOD values: 0.01–0.1 ng/mg and LOQ: 0.05–2.00 ng/mg [322]. Details of other hair analysis studies using UPLC are summarized in Table 4.
Table 4. UPLC technique in the analysis of various substances in hair.

2.5. Nails

Nails can be used as a material for testing substances that accumulate in the nail plate. A nail is a highly keratinized tissue. Incomplete destruction of this structure can lead to low recovery of analytes. To remedy this situation, cryogenic grinding should be used instead of traditional cutting. Low-temperature grinding assisted by liquid nitrogen breaks down the keratin structure and significantly increases the extraction surface area [324]. Previous studies have primarily involved the analysis of drugs or doping agents. Nail sampling is non-invasive, easy, and safe, minimizing patient discomfort. Analysis can also be performed on nail samples collected postmortem due to the high stability of the compounds in this material [325]. Nails can also be used to diagnose chronic diseases. A method of determining compounds intermediate advanced glycation end products that are associated with the development of diabetic complications has been successfully carried out. For this purpose, UPLC with time-of-flight UPLC-ESI-TOF-MS was used [326]. The same method was applied to determine the concentration of ultraviolet (UV) filters in human nail samples. In order to determine the concentration of filters, nails were treated by ultrasonic cleaning, then washed with ultrapure distilled water, rinsed with acetone and methanol, freeze-dried and ground to small powder [327]. UV-filters are chemicals that play an important role in protecting the skin from the sun radiation, but they can also accumulate in the skin and cause skin irritation and photoallergic reactions. The compounds studied are present in the nail in small amounts, so the high sensitivity of UPLC was essential to detect the dicarbonyl intermediates of advanced glycation end products. The collected nail samples were rinsed with 0.1% sodium dodecyl sulfate solution and distilled water, dried under vacuum and ground into powder [325]. Lorazepam and 3-O-glucuronide were determined from human fingerprint deposits using UPLC-MS-MS. The analysis was performed on a Waters C18 column (150 × 2.1 mm, 1.7 µm) using a mobile phase gradient, A—ammonium formate/formic acid, B—ACN/formic acid, and a flow rate of 250 µL/min [328,329]. A summary of other UPLC studies using nails is presented in Table 5.
Table 5. UPLC technique in the analysis of various substances in nails.

2.6. Saliva, Tears and Gastric Fluid

Unlike blood samples, the oral fluid collection method is non-invasive and possible even by non-medical personnel. Saliva and gastric fluid are highly complex biological matrices. Their direct injection into an UPLC system, particularly when combined with MS, leads to significant analytical problems. Salts, mucins, bile acids and proteins present in body fluids interfere with the ion generation process in the MS source, most commonly leading to ion suppression [330]. Furthermore, the extremely low pH of gastric juice and the presence of digestive enzymes, like pepsin, can cause chemically unstable compounds to degrade before the separation [331]. To overcome the negative impact of the matrix and protect the UPLC column, it is essential to follow appropriate sample preparation procedures. The most effective methods include SPE and protein precipitation [332]. Oral fluid is a biological material that can be used for roadside testing, for example, because of its ability to detect recently consumed drugs. In testing for the presence of illegal substances, it is important to use a multicomponent method with a low detection limit due to the limited amount of oral fluid. Badawi et al. developed a UPLC-MS-MS method for detecting 29 illegal substances and drugs in oral fluid samples in one chromatographic run. The substances detected included benzodiazepines, opioids, amphetamine and cocaine. For the determination 200 mg of oral fluid was collected using a Saliva-Sampler, diluted with ammonium acetate/methanol buffer (90:10, v/v). The prepared samples were applied to columns and eluted with acetonitrile and aqueous ammonium hydroxide solution [333]. The UPLC method is also used for pharmacokinetic studies and assessing how drug actives are absorbed and metabolized in the body after their oral administration. This allows for a better understanding of drug absorption and distribution processes, which can help optimize the dosage and effectiveness of drug therapy. Onoue et al. used the UPLC method for pharmacokinetic profiling after oral administration of tranilast formulations. Based on the results of the UPLC analysis, it was possible to determine the absorption time, the maximum concentrations (Cmax) and the time at which the maximum concentration (Tmax) of the drug in the gastric fluid was reached [334]. The system parameters used for saliva and gastric fluid determinations are presented in Table 6.
Table 6. UPLC technique in the analysis of various substances in saliva, tears and gastric fluid.

