INTRODUCTION:

Etoricoxib (Fig. 1) specifically suppresses Cyclooxygenase 2 (COX2) without impacting COX1, in contrast to other NSAIDs. Thus, it prevents the synthesis of inflammatory prostaglandins without influencing the production of prostaglandins that are essential for upholding renal function, protecting the stomach mucosa, and many other critical functions.

Given that conventional NSAIDs can lead serious complications with the digestive system, including ulcers and bleeding from the gastrointestinal tract, and perforations that might require hospitalization or result in death, it is recommended to use Etoricoxib instead. Acute gouty arthritis, rheumatoid arthritis, and osteoarthritis are its primary uses^1-5. Furthermore, there aren't many studies on Etoricoxib that have used HPTLC, UV, and HPLC^6-14. HPLC-MS/MS was used to measure Etoricoxib in human plasma^15-17. ETC (Etoricoxib) was also determined using capillary zone electrophoresis¹⁸, spectrophotometric¹⁹, and HPLC-techniques^20,21. Using HPTLC²², Q-TOF mass spectrometry, and UPLC–ICP-MS²³, ETC was identified in the serum as well as synovial fluid of individuals suffering from inflammatory arthritis. Inorganic components are a critical concern.

Figure 1: Structure of Etoricoxib

The ICP-MS was used to identify the presence of heavy metals in rice, vegetables, cereals, breast milk, nutritional supplements, solid waste, and edible oils and fats, but not in Etoricoxib, according to several published papers²⁴. Monitoring of heavy metals in in-process, intermediate, and final medicinal compounds is essential for the pharmaceutical sector since even at extremely low concentrations, these metals can be dangerous and pose serious health hazards. In many instances, elemental impurities are introduced into therapeutic compounds throughout the synthesis process from multiple sources, including solvents, reagents, electrodes, raw materials, catalysts, reaction containers, and various equipment. The implementation of instrumental methods such as INAA, AAS, XRF, ICP-AES, and very high sensitive ICP-MS is critical for the precise identification of inorganic metal impurities in pharmaceutical products, thereby enabling rapid analysis of heavy metals^25-30. For the measurement of heavy metals in medicinal materials, the aforementioned techniques AAS, ICP-AES, and ICP-MS are thought to be highly selective, sensitive, and rapid. At half of the maximum allowable concentration (MAC), the ICP-MS offers enhanced accuracy and precision at high throughput, eliminating the need for supplementary accessories, and it remains as sensitive as the previously discussed techniques³¹. There are currently no reports in the literature on utilize of the ICP-MS method to determine the presence of 8 heavy metals in Etoricoxib. Therefore, utilizing the microwave-assisted acid digestion ICP-MS method, the current work concentrated on determining the presence of some specific heavy metals in Etoricoxib (Fig. 2).

MATERIALS AND METHODS:

Instrumentation:

Taking into account the parameters, the Thermo ICP-MS model 2030 with AGILENT was used to perform the heavy metals analysis. The following are the terms of operation: A Nebulizer Plasma; Spray chamber temperature: 2°C; gas flow rates: 1.05 Helium Gas Flow: 15 L/min; ICP RF power: 1550 W; gas flow rates: 4.3.

Reagents and materials:

The solutions used included trace metal grade Nitric acid (Fluka), along with Cadmium, Lead, Arsenic, Mercury, Vanadium, Nickel, Iron, and Aluminum, all sourced from Inorganic Ventures, as well as Indium (ICP grade). A Tuning Solution from Agilent and Milli-Q water were also part of the preparations, along with Hydrogen Peroxide (Merck AR grade). All solution preparations were performed in a fume hood for safety.

Nitric acid is utilized in ICP-MS measurements as a reagent blank and a washing solution because it exhibits the least complex spectra of all acids and the lowest background levels relative to pure water. Consequently, it is crucial to select the appropriate grade of nitric acid, such as ICP grade from Fluka, Batch No.: 1117050, for effective elemental analysis.

Preparation of solutions Diluent:

Added around 20mL of concentrated nitric acid (69%) to a 1000mL flask that already holds 300mL of water, and then dilute to the final volume with more water.

