INTRODUCTION:

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain, inflammation and fever. NSAIDs are the aryl-propionic derivatives whish shows good activity as a analgesic, anti-inflammatory and antipyretic.¹ By inhibiting the cyclooxygenase enzymes, which are involved in the synthesis of prostaglandins, Non-steroidal anti-inflammatory drugs have a therapeutic effect by inhibiting the synthesis of certain prostaglandins.^2,3 As a result of the potential for additive or synergistic effects and the possibility of reducing drug-induced toxicities associated with higher doses of individual drugs, combination therapy is now of increasing importance in a variety of disease conditions. Examples of combination therapies include zaltoprofen, loxoprofen, ketoprofen, and flurbiprofen.⁴

In this paper, we discuss current advances in analytical methods for estimating zaltoprofen, loxoprofen, ketoprofen, and flurbiprofen alone or in combination with other drugs in different biological media, such as human plasma and urine. The topic of various analytical procedures is covered, ranging from simple, intermediate selectivity and sensitivity analytical methods to advanced, extremely selective and sensitive chromatographic methods used in contemporary analytical labs. In this review, sample pretreatment techniques like solid phase extraction, separation techniques like high performance liquid chromatography (HPLC), and UV-visible spectroscopy techniques will all be critically analyzed.

Chemistry of NSAIDs:

Non-steroidal anti-inflammatory drugs are the derivatives of the aryl-propionic derivatives, some NSAIDs like zaltoprofen, loxoprofen, ketoprofen, and flurbiprofen are discussed here their analytical methods such HPLC, and UV-visible spectroscopy methods.

Zaltoprofen (ZLT) is synthesized from propionic acid. Chemically it is 2-(10-oxo-10, 11-1) dihydrodibenzo [b, f] thiepin-2-yl) propionic acid (Fig. 1) It is a preferred COX-2 inhibitor that targets inflammation-related PGE2 synthesis and inhibits it there. Additionally, it has an inhibitory effect on bradykinin's nonciceptive responses.⁵ Loxoprofen sodium (LXP) is a prodrug recently developed novel NSAID and loxoprofen (Fig. 2) is an active metabolite of a propionic acid derivative. Chemically speaking, it is sodium-2-[4-(2-oxocyclopentyl-1-methyl) phenyl] propionate dihydrate. It contains anti-inflammatory and antipyretic activities.^6,7 Ketoprofen (KTP) is chemically 2-(3-benzolphenyl) propionic acid an important non-steroidal anti-inflammatory drug with anti-inflammatory, analgesic and antipyretic properties (Fig.3). ketoprofen has been used to treat several acute and chronic inflammatory diseases and used to treat osteoarthritis, rheumatoid arthritis, abdominal cramps associated with menstruation, and ankylosing spondylitis.^8,9 Flurbiprofen (FLB), a non steroidal anti-inflammatory drug is a phenylalkanoic acid derivative (2-2-Fluoro-4-biphenyl 4-yl, propionic acid) having molecular weight 244.3g/mol with molecular formula of C15H13FO2. Flurbiprofen (Fig. 4) is commercially available as a racemate blend of (+) Sand (-) R-enantiomers. The enanteomeric form of the drug has potentially developing role in the treatment of Alzheimer’s disease and metastatic prostate cancer with anti-inflammatory activity.¹⁰

Fig. 1 Chemical Structure of Zaltoprofen

Fig. 2 Chemical Structure of Loxoprofen

Ketoprofen Flurbiprofen

Fig. 3 Chemical Structure of Ketoprofen

Fig. 2 Chemical Structure of Loxoprofen

UV-Visible Spectroscopy methods for ZLT in alone and combinations:

The most significant spectrophotometric method that is most frequently employed for the analysis of a wide range of chemicals is regarded to be UV-VIS spectroscopy. The foundation of this method is the measurement of the electromagnetic radiation's interaction with substances at a specific wavelength.¹¹ Total four methods reported for estimation of ZLT in single and combination dosage form by using UV-visible spectroscopic methods. Table no 1. That provides the summary of reported spectrophotometric methods including sample matrix, methods, linearity and Detection wavelength.^12-15