2.7. Cerebrospinal Fluid

UPLC is a powerful tool in cerebrospinal fluid testing that is used in diagnosis, research and monitoring treatment of neurological diseases. An UPLC-MS-MS technique with positive ESI was developed and validated for the determination of histamine and its major metabolite tele-methylhistamine in cerebrospinal fluid. The LOD obtained (12.5 pM) was about 200 lower than that obtained previously by LC-MS-MS method [339]. UPLC can be used to identify and measure various biomarkers associated with Alzheimer’s disease, such as β-amyloid, tau-phosphorylated protein, and brain metabolites. Changes in the levels of these biomarkers in biological samples can be an indicator of the presence and severity of the disease. The goal of the study by Lame et al. was to develop a more efficient method for quantifying amyloid-β peptides. Current methods are mainly based on immunological techniques that require very specific antibodies and reagents. However, these tests are very time-consuming and expensive. A mixed-phase solids extraction and UPLC-MS-MS method for the simultaneous determination of amyloid beta peptides in human cerebrospinal fluid was described. The method used has similar sensitivity to enzymatic assays but provides higher throughput and is more cost-effective [340]. UPLC also enables monitoring drug concentrations in cerebrospinal fluid, which is important in the treatment of nervous system diseases. For example, the UPLC-MS-MS method was used to quantify vitamin B6 in human cerebrospinal fluid collected via lumbar puncture. Sample preparation involved precipitation of protein with trichloroacetic acid containing a stable isotope labeled vitamin B6 compounds. This method enables the detection of reduced concentrations of pyridoxal and pyridoxal-5-phosphate and therefore has potential for routine diagnostic use [341]. Information on the determination of cerebrospinal fluids is provided in Table 7.
Table 7. UPLC technique in the analysis of various substances in cerebrospinal fluid.

2.8. Feces

Girlanda et al. used UPLC-QTOF-MS to monitor intestinal transplant rejection. The study used metabolomics, which involves analyzing the metabolic profile of intestinal transplant patients. For the analysis, they used ileostomy fluid or fecal samples from 11 cases of bowel rejection and 45 cases of non-rejection. Separation was performed using a reversed phase system consisting of: 2% ACN in water with 0.1% formic acid (A) and 2% water in ACN with 0.1% formic acid (B) as eluent and C18 column (50 × 2.1 mm, 1.7 µm) as stationary phase [344]. UPLC/Q-TOF was also used to study the fecal metabolome of healthy people and patients with cirrhosis and hepatocellular carcinoma. Collected fecal samples were stored at −80 °C. For analysis, the samples were thawed at room temperature and mixed with methanol. The supernatants were filtered and injected directly onto the BEH C18 (100 × 2.1 mm, 1.7 µm) column. The mobile phase consisted of water and acetonitrile, each containing 0.1% formic acid. The method proved effective and convenient for analyzing stool samples, and therefore may be useful in the early diagnosis of liver cirrhosis and hepatocellular carcinoma [345]. Ileostomy and colostomy secretions, aspirated colonoscopy fluid, and stool were used to determine biomarkers of intestinal transplant rejection. The analysis was performed using UPLC-TOF-MS using a C18 column (50 × 2.1 mm, 1.7 µm) and a mobile phase composed of: A—2% ACN in water containing 0.1% formic acid; B—2% water in ACN containing 0.1% formic acid (gradient elution) at a flow rate of 0.5 mL/min [344]. Cao et al. analyzed the fecal metabolome by UPLC-QTOF-MS using a BEH C18 column (100 × 2.1 mm, 1.7 µm) and a gradient mobile phase composed of water and ACN, each containing 0.1% formic acid (flow rate 0.4 mL/min) [345].
The main problem with the analysis is that feces are a heterogeneous material, which makes it difficult to obtain reproducible results between successive weightings of the same sample [346]. One solution may be homogenization through the precipitation of proteins and lipids, followed by extraction using pure solvents such as methanol or acetonitrile [347]. Freezing and centrifugation also allow for the removal of larger solid particles and precipitated lipids [348].