Preparation of standard stock solutions:

Preparation of Standard Stock Solution-A (10ppm):

To create Standard Stock Solution-A (10ppm), transfer 0.5mL each of the 1000ppm standard solutions of lead (Pb), cadmium (Cd), and arsenic (As) into a 50mL polypropylene tube or volumetric flask, and fill to the mark with the diluent.

To prepare Standard Stock Solution-B, combine 1.25 mL each of Pb and Cd, along with 3.75mL of As from the previously prepared Standard Stock Solutions-A. Additionally, add 0.075mL of Hg, 0.25mL of V, 0.50 mL of Al, 0.50mL of Fe, and 0.50mL of Ni from 1000 ppm standard solutions into a 50mL polypropylene tube or volumetric flask, and fill the remainder of the volume with diluent to achieve a concentration of 0.25ppm.

For the preparation of the 100% Standard Solution, transfer 0.8mL each of Al, Cd, Pb, Hg, V, As, Ni, and Fe from Standard Stock Solution-B into a 50mL polypropylene tube or volumetric flask. Complete the preparation by adding diluent to reach the desired volume.

To prepare the sample solution, weigh 0.2g of the sample and lay it into a microwave digestion vessel. Add 5mL of nitric acid and 2mL of H₂O₂. Digest the sample according to the specified digestion conditions. Once digestion is complete, transfer the sample into a 25 mL polypropylene tube and dilute to the required concentration using diluent.

Spiked 100% Sample solution:

In the preparation of the spiked 100% sample solution, 0.2grams of the sample were placed into a microwave digestion vessel. Subsequently, 5ml of HNO₃ and 2ml of H₂O₂were added, along with 0.4ml each of cadmium, lead, arsenic, mercury, vanadium, nickel, aluminum, and iron sourced from a 100% standard solution. The sample underwent digestion according to the specified parameters. After digestion, it was transferred to a 25ml polypropylene tube and diluted to the appropriate concentration with a diluent.

Sample solution preparation in the microwave digestion system:

Sample digestion for validation was executed within a closed system that ensured controlled temperature and pressure conditions. An Xpert microwave (Berghof, Germany) with Teflon containers was utilized for this process. The parameters for the microwave digestion process were configured to 150°C, incorporating a 5-minute ramp time, a 25-minute hold time, and a power setting of 1200 watts to thoroughly decompose Etoricoxib. The preparation of the sample blank solution mirrored that of the sample preparation, omitting the sample itself.

Blank Sample solution’s preparation:

Without any preparation of the sample, it was inserted into the microwave digestion vessel. In this vessel, 5ml of aforementioned acid and 2ml of H₂O₂were subsequently added. Following this, 0.4ml of cadmium, lead, arsenic, mercury, vanadium, nickel, aluminum, and iron from a 100% standard solution were transferred. The digestion was carried out under the specified conditions. After digestion, the sample was moved to a 25ml polypropylene tube and diluted to the desired concentration with an appropriate diluent.

Validation of the proposed method:

Designing an experiment to test Specificity and analyzing the data:

The term specificity denotes the capacity of a method to accurately identify the analyte in the presence of various components, including 8 elemental impurities, which may be present in the sample, namely Etoricoxib. By using ICP-MS analysis to measure the interference between blank and standard solutions, specificity was evaluated. Table 1 is evidence for that the interference between the test and blank blanks was less than 3.0%, indicating that the approach is specific. This assessment involved aspirated standard blank, calibration standards, calibration blank (ten repetitions), and the standard check solution, with the findings represented as recovery of concentration.

Designing an experiment to test linearity and analyzing the data:

The spiked solutions made for the linearity calculation and the experimental analysis of working standard solutions. ICP-MS Masshunter software was used to calculate standard linearity, which was based on the linear regression of the experimental versus the theoretical concentration of five Working Standard (WS0, WS1, WS2, WS3, and WS4) solutions for each element Cd, Pb, As, Hg, V, Ni, Fe, and Al. For each element, the linear regression analysis of the experimental concentration versus the theoretical concentration of the test solutions (levels: QL, L-1 to L-4) was employed to assess the linearity of the samples. If the result exceeded zero, the average concentration of the Level 0 test solution was subtracted from the concentrations of the spiked test solution. The y-intercept, slope, and correlation coefficient (r2) were calculated and displayed (refer to Table 2 to Table 9 and

Figure 2 to Figure 9).

