INTRODUCTION:

High performance liquid chromatography (HPLC) has proven to one of the major analytical technique used in the qualitative and quantitative analysis of drugs worldwide. More than 90% of drugs prescribed in official pharmacopoeias are being analyzed HPLC. The pharmaceutical industries and academic institutions are adopting the more advanced chromatographic techniques. UHPLC only first appeared in 2004 when Waters created their own trademarked ultra-performance chromatography (UPLC) systems. Since then, companies such as Thermo and Agilent have developed their own UHPLC systems. The basic feature in HPLC is the separation column and the material packed inside it, is the growth of this technique. By using smaller particles, speed of analysis, peak capacity can be extended to new limits and the sample can be analyzed in a shorter period of time^1-10.

Development of UHPLC Column Packing:

However certain analytical requirements cannot be fulfilled by HPLC technique. Such as determination of complex samples such as formulation excipients, biological samples, drug metabolites, degradation products, impurities, and drug isomers by HPLC, several problem arises related to determination of analytes at low level (0.1%), speed of analysis and resolution per unit time. For the need of high resolution separation, the researchers were involved in the designing of sub-2µm particles. Porous packing materials can tolerate higher pressure and give much higher sample capacity than non-porous packings. First time in the year 1999, Waters developed the hybrid particle technology (HPT) column for HPLC. The second generation hybrid material particle composed with bridged ethylsiloxane/silica hybrid (BEH) structure was developed which provides improved efficiency, strength and pH range. From the above development in column packing material and particle size, Waters Company was given the trade name of UHPLC, which was known as UPLC^11-26. The BEH Particle Chemistry is presented in Figure 1.

Figure 1. BEH Particle Chemistry

In this review article author provides the information of development of UHPLC and its recent applications with examples of some of the most advanced work in the pharmaceutical analysis.

Recent Applications of UHPLC:

1. Method Development and Validation:

Method development and validation is a time-consuming and complicated process. Analysts need to evaluate combinations of mobile phase, pH, temperature, column chemistries, and gradient profiles to get a robust, reliable separation for every compound. Using UHPLC, analysis times become as short as one minute, methods can be optimized in just one or two hours, significantly reducing the time required for method development and validation²⁷.

2. Manufacturing and QA/QC:

Identity, purity, quality, safety and efficacy are the important factors to be considered while manufacturing a drug product. The successful production of quality pharmaceutical products requires that raw materials and finished pharmaceutical products meet purity specifications. Continued monitoring of material stability is also a component of quality assurance and control. UHPLC is used for the highly regulated, quantitative analyses performed in QA/QC laboratories. The supply of consistent and high quality products plays an important role in a registered analytical method²⁸.

3. Determination of FDC Products:

A fixed dose combination (FDC) product is a formulation of two or more drugs combined in a single dosage form available in certain fixed doses. Method development for two or more drugs becomes very complex if the solubility varies greatly. Hence they need to be analyzed by more sophisticated techniques such as UHPLC-PDA, UHPLC-Q-TOF/MS. A large number of samples per day can be analyzed due to the short analysis times^{29, 30}.

4. Identification of Impurities and Degradation Products:

The analytical technique mostly used for forced degradation studies is HPLC-UV and/or HPLC-MS but the main drawback is that these techniques are time consuming and not provide adequate information regarding resolution of all the impurities and degradation products. Due to this requisition, UHPLC-PDA is the next simple advanced technique which can be applied for identification of impurities and degradation products of pharmaceuticals. The PDA (Photodiode Array Detection) gives three- dimensional images of peaks of compounds, by which impurities can be easily traced out. Mass spectrometry is also being used for the detection of impurities. The UHPLC/Q-TOF-MS system provide changeable collision energy values allows the generation of mass information with acceptable accuracy and precision, which is ultimately helpful in structure elucidation, identification of fragmentation patterns of the drugs, identification of degradation products and establishment of degradation mechanisms^31-33. The author was successfully applied the UPLC/Q-TOF-MS technique for determination of aceclofenac and paracetamol and their degradation products in tablets²⁷.