2.9. Seminal Plasma

UPLC can help identify potential abnormalities in the composition of seminal fluid, which can be crucial in diagnosing male infertility, which has become a global problem. This technique is also used in scientific research aimed at understanding the chemical composition of seminal fluid and its impact on male reproduction and health. Currently, HPLC is a widely used method, but limitations such as long analysis time, low sensitivity, and the need to analyze large amounts of genomic DNA make it unsuitable for large-scale clinical analysis. Wang et al. developed a UPLC-MS-MS method for detecting global DNA methylation in human sperm. As the mobile phase, they used: 5.0% methanol and 95% water (with 0.1% formic acid) at a flow rate of 0.3 mL/min. The presented method may find application in studying epigenetic mechanisms of male infertility [349]. The analysis of uridine content in seminal plasma was performed by UPLC-MS system using an HSS T3 column (100 × 2.1 mm, 1.7 µm) and a mobile phase composed of: A—water, 0.1% formic acid B—ACN, 0.1% formic acid (gradient elution) [350]. Wang et al. analyzed seminal plasma samples for DNA methylation using a UPLC-MS-MS system equipped with a Zorbax SB-C18 column (100 × 2.1 mm, 1.8 µm) and a mobile phase gradient: 5% methanol, 95% water (with 0.1% formic acid) at a flow rate of 0.3 mL/min [349].