HPLC/Bioanalytical methods for ZLT in alone and combinations:

Due to its very effective separations and often high detection sensitivity, HPLC is the most widely used separation method in contemporary pharmaceutical and biomedical analysis. Due to the HPLC method's numerous benefits, including its speed, specificity, accuracy, precision, and ease of automation, the majority of medications in multi-component dosage forms can be examined using this technique. The development and validation of HPLC procedures are crucial to novel discoveries, the creation of pharmaceutical medications, and numerous other human and animal investigations. To compare a defined characteristic of the drug substance or drug product to predetermined acceptance criteria for that characteristic, an analytical technique is designed.¹⁶

Table no 1 Pharmaceutical Analysis of ZLT via Spectroscopic methods alone and combinations.

Sr. No	Drugs	Pharmaceutical Matrix	Method		Linearity (µg/ml)	Accuracy study (%)	Detection (λ max) nm	Ref.
1.	ZLT	Bulk Material & Tablet	I	UV Spectrophotometry method	1-40	99.53	243.5	12
			II		5-100	99.77	338.
2.	ZLT + PCM	Bulk Material & Tablet	I	UV Spectrophotometry method	ZLT-1-5	ZLT-98.6 - 99.0	ZLT-227	13
					PCM-4.06-20.3	PCM –98.4 - 98.8	PCM -243
3.	ZLT + PCM	Bulk Material & Tablet	I	simultaneous equation method	ZLT-8-13	ZLT- 99.76 PCM- 99.87	ZLT- 227.5 PCM- 247.5	14
			II	Q-Absorbance ratio method	PCM -4-9	ZLT- 99.87 PCM- 100.13	ZLT-236 PCM-236
4.	ZLT + PCM	Bulk Material & Tablet	I	simultaneous equation method	2-18	ZLT- 99.87 PCM- 100.02	245 & 227	15
			II	Q-Absorbance ratio method		ZLT- 99.84 PCM- 99.82	237.5 & 227

Table no 2 Pharmaceutical Analysis of ZLT via HPLC methods in alone and combination.

Sr. No.	Drugs	Pharmaceutical or Biological Matrix	Column	Chromatographic Conditions	Linearity µg/mL	Ref.
1.	ZLT (HPLC)	Bulk Material and Human Plasma	Intensil C18 (250 x 4.6 mm, 5 𝜇m)	M.P- Phosphate Buffer : ACN (40:60%, v/v), (pH-3.0), Flow rate - 1.0 mL/min. Mode of analysis – Isocratic Detection – 254 nm Internal Standard- Nevirapine	0.15 - 20	17
2.	ZLT (HPLC)	Bulk Form and Rat plasma	Chiralcel OJ-H C18 (150 x 4.6 mm, 5 𝜇m)	M.P- Hexane: Isopropanol: Triflouroacetic acid (90:10:0.1%, v/v/v) Flow rate – 0.8 mL/min Mode of analysis – Isocratic Detection – 244 nm	0.10 – 75	18
3.	ZLT (HPLC)	Bulk Material and Tablet	Inertsil ODS C18 (150 x 4.6 mm, 5 𝜇m)	M.P- 0.01 M KH2PO4 Buffer: ACN (45:55%, v/v), (pH-3.0), Flow rate – 0.8 mL/min. Mode of analysis – Isocratic Detection – 240 nm	50-150	19
4.	ZLT (HPLC)	Bulk Form and Rat plasma	Capcell Pak C18 (150 x 1.5 mm, 5 𝜇m)	M.P- 10 mM Phosphate Buffer: ACN (65:35%, v/v), (pH-6.8), Flow rate – 0.5 mL/min. Mode of analysis – Isocratic Detection – 250 nm	0.2 - 10.0	20
5.	ZLT + PCM (HPLC)	Bulk Material and Tablet	LC-20 AT C18 (250 x 4.6 mm, 5 𝜇m)	M.P- Potassium Buffer: Methanol (50:50%, v/v), (pH-4.0), Flow rate – 1.0 mL/min. Mode of analysis – Isocratic Detection – 220 nm	ZLT- 8-24 PCM- 32.5-97.5	21

Table no 3 Pharmaceutical Analysis of ZXP via HPLC methods alone and combinations.