5. Dissolution Testing:

For quality control and release in drug manufacturing, dissolution testing is essential in the formulation, development and production process. The dissolution profile is used to demonstrate reliability and batch-to-batch uniformity of the active ingredient. For quality control and release in drug manufacturing, dissolution testing is essential in the formulation, development and production process. In sustained-release dosage formulations, testing higher potency drugs is particularly important where dissolution can be the rate-limiting step in medicine delivery. UPLC provides precise and reliable automated online sample acquisition. It automates dissolution testing, from pill drop to test start, through data acquisition and analysis of sample aliquots, to the management of test result publication and distribution³⁴.

6. Analysis of Sustained Release Tablets:

In-vitro dissolution study of sustained release tablets are being carried out by UPLC-PDA methods. The use of PDA detector in such studies provides the much specific peaks in chromatograms of drugs alongwith excipients of formulations. Some of these studies were carried out in developed sustained release tablets using mobile phase for UPLC analysis consisted of acetonitrile-2 mM ammonium acetate (40:60, v/v)^35-37.

7. Pharmacokinetic and Bioequivalence Studies:

For pharmacokinetic, toxicity, and bioequivalence studies, quantitation of a drug in biological samples is an important part of development programs. The sensitivity and selectivity of UPLC-PDA at low detection levels generates accurate and reliable data that can be used for a variety of different purposes, including statistical pharmacokinetics (PK) analysis^38-44.

8. Identification of Metabolites:

After the development stage of any chemical compound, its metabolite identification is a mandatory process. For complete knowledge of therapeutic effectiveness of the compound, it is essential to identify all of related metabolites. It has been used successfully in metabolite study using selected MS/MS transitions of molecular ion and product ions for quantification in sample matrix. The identification of the human metabolites of paracetamol was carried out by HPLC monolithic column and sub-2 μm particle UPLC columns along with TOF-MS. The UHPLC system produced the sensitivity and detected metabolites by three times more than the HPLC system. The metabolite profiling has been investigated in various biological samples by applying UHPLC/Q-TOF coupled with MetaboLynx™ software. Biotransformation of new chemical entities (NCE) is necessary for drug discovery. When a compound reaches the development stage, metabolite identification becomes a regulated process^45-49.

9. Metabonomic Studies:

The biochemical changes in the drug product when it exposed to human system is known as metabonomics. Metabonomic studies are helpful in the discovery new metabolites of drug. By the identification of metabolites, its therapeutic and toxic aspects can be determined. It has been employed in pharmaceutical development particularly in the fast in-vitro and in-vivo studies of drug products. The chemical structures of various constituents in red and white ginseng used in Chinese formulations were determined by this technique. UPLC used for accurate, reliable and reproducible analysis of amino acids in the areas of protein characterizations, cell culture monitoring and the nutritional analysis of foods^50-52.

10. Determination of Phytoconstituents:

Determination of phytoconstituents analysis involves usage of several analytical techniques for the isolation and characterization of phytoconstituents. Primitive techniques basically involved usage of UPLC-MS for the isolation and determination of phytoconstituents i.e. characterizations and quantitation of phytoconstituents has been reported in Piper betle⁵³.

11. Analysis of Natural Products and Herbal Medicine:

UPLC provides high-quality separations and detection capabilities to identify active compounds in highly complex samples that results from natural products and traditional herbal medicines. UPLC–Q-TOF-MS/MS was applied for the fingerprinting of Traditional Chinese Formula SiJunZiTang⁵⁴.

12. Peptide Mapping:

The identification of chemical structure of the Peptide connected within the protein is known as peptide mapping. This technique provides authentic results in the when employed in the analysis complex molecules such as proteins. The structural identification of proteins can become easier by applying the time-of-flight mass detection⁵⁵.

13. Amino Acid Analysis:

Amino acid analysis is a well established technique for determining all 20 common amino acids in proteins or peptides, as well as modified residues that might arise from posttranslational modifications. Amino acid analysis is a well accepted and adopted analytical method in biotechnology, and it has been adapted to operate in the UHPLC framework⁵⁶.