3. Summary

UPLC appears to be highly efficient and reliable compared to other chromatographic techniques. Operating at higher pressures translates to faster flow rates, and the use of shorter columns shortens retention times, which are significant advantages over HPLC. The technique can also be more environmentally friendly, using fewer solvents and generating less waste than HPLC. The aim of this article was to collect data from various publications to discuss the applications of UPLC in the study of different classes of chemical compounds (drugs, biomarkers, metabolites, hormones, nutrients and toxic substances) in biological samples, which are highly complex. They contain proteins, lipids, phospholipids and salts, which elute alongside the analyte. In techniques such as UPLC-MS-MS, these components can compete with the analyte for ionization, leading to ion suppression, ion enhancement and a reduction in the sensitivity and accuracy of quantitative measurements. To minimize these interferences, advanced sample preparation techniques such as SPE and protein precipitation are employed, and isotope-labelled internal standards are used. In UPLC, matrices cause signal attenuation or amplification, which adversely affects precision. In accordance with regulatory guidelines (e.g., ICH M10), the assessment of matrix effects is an integral and critical part of the validation of a bioanalytical method. Validation checks whether the use of a suitable internal standard (preferably isotopically labelled) effectively compensates for signal variability caused by the matrix. Robustness refers to the ability of an analytical method to remain unaffected by small, deliberate changes to the method’s parameters [351]. Repeatability and precision are measures of the consistency of results between independent repetitions of an analysis of the same material. Validation ensures the reliability of the method in accordance with FDA guidelines, whilst high robustness and reproducibility ensure its stability during routine analysis of biological samples. In accordance with the current ICH M10 guidelines, which have also been adopted by the FDA and the EMA, the lower limit of quantification (LLOQ) should be the lowest point on the calibration curve for which acceptable accuracy (±20%) and precision (CV ≤ 20%) have been demonstrated. For the remaining levels of the calibration curve, the criteria required are ±15% for accuracy and ≤15% for precision, respectively. The limit of detection (LOD), on the other hand, is of secondary importance; it serves only to confirm the ability to detect the analyte and is not subject to the accuracy and precision requirements applicable to quantitative determinations. The guidelines require an assessment of selectivity, matrix effects, calibration curve linearity, recovery, stability, precision and accuracy, both within a single analytical run and between runs. In LC-MS-MS methods, the LLOQ should be confirmed experimentally in the biological matrix by demonstrating the required accuracy and precision, and not solely on the basis of detector sensitivity. The use of appropriately selected internal standards, including isotopically labelled ones in many cases, and the optimization of sample preparation (SPE or protein precipitation) and chromatographic conditions (RP or HILIC, depending on the polarity of the analyte) help to minimize matrix effects and improve the reproducibility of determinations. Consequently, a validated method should demonstrate resistance to matrix variability and meet the accuracy and precision requirements set out in the ICH M10 guidelines [352,353,354].
Sample preparation before analysis is a crucial step in the entire process. Among the most commonly analyzed biological materials, whole blood, tissues, and plasma are the most challenging. Whole blood is widely considered one of the most difficult matrices for chromatographic analysis due to the presence of red blood cells, its high protein content and high viscosity. The preparation typically involves cell lysis, protein precipitation or SPE. Tissue homogenates are even more challenging than whole blood because they require homogenization, standardization of tissue mass, extraction from a highly complex mixture of lipids, proteins, and cellular components, and often multi-step purification. Liver and brain tissue contain vast amounts of phospholipids, which can strongly suppress ionization in UPLC-MS-MS. Plasma is the most commonly used matrix in bioanalysis, but not because it is the easiest to process. The main problem is the high concentration of albumin, globulins and phospholipids. For this reason, protein precipitation or SPE extraction is routinely used [355]. Pretreatment of hair and nails often involves appropriate rinsing, for example, in methanol, acetone, or dichloromethane, drying, and pulverization to obtain appropriately small particles. Preparation of urine samples is similar but usually simpler, as urine contains significantly less protein. For more complex analyses, additional extraction techniques, such as SPE or liquid–liquid extraction, can also be used. The required sample volume for chemical and bioanalytical analysis depends on the sensitivity of the method, the matrix type, and the analyte concentration. Chromatographic techniques such as HPLC typically require relatively larger sample volumes, which translates to lower detection sensitivity (e.g., with UV detectors). Furthermore, they require sufficient material for extraction and purification, meaning that hundreds of µl to several ml are often required for biological samples (e.g., plasma, serum, urine). This can be problematic when sample size is limited (e.g., pediatrics, neonatology). The introduction of UPLC, often coupled with high-sensitivity detectors such as MS, has significantly reduced the required sample volume due to several key features, including increased sensitivity and separation efficiency, which allows for handling smaller amounts of analyte without signal loss; shorter columns with finer grain sizes, which translates into higher signal concentration and better signal-to-noise ratio; shorter analysis times and smaller dilutions (less analyte loss); and improved compatibility with microextraction (e.g., small-scale SPE). Thanks to this, it has become possible to analyze samples of very small volume, e.g., neonatal blood (several to a dozen or so µL), dried blood drops (DBS), microsamples of biological fluids collected in a minimally invasive manner. Typical sample volume requirements for the classical HPLC-UV method are often 0.5–2 mL, while for LC-MS-MS/UPLC-MS-MS 10–100 µL of serum or several mm of blood from DBS. In summary, UPLC, especially when combined with MS, has enabled the transition from milliliter to microliter analyses, revolutionizing diagnostics in situations where the available quantity of biological material is critically limited. At the same time, the smaller the sample, the greater the impact of preparation errors, matrix heterogeneity, and analyte losses.
Despite many advantages, miniaturization has certain limitations, including: limited repeatability of very small samples (pipetting error, matrix heterogeneity); problems with sample representativeness (e.g., DBS may not reflect all blood uniformly); analyte adsorption on surfaces (losses at very low concentrations); instrumentation requirements (UPLC-MS-MS is expensive and requires stable operating conditions); complicated microvolume sample preparation (more difficult SPE, higher risk of percentage losses); detection limit dependent on the matrix, not only on the instrumentation.
There is no single “most suitable” biological matrix for UPLC, as this technique can be applied to a wide range of materials; however, in practice, plasma or blood serum are most commonly chosen and best-characterized biological matrix. This is not due to limitations of the UPLC technique itself, but rather to the fact that plasma most accurately reflects the body’s exposure to a substance, is widely used in pharmacokinetic studies, and has the largest number of validated analytical procedures [356]. The lowest LODs/LOQs are typically achieved in matrices with the lowest protein and lipid content, as these limit the matrix effects responsible for suppressing ionization. For this reason, cerebrospinal fluid, urine, and often saliva allow for lower limits of detection than plasma or whole blood, provided the analyte is present in these matrices at a sufficient concentration. At the same time, in bioanalytical practice, plasma remains the most commonly analyzed matrix, even though it does not provide the lowest LODs. It is chosen primarily because it best reflects the body’s exposure to the drug and its metabolites [355].
The choice of column for research was determined by the type of matrix and the properties of the analytes. In the literature reports reviewed, BEH C18 columns were most commonly used for analyzing compounds of moderate and low polarity, due to their wide applicability in analyzing compounds of moderate and low polarity. HSS T3 columns were preferred for analyzing metabolites of higher polarity, particularly when better retention under reversed-phase conditions was required, whereas HILIC columns were used less frequently and were typically reserved for highly polar compounds, including amino acids, nucleosides, and small endogenous metabolites.
UPLC is often coupled with other detection techniques that enable not only the separation but also the identification and quantification of compounds. Most often, this is MS or MS-MS, which enable highly selective and sensitive detection of compounds even in trace amounts, which is difficult to detect in biological samples. Such systems significantly improve analytical capabilities and are used in numerous fields, such as pharmacokinetics, bioanalysis, toxicology, and the analysis of drugs and their metabolites. Most studies using MS detection have used ESI, operating primarily in positive ion mode, while triple quadrupole mass spectrometers have been used primarily for targeted quantitative analyses, while high-resolution (QTOF) instrumentation has been used in metabolomics and biomarker discovery.
In summary, the reviewed literature clearly indicates a preference for reversed-phase UPLC using BEH C18 columns coupled with ESI-MS detection. Sample preparation depends primarily on the complexity of the matrix rather than the analytical procedure. Protein precipitation is sufficient for most liquid biological samples, whereas SPE is reserved for applications requiring increased sensitivity. However, HILIC is typically preferred only for highly polar analytes that cannot be adequately analyzed under reversed-phase conditions. Matrix effects, insufficient retention of polar metabolites, and the lack of harmonized sample preparation protocols remain the main analytical limitations.
Despite its many advantages, UPLC poses significant analytical and technical challenges. Operating at elevated pressures requires expensive equipment, fine stationary phase particles are more susceptible to contamination, and in the mass spectrometer, plasma components can affect analyte ionization, making the use of internal standards essential. Though some difficulties, UPLC has a fairly wide range of applications in the analysis of compounds in a complex matrix, such as biological material.
To sum up, the information collected in the above manuscript regarding the conditions of drug analysis in biological material should be useful for a wide range of researchers dealing with this subject and working with UPLC equipment (especially with MS detection). We hope that our work will serve as a guide, allowing for quick identification of the conditions under which a specific drug can be determined in the tested material. With the information contained in our work at hand, researchers can quickly find basic information on how to prepare a sample, what column to use, and what solvents they will need. Details on, for example, specific volumes can be found in the indicated publication, without the need to search through large databases.