Designing an experiment to test precision and analyzing the data:

"Relative standard deviation," which was determined as a percentage by using the standard deviation divided by the mean of replicated samples, was used in the study to define precision. We examined six distinct sample preparations that were spiked with 8 elements at a 100% level of specification (Working Standard WS2) to ascertain the eight elements concentration for each with the purpose of illustrate the accuracy of the suggested method. Determine the average result and the percentage RSD for the analyte content (μg/g) as indicated to assess the method's precision. According to the results of the ruggedness study, the percentage RSD for the eight elements content (μg/g) for six preparations of each sample spike with 100% level should not exceed 15.0% in order to assess the method's ruggedness.

In the repeatability study (Tables 10 and 11), six distinct sample solutions were prepared, each spiked at a 100% specification level by two different analysts. These solutions were analyzed using the verification method on a different day to evaluate the method's intermediate precision. It is necessary to calculate the average individual %RSD for analyte content (μg/g) and the overall percentage RSD of analyte content (μg/g) to assess both method precision and intermediate precision. The robustness of the ICP-MS technique for Etoricoxib was examined by determining the elements present in six different test preparations and calculating the %RSD for each element. The ruggedness parameter was evaluated through different analyses conducted on different days and using different equipment.

Designing an experiment to test accuracy and analyzing the data:

There are two methods to assess the procedure's accuracy: doping the element's corresponding concentration solution during test preparation and figuring out the amount of trace elements present. A percentage recovery [%] can be used to represent this. As part of the method validation, the specification level concentration of eight elements is spiked into the sample at the Working Standards (WS1, WS2, and WS3) for each element. Recovery investigations were conducted at Level 1, 2, and 3 concentrations. The recovery rate that was obtained was well within the accuracy range of 70% to 150% (Table 9).

Designing an experiment to test sensitivity and analyzing the data:

The primary calibration standard, which corresponds to 25% of the specified level, serves to identify the expected LOQ value, with the LOD value being half that of the LOQ value. In order to establish LOD and LOQ values using a cutting-edge analytical technique, evaluate the blank solution, the LOD solution, and six injections of the LOQ solution (i.e., the 25% specification level) in ICP-MS. The LOD and LOQ for each element were determined in relation to the test concentration (see Table 13). The LOD response was lower than the average significant interference from ten calibration blanks at the mass of each analyte.

Designing an experiment to test Robustness and analyzing the data:

A test of the robustness of the developed ICP-MS technique was conducted. There were minor adjustments made to the microwave digestion settings regarding the acid concentration given to the samples. All samples underwent digestion, followed by dissolution and were analyzed using ICP-MS as per the specified instrumental conditions for the proposed method. Table 7 presents the results as the relative difference between the measurements obtained during the robustness test and the reference measurement, which is based on the repeatability measurement results. The effects of reducing, increasing, and real nitric acid concentrations are referred in Table 7. 8 elements results of the robustness test satisfied the acceptance standards, which state that there must be less than or equal to 1% of the relative deviations between the measurements of samples prepared under the prescribed conditions and those made with changed preparation. Every condition modification that was tested for each element under examination met the requirements and validated the robustness and resistance of the technique employed for the trace elements in the analysis of Etoricoxib.

Batch Analysis:

A triplicate batch analysis was performed in accordance with the quality control procedures for the Etoricoxib API molecule, with the results summarized in Table 13. The current study utilized ICP-MS to analyze eight heavy metals from a single batch, revealing that the results fell well within the specified limits.

RESULTS AND DISCUSSION:

Specificity:

Specificity was evaluated by preparing 100% of the individual elements for Etoricoxib and injecting them into ICP-MS. The assessment involved analyzing the interference between the blank and standard solutions for the elements Cd, As, Hg, V, Ni, Fe, Al, and Pb. The interference noted between the blank and test blank was under 3.0%, confirming the specificity of the method (as detailed in Table 1).