14. Glycoprofiling (Glycan Analysis):

In general, glycoproteins contain glycans, or oligosaccharides (sugars), and usually do not contain attached monosaccharides. Characterization of any glycoprotein requires the determination of the sugars that are present, measurement of their configurations as glycans, determination of the site or sites of attachment on the protein, and finally, the distribution of glycoforms. The proportion of the glycoforms is most often measured using intact-protein UPLC-MS⁵⁷.

15. Vitamin analysis:

Several UPLC-MS methods have been reported for the analysis of vitamin B complex (thiamin, riboflavin, biotin, nicotinic acid, pyridoxine, pyridoxamine, pyridoxal, pantothenic acid, FAD, and nicotinamide) analysis in human milk. UPLC-MS coupled with ESI techniques is used to analyze vitamin B from milk sample⁵⁸.

16. Determination of alkaloids:

Ortega et al. reported identification and quantification of alkaloids, theobromine, and caffeine in cocoa sample using UPLC-MS/MS. It has also been reported for alkaloid profiling of medicinal plants having cytotoxic properties. It is used for analysis of various alkaloids such as sanguinarine, berberine, protopine, and chelidonine⁵⁹.

17. Screening of Antibiotics in Surface and Wastewater:

This technique has been applied in the detection of antibiotics from surface water, influent and effluent wastewaters. These compounds are carried by washing of machineries and transferred in to the wastewater during the manufacturing process. Several antibiotics such as ofloxacin, ciprofloxacin along with other were determined and confirm the presence of the residues of such substances in wastewater in the pharmaceutical industries⁶⁰.

18. Therapeutic Drug Monitoring:

The monitoring of β-lactam antibiotic concentration in plasma of patients with different pharmacokinetics. UPLC-MS/MS method was applied for the simultaneous estimation of two β -lactamase inhibitors and seven β- lactam antibiotics in human plasma⁶¹.

19. Screening of Synthetic Compounds:

The technique has become critical tools for use in high-throughput quality control screening of synthetic medicinal compounds. The use of more conventional techniques such as NMR cannot address these high throughput analytical needs due to relatively poor sensitivity, high sample purity requirement, necessity of operator expertise and the use of costly solvents. To simplify the analytical procedures, automation in combination with application of software for exact mass measurement is demonstrated⁶².

20. Analysis of Antioxidants and Phenolic Compounds:

It’s been well-know that antioxidant has ability to fight against free radicals since free radicals are considered as a causative agent for several diseases. However, use of antioxidant has increased in food industry due to its antimicrobial property. Phenolic profiling as well as antioxidant activities can be analyzed UPLC-ESI-MS/MS in Salvia species in some of the medicinal plants from South West Anatolia, Turkey. It was first reported for the analysis of individual phenolic profiles of S. potentillifolia, S. albimaculata, and S. nydeggeri⁶³.

21. Identification of Unknown Pesticides:

The method is used in the identification of pesticides in the vegetables and fruits. The identification of these toxic materials from vegetables is essential to public health, which can be determined by this sensitive method. The pesticide residue present at very low concentration level collected from packaging materials used for packaging of fruits were analyzed by technique⁶⁴.

22. Analysis of Doping Agents:

Method has been applied for doping control and analyses of doping agents from various classes such as β-blockers, stimulants, diuretics, and narcotics. However the developed methods have been used for screening screening of the doping agents, then finally applied for quantification. The method was found reliable for the determination of these restricted drugs by the World Anti-Doping Agency (WADA). The applied method was validated as per the guidelines described in the World Anti-Doping Code⁶⁵.

23. Screening of Organic Pollutants in Water:

It is applied for determination of organic contaminants in natural and waste water. The samples were obtained from solid-phase extraction procedure. The analysis was carried out by standard addition technique. Organic pollutants from various sources were mixed with water samples in the range concentration levels and analyzed by this technique. The developed method was applied for detection and identification of several organic contaminants, antibiotics, anti-inflammatory and analgesic drugs⁶⁶.

24. Iodinated Byproducts in Drinking Water (IBP):

With the help of UPLC coupled to electrospray ionization-triple quadrupole mass spectrometer (ESI-tqMS), several iodinated byproducts in water (IDBPs) treated with chlorine and chlorine-ammonia have been analyzed quantitatively and their structures were proposed⁶⁷.