4. Practical Recommendations

Based on the reviewed studies, a practical decision framework for UPLC-based bioanalytical method development can be proposed. For compounds with low to moderate polarity (including most pharmaceutical substances, lipids, xenobiotics, and their metabolites), BEH C18 columns remain the preferred first-choice stationary phase because of their broad applicability and successful use across diverse biological matrices. For more polar analytes, HSS T3 columns may provide enhanced retention while maintaining the advantages of reversed-phase chromatography. When analytes are highly polar and insufficiently retained under RP conditions, HILIC columns offer a more suitable alternative, particularly for amino acids, nucleosides, sugars, and endogenous metabolites. The studies analyzed consistently demonstrated that the HILIC technique provides superior retention and separation of these analytes in cases where RP systems failed to ensure an adequate degree of retention.
The choice of sample preparation should be guided by analytical objectives and matrix complexity, with protein precipitation being most suitable for rapid, high-throughput analyses, whereas SPE is preferable when higher sensitivity, improved selectivity, and reduced matrix effects are required, particularly for trace-level quantification and complex matrices. For tissues, homogenization followed by extraction and additional purification was usually necessary, whereas urine often required only dilution, filtration, or SPE because of its lower protein content.
Similarly, the selection of the detection technique should reflect the study purpose: MS/MS remains the method of choice for targeted quantitative analysis, high-resolution MS (QTOF/TOF-MS) is most advantageous for untargeted profiling and metabolomics applications, while UV, PDA, DAD, or fluorescence-based detectors offer lower costs and simpler instrumentation but and generally provide lower sensitivity and selectivity and are therefore more suitable for routine analysis of known analytes present at relatively high concentrations.
This framework, derived from the reviewed literature, may facilitate a more rational selection of chromatographic conditions for specific analytes, matrices, and analytical goals.
These practical possibilities can be used to develop and optimize methods for UPLC applications.