Sr. No.	Drugs	Pharmaceutical or Biological Matrix	Column	Chromatographic Conditions	Linearity µg/mL	Ref.
1.	LXP (HPLC)	Bulk Material and Human Plasma	Mediterranea Sea C18 (250 x 4.6 mm, 5 𝜇m)	M.P- ACN: 0.01 M NaH2PO4 Buffer (55:45%, v/v), (pH-6.5), Flow rate – 1.0 mL/min. Mode of analysis – Isocratic Detection – 220 nm Internal Standard –Ketoprofen	0.1- 10 ppm	22
2.	LXP (HPLC)	Bulk Material and Human Plasma	Hypersil BDS C18 (250 x 4.6 mm, 5 𝜇m)	M.P- ACN: Water (40:60%, v/v), (pH-3.0), Flow rate – 1.0 mL/min. Mode of analysis – Isocratic Detection – 225 nm Internal Standard –Ketoprofen	0.10 to 10.0 μg/mL	23
3.	LXP + M-I + M-II (HPLC)	Bulk Material, Human Plasma and Urine	ODS C18 (250 x 4.6 mm, 5 𝜇m)	M.P- ACN: Water (35:65%, v/v), (pH-3.0), Flow rate – 1.2 mL/min. Mode of analysis – Isocratic Detection – 220 nm Internal Standard –Ketoprofen	-	24

Table no 4 Pharmaceutical Analysis of KTP via HPLC methods alone and combinations.

Sr. No.	Drugs	Pharmaceutical or Biological Matrix	Column	Chromatographic Conditions	Linearity µg/mL	Ref.
1.	KTP (HPLC)	Bulk Material and Human Plasma	Zorbax SB-C18 (100 x 4.6 mm, 3.5 𝜇m)	M.P- ACN: trifluoroacetic acid in water (55:45%, v/v), Flow rate – 1.5 mL/min. Mode of analysis – Isocratic Detection – 257 nm	153.2 - 19155 ng/mL	25
2.	KTP (HPLC)	Bulk Material and Tablet formulation	LiChrosorb C18 (250 x 4.6 mm, 5 𝜇m)	M.P- 0.1M ammonium acetate buffer (pH 6.9): ACN: tetrahydrofuran (73:20:5:2%, v/v/v/v) Flow rate – 1.0 mL/min. Mode of analysis – Isocratic Detection – 230 nm	5.00-100.0 μg/mL	26
3.	KTP (HPLC)	Bulk Material	Kromasil C18 (150 x 4.6 mm, 5 𝜇m)	M.P- Phosphate buffer (pH-6.8 ): Methanol (50: 50%, v/v) Flow rate – 1.0 mL/min. Mode of analysis – Isocratic Detection – 258 nm	0.05–250 μg/mL	27
4.	KTP + THC (HPLC)	Bulk Material and Tablet formulation	Thermo scientific C18 (250 x 4.6 mm, 5 𝜇m)	M.P- ACN: Water: Phosphate buffer (pH 3.0) (60:30:10%, v/v/v). Flow rate – 1.0 mL/min. Mode of analysis – Isocratic Detection – 260 nm	KTP – 20- 100 THC - 4-20	28

Table No 5 Pharmaceutical Analysis of FLB via HPLC methods alone and combinations.