Table 1: 8 elements of specificity data

S. No.	Element Name	Blank response (cps)	LOD solution response (cps)
1	Al	1415.15	73374.84
2	As	658.28	1309.65
3	Cd	4.97	708.175
4	Fe	29609.52	931221.085
5	Hg	172.14	3301.275
6	Ni	386.44	37569.695
7	Pb	861.68	7369.85
8	V	118.25	43107.92

Linearity:

Calibration solutions were employed to establish calibration curves represented by the equation y = ax + b, where y denotes the signal intensity and x signifies the known concentration of the analyte in the calibration solution. Five different concentrations of each element standard were examined in order to assess the ICP-MS method's linearity under the best possible conditions. The counts per second (CPS) were recorded, and calibration curves were plotted across a range from the limit of quantification (LOQ) to 200%.The squared correlation co-efficient was found to be 0.9997 for Aluminum (Fig.3 and Table 2), 0.9998 for Arsenic (Fig.4 and Table3), 0.9999 for Cadmium (Fig.5 and Table4), 0.9997 for Mercury (Fig.7 and Table6), 0.9999 for Iron (Fig.6 and Table5), 0.9998 for Lead (Fig.9 and Table8), 0.9998 for Nickel (Fig.8 and Table7) and 0.9998 for Vanadium (Fig.10 and Table9). For each element (Cd, Pb, Al, As, Cd, Fe, Hg, V, Ni, Pb, and V) in Etoricoxib, the correlation coefficients were R² ≥ 0.999, satisfying the necessary requirements. This confirms the linearity of the ICP-MS method across the specified range of Etoricoxib. The associated results can be found in Table 2-9 (supplementary data).

Table 2: Linearity data of Aluminium

Linearity level		Conc. (PPb)	Corrected 0. /CPS
Aluminium Content	1	40	115334.53
	2	80	292371.39
	3	160	586447.02
	4	240	880521.07
	5	320	1174596.80
	CC		0.9997
	Intercept		-19995.87
	Slope		3749.11

Figure 3: Linear Graph for Aluminium

Table 3: Linearity data of Arsenic

Linearity level		Conc. (PPb)	Corrected CPS
Arsenic Content	1	3	1761.02
	2	6	3990.93
	3	12	7970.75
	4	18	11810.57
	5	24	15750.39
	CC		0.9998
	Intercept		-79.38
	Slope		661.60

Figure 4: Linear Graph for Arsenic

Table 4: Linearity data of Cadmium

Linearity level		Conc. (PPb)	Corrected CPS
Cadmium Content	1	1	1311.38
	2	2	2927.57
	3	4	5659.94
	4	6	8492.32
	5	8	11324.69
	CC		0.9999
	Intercept		-17.61
	Slope		1419.24

Figure 5: Linear Graph for Cadmium

Table 5: Linearity data of Iron

Linearity level		Conc. (PPb)	Corrected CPS
Iron Content	1	40	1832832.65
	2	80	3487235.55
	3	160	7396041.37
	4	240	11104846.92
	5	320	14813653.02
	CC		0.9999
	Intercept		-117911.72
	Slope		46695.44

Figure 6: Linear Graph for Iron

Table 6: Linearity data of Mercury

Linearity level		Conc.(PPb)	Corrected CPS
Mercury Content	1	6	6230.41
	2	12	14058.77
	3	24	26314.63
	4	36	39570.37
	5	48	52827.04
	CC		0.9997
	Intercept		162.21
	Slope		1096.75

Figure 7: Linear Graph for Mercury

Table 7: Linearity data of Nickel

Linearity level		Conc. (PPb)	Corrected CPS
Nickel Content	1	40	71752.95
	2	80	159626.85
	3	160	302374.61
	4	240	454122.25
	5	320	605869.74
	CC		0.9998
	Intercept		1385.29
	Slope		1889.07

Figure 8: Linear Graph for Nickel

Table 8: Linearity data of Plumbum

Linearity level		Conc. (PPb)	Corrected CPS
Plumbum Content	1	1	9798.56
	2	2	25676.55
	3	4	53432.57
	4	6	81188.58
	5	8	108944.60
	CC		0.9998
	Intercept		-3298.97
	Slope		14073.13

Figure 9: Linear Graph for Plumbum

Table 9: Linearity data of Vanadium

Linearity level		Conc. (PPb)	Corrected CPS
Vanadium Content	1	20	81097.59
	2	40	180297.72
	3	80	344703.90
	4	120	517110.09
	5	160	689516.32
	CC		0.9998
	Intercept		698.21
	Slope		4307.70

Figure 10: Linear Graph for Vanadium

Precision:

The %RSD values for each element were determined as follows: 0.76 for aluminium (Al), 1.7 for vanadium (V), 0.44 for iron (Fe), 0.26 for nickel (Ni), 0.89 for arsenic (As), 1.81 for cadmium (Cd), 0.58 for mercury (Hg), and 1.68 for lead (Pb). The total %RSD for the concentrations of 8 elemental impurities (μg/g) across twelve preparations, which included evaluations of method precision, intermediate precision, sample spiking at a 100% level of repeatability, and ruggedness studies, did not surpass 20.0%.