Author Contributions

Conceptualization, M.D. (Monika Dąbrowska); formal analysis, P.D., M.S. and P.T.; investigation, N.H., I.D. and M.D. (Mariia Data); writing—original draft preparation, N.H. and I.D.; writing—review and editing, M.D. (Monika Dąbrowska), M.S. and N.H.; visualization, I.D. and N.H.; supervision, M.D. (Monika Dąbrowska). All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

6-MAM6-Monoacetylmorphine
ACNAcetonitrile
ADAlzheimer’s disease
ADMAAsymmetric dimethylarginine
AGEsAdvanced glycation end products
AMAmitriptyline
BDSBase deactivated silica
BEHBridged ethyl hybrid
BZEBenzoylecgonine
CCαDecision limit
CCβCapacity of decision
C18Octadecylsilane (reversed-phase column)
C8Octylsilane (reversed-phase column)
CEMAN-acetyl-S-(2-cyanoethyl)cysteine
CHEMAN-acetyl-S-(1-cyano-2-hydroxyethyl)cysteine
DADDiode array detector
DBD-PyNCSDerivatization reagent (benzoxadiazole derivative)
DHEADehydroepiandrosterone
DLRacemic mixture
ESIElectrospray ionization
EtGEthyl glucuronide
F-EFVFluorinated efavirenz
FAFormic acid
GCGas chromatography
GHBGamma-hydroxybutyrate
GOGlyoxal
HDACHistone deacetylase
HEMAN-acetyl-S-(2-hydroxyethyl)cysteine
HILICHydrophilic interaction liquid chromatography
HMGHydroxymidazolam glucuronide
HPHigh pressure
HPLCHigh-performance liquid chromatography
HRMSHigh-resolution mass spectrometry
HSS T3High strength silica T3 column
ICP-MSInductively coupled plasma mass spectrometry
KEKetamine
LCLiquid chromatography
LILidocaine
LLOQLower limit of quantification
LLODLower limit of detection
LODLimit of detection
LOQLimit of quantification
M3GMorphine-3-glucuronide
M3SMorphine-3-O-sulfate
M6GMorphine-6-glucuronide
M6SMorphine-6-O-sulfate
MDA3,4-Methylenedioxyamphetamine
MDEA3,4-Methylenedioxyethylamphetamine
MDMA3,4-Methylenedioxymethamphetamine
MRM-MSMultiple reaction monitoring mass spectrometry
MGMethylglyoxal
MHDMonohydroxy metabolite
MORMorphine
MSMass spectrometry
MS-MSTandem mass spectrometry
NANaringin
NENorepinephrine
NIBNorisoboldine
NMMAN-monomethylarginine
NONortriptyline
OHMHydroxymidazolam
OVOpen vessel
OXCOxcarbazepine
PAHPolycyclic aromatic hydrocarbons
QTOF-MSQuadrupole time-of-flight mass spectrometry
SDMASymmetric dimethylarginine
SDSSodium dodecyl sulfate
SPESolid-Phase-Extraction
T3High-strength silica column type
TDIToluene diisocyanate
TFATrifluoroacetic acid
TOF-MSTime-of-flight mass spectrometry
UHPLCUltra-high-performance liquid chromatography
ULOQUpper limit of quantification
UPLCUltra-performance liquid chromatography
UVUltraviolet detection

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Specifics of Classical Molecular Dynamics Simulation of the Raman Spectrum of the CO2 Fermi Dyad
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