25. Toxicity Studies:

During the drug development process, toxicity issue causes a fall out of drug candidates and this causes monetary loss to the organization. It is a complicated task to estimate candidate drugs for possible inhibition or initiation of metabolizing enzymes, toxicity or drug-drug interactions in the body. UPLC allows precise detection due to its high resolution. Further, its sensitivity also allows the detection of the peaks at low concentrations. These factors lessen the time for analysis and decrease failure of sample analysis⁶⁸.

The UHPLC Applications with their examples of drugs analyzed are presented in Table 1.

Table-1 UHPLC Applications with Details of Column, Mobile Phase Composition and Detection Technique Used

S. No.	Applications	Drugs	Column	Mobile Phase Composition	Detection	Ref.
1	Method Development and Validation	Metformin, Glimepiride and Pioglitazone Tablets	BEH C-18	Acetonitrile: 2Mm Ammonium Acetate (50:50, % V/V)	PDA Detector	[27]
2	Manufacturing and QA/QC	Pharmaceutical Production (GMP)	Monolithic and 3-micron particle	Acetonitrile: 2Mm Ammonium Acetate (50:50, % V/V)	UV Detector	[28]
3	Determination of FDC Products	Aceclofenac and Paracetamol Tablets	BEH C-18	Acetonitrile: 2Mm Ammonium Acetate (40:60, % V/V)	Q-TOF-MS	[29, 30]
4	Identification of Impurities and Degradation Products	Telmisartan and Hydrochlorothiazide	BEH C-18	Acetonitrile: 2Mm Ammonium Acetate (50:50, % V/V)	Q-TOF-MS	[31, 32]
4	Identification of Impurities and Degradation Products	Valsartan	BEH C-18	Acetonitrile: 2Mm Ammonium Acetate (50:50, % V/V)	Q-TOF-MS	[33]
5	Dissolution Studies	Rabeprazole	BEH C-18	Acetonitrile: Phosphate Buffer (35:65, % V/V)	UV Detector	[34]
6	Analysis of Sustained Release Tablet	Aceclofenac and Paracetamol Tablets	BEH C-18	Acetonitrile:2Mm Ammonium Acetate (40:60, % V/V)	PDA Detector	[35]
6	Analysis of Sustained Release Tablet	Telmisartan and Hydrochlorothiazide Tablets	BEH C-18	Acetonitrile:2Mm Ammonium Acetate (40:60, % V/V)	PDA Detector	[36, 37]
7	Pharmacokinetic and Bioequivalence Studies	Aceclofenac and Paracetamol Tablets	BEH C-18	Acetonitrile: 2Mm Ammonium Acetate (40:60, % V/V)	Q-TOF-MS	[38, 39]
		Telmisartan and Hydrochlorothiazide	BEH C-18	Acetonitrile: 2Mm Ammonium Acetate (40:60, % V/V)	Q-TOF-MS	[40]
		Anti-hypertensive drugs	BEH C-18	Acetonitrile: 2Mm Ammonium Acetate (40:60, % V/V)	Q-TOF-MS	[41]
		Nifedipine	BEH C-18	Acetonitrile-10 mmol/L Ammonium acetate (75:25, v/v)	Triple-q-MS/MS	[42]
		Amlodipine	BEH C-18	Water: Acetonitrile, with 0.3% formic acid	ESI-triple-Q-MS/MS	[43]
		Piperine	RP C-18	Methanol-Water (72:28, v/v)	Q-TOF-MS	[44]
8	Identification of Metabolitees	Acetaminophen	Monolithic C-18	Water: Acetonitrile, with 0.1% formic acid	Q-TOF-MS/MS	[45, 46]
		Avicularin	BEH C-18	Water: Acetonitrile, with 0.1% formic acid	ESI-QTOF-MS	[47]
		Tectorigenin	BEH C-18	Water: Acetonitrile, with 0.1% formic acid	ESI-QTOF-MS	[48]
		Nicotine	HILIC C-18	Water: Acetonitrile, with 0.1% formic acid	Tandem-MS/MS	[49]
9	Metabonomic studies	Ginseng	BEH C-18	Water: Acetonitrile, with 0.1% formic acid	Q-TOF-MS/MS	[50-52]