Sr. No.	Drugs	Pharmaceutical or Biological Matrix	Column	Chromatographic Conditions	Linearity µg/mL	Ref.
1.	FLB	Bulk Material and Tablet formulation	Ace C18 (250 x 4.6 mm, 5 𝜇m)	M.P- ACN: 0.05 M potassium dihydrogen phosphate solution (pH 3.5), (60:40%, v/v) Flow rate – 1.0 mL/min. Mode of analysis – Isocratic Detection – 254 nm	0.10-5.0 μg/mL	29
2.	FLB	Bulk Material and Tablet formulation	Gemini C18 (250 x 4.6 mm, 5 𝜇m)	M.P- ACN: 30 mM disodium hydrogen phosphate solution (pH 7.0): ACN (50:50%, v/v) Flow rate – 1.0 mL/min. Mode of analysis – Isocratic Detection – 247 nm	5-50 μg/mL	30
3.	FLB	Bulk Form and Rat plasma	Diamond C18 (250 x 4.6 mm, 5 𝜇m)	M.P- ACN: 0.05 M potassium dihydrogen phosphate solution (pH 3.5), (60:40%, v/v) Flow rate – 1.0 mL/min. Mode of analysis – Isocratic Detection – 254 nm	0.2–50 μg/mL	31
4.	FLB + TCS	Bulk Material and Dental Gel formulation	Agilent ZORBAX SB-C18 (250 x 4.6 mm, 5 𝜇m)	M.P- ACN: Citric Acid (pH 3.2), (90:10%, v/v) Flow rate – 0.3 mL/min. Mode of analysis – Isocratic Detection – 242 nm	FLB-15–240 μg/mL TCS- 10–160 μg/mL	32
5.	FLB + RNT	Bulk Material and Tablet formulation	Gemini C18 (250 x 4.6 mm, 5 𝜇m)	M.P- ACN: 0.2 M potassium dihydrogen phosphate solution (pH 5.8), (50:50%, v/v) Flow rate – 1.0 mL/min. Mode of analysis – Isocratic Detection – 245 nm	10-100 μg/mL	33

DISCUSSION:

There are only a few analytical techniques for estimating the amounts of pharmaceuticals like TCS, RNT, THC, and PCM in conjunction with other drugs like ZLT, LXP, KTP, and FLB employing HPLC (simple, bioanalytical, and stability-indicating) and UV Spectrophotometry. It has also been stated that twenty-one analytical methods have been established and used to measure ZLT, LXP, KTP, and FLB.

CONCLUSION:

The study of several analytical techniques for identifying ZLT, LXP, KTP, and FLB in pharmaceutical formulations, human and rat plasma, and bulk form includes HPLC, bio-analytical, and UV spectroscopy techniques. The combination of water and methanol is among the most frequently used solvents for sample processing. Different buffer solutions with acidic pH, acetonitrile, and water are some of the different solvents utilised for the separation of ZLT, LXP, KTP, and FLB. For analysis employing reverse phase chromatography, isocratic mode is used for the majority of HPLC procedures. The researcher may learn important details about the many techniques used for ZLT, LXP, KTP, and FLB analysis from the current review paper. UV-visible spectroscopy method available only for ZLT in single and combinations. It can also learn about the numerous possibilities available for ZLT, LXP, KTP, and FLB analysis.

ACKNOWLEDGEMENT:

The principal of the Poojya Sane Guruji Vidya Prasarak Mandal, Shahada, Dist. Nandurbar (MS) 425 409, is gratefully acknowledged by the authors for providing the essential library resources.

Abbreviations Used:

· ACN – Acetonitrile

· FLB – Flurbiprofen

· HPLC- High performance liquid chromatography

· KTP – Ketoprofen

· LC- Liquid chromatography

· LXP – Loxoprofen

· NSAIDs - Non-steroidal anti-inflammatory drugs

· PCM – Paracetamol

· pH- Power of hydrogen

· RNT – Ranitidine

· TCS – Triclosan

· THC – Thiocolchicoside

· ZLT – Zaltoprofen

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Received on 04.06.2023 Modified on 01.07.2023

Asian J. Pharm. Ana. 2023; 13(4):261-266.

DOI: 10.52711/2231-5675.2023.00043