10	Determination of Phytoconstituents	Eugenyl acetate & Eugenol in Piper betle leaf	BEH C-18	Water: Acetonitrile, with 0.1% formic acid	ESI-MS/MS	[53]
11	Analysis of Herbal Medicine	Chinese Formula- SiJunZiTang	BEH C-18	Water: Acetonitrile, with 0.1% formic acid	Q-TOF-MS/MS	[54]
12	Peptide Mapping	Peptides	BEH C-18	Water: Acetonitrile, with 0.1% formic acid	ESI-TOF-MS/MS	[55]
13	Amino Acid Analysis	Amino Acids	BEH C-18	25% to 60% Acetonitrile: Water	ESI-TOF-MS/MS	[56]
14	Glycoprofiling (Glycan Analysis)	Glycoproteins	BEH C-18	Water: Acetonitrile, with 0.1% formic acid	UPLC-MS/MS	[57]
15	Vitamin analysis	Thiamin, Riboflavin, Biotin, Nicotinic acid and Pyridoxine,	UPLC HSS T3	2.5 mmol/L Ammonium Formate in Water & Acetonitrile	ESI-MS/MS	[58]
16	Determination of alkaloids	Procyanidins, Theobromine and Caffeine	Acquity HSS T3	Water/Acetic acid (99.8/0.2, v/v) and Acetonitrile	Triple- q-ESI-MS/MS	[59]
17	Screening of Antibiotics in Surface and Wastewater	Ofloxacin, Ciprofloxacin, Erythromycin	BEH C-18	Acetonitrile: Ammonium Acetate (50:50% V/V)	Hybrid QTOF-MS	[60]
18	Therapeutic Drug Monitoring	Progestin	BEH C-18	Water: Acetonitrile, with 0.1% formic acid	Tandem-MS/MS	[61]
19	Screening of Synthetic Compounds	Anti-hypertensives Anti-diabetics	BEH C-18	Acetonitrile: 2mM Ammonium Acetate (50:50% V/V)	Q-TOF-MS/MS	[62]
20	Analysis of Antioxidants and Phenolic Compounds	Phenolic compounds	BEH C-18	0.5% Acetic Acid in water and 0.5% Acetic Acid in methanol	ESI-MS/MS	[63]
21	Identification of Unknown Pesticides	Carbendazim, Imazalil, and Ethoxyquin	BEH C-18	Acetonitrile: Ammonium Acetate (50:50% V/V)	Q-TOF-MS/MS	[64]
22	Analysis of Doping Agents	Beta-blockers, Stimulants and Narcotics	BEH C-18	Acetonitrile: Ammonium Acetate (50:50% V/V)	Q-TOF-MS/MS	[65]
23	Screening of Organic Pollutants in Water	Organic Pollutants	BEH C-18	Acetonitrile: Ammonium Acetate (50:50% V/V)	Q-TOF-MS/MS	[66]
24	Iodinated Byproducts in Drinking Water (IBP)	Polar Iodinated Byproducts	BEH C-18	Acetonitrile: Ammonium Acetate (50:50% V/V)	ESI-triple- quadrupole MS	[67]
25	Toxicity Studies	Galactosamine	HILIC-UPLC C-18	Acetonitrile: Ammonium Acetate (50:50, % V/V)	HILIC-UPLC-TOF-MS	[68]

CONCLUSION:

In the presented review article the information of development of UHPLC and its recent applications with examples of some of the most advanced work in the pharmaceutical analysis has been described. The analytical method development is a critical factor in the development and regulatory compliance of pharmaceutical products. Qualitative and quantitative analysis is important because of drug quality as it determines the efficacy of any drug or dosage form. UHPLC has been successfully applied for identification and determination of compounds in almost every area of chromatographic and pharmaceutical analysis. It provides the fast, better chromatographic separation and shorter chromatographic run time as compared to conventional HPLC technique.

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Received on 24.11.2022 Modified on 15.04.2023

Asian J. Pharm. Ana. 2024; 14(1):39-46.

DOI: 10.52711/2231-5675.2024.00008