Table 10: Repeatability data of 8 elements

Standards		Preparations						Mean	SD	% RSD
Standards		@1	@II	@III	@IV	@V	@VI	Mean	SD	% RSD
Al	Weight of sample in (gm)	0.20092	0.20087	0.20082	0.20077	0.20072	0.20067	79.08	0.601	0.76
	Corrected Conc (ppb)	159.76	158.92	158.08	157.24	156.41	158.56
	Al content in ppm	79.88	79.46	79.04	78.62	78.205	79.28
V	Weight of sample in (gm)	0.20092	0.20087	0.20082	0.20077	0.20072	0.20067	40.19	0.684	1.70
	Corrected Conc (ppb)	80.98	81.98	79.05	81.74	79.78	78.81
	V content in ppm	40.49	40.99	39.525	40.87	39.89	39.41
Fe	Weight of sample in (gm)	0.20092	0.20087	0.20082	0.20077	0.20072	0.20067	80.12	0.355	0.44
	Corrected Conc (ppb)	161.2	160.09	161.04	159.98	159.52	159.65
	Fe content in ppm	80.6	80.045	80.52	79.99	79.76	79.83
Cd	Weight of sample in (gm)	0.20092	0.20087	0.20082	0.20077	0.20072	0.20067	2.03	0.037	1.81
	Corrected Conc (ppb)	4.12	3.97	4.11	3.99	4.05	4.15
	Cd content in ppm	2.06	1.99	2.06	2.00	2.03	2.08
Ni	Weight of sample in (gm)	0.20092	0.20087	0.20082	0.20077	0.20072	0.20067	79.92	0.207	0.26
	Corrected Conc (ppb)	160.24	159.35	160.22	160.06	159.33	159.78
	Ni content in ppm	80.12	79.68	80.11	80.03	79.67	79.89
As	Weight of sample in (gm)	0.20092	0.20087	0.20082	0.20077	0.20072	0.20067	6.01	0.054	0.89
	Corrected Conc (ppb)	12.12	11.91	12.09	11.85	12.06	12.04
	As content in ppm	6.06	5.96	6.05	5.93	6.03	6.02
Hg	Weight of sample in (gm)	0.20092	0.20087	0.20082	0.20077	0.20072	0.20067	11.98	0.070	0.58
	Corrected Conc (ppb)	24.07	24.14	23.79	23.82	23.96	24.03
	Hg content in ppm	12.035	12.07	11.90	11.91	11.98	12.02
Pb	Weight of sample in (gm)	0.20092	0.20087	0.20082	0.20077	0.20072	0.20067	2.01	0.034	1.68
	Corrected Conc (ppb)	4.07	4.09	3.91	3.97	4.05	4.02
	Pb content in ppm	2.035	2.05	1.96	1.99	2.03	2.01

Table 11: Intermediate precision data of 8 elements

Standards		Preparations						Mean	SD	% RSD
Standards		@1	@II	@III	@IV	@V	@VI	Mean	SD	% RSD
Al	Weight of sample in (gm)	0.20063	0.20081	0.20042	0.20017	0.20022	0.20037	80.17	0.624	0.78
	Corrected Conc (ppb)	159.55	159.14	162.08	159.24	160.41	161.56
	Al content in ppm	79.775	79.57	81.04	79.62	80.205	80.78
V	Weight of sample in (gm)	0.20063	0.20081	0.20042	0.20017	0.20022	0.20037	40.38	0.822	2.04
	Corrected Conc (ppb)	81.98	80.18	78.88	82.74	78.99	81.81
	V content in ppm	40.99	40.09	39.44	41.37	39.50	40.91
Fe	Weight of sample in (gm)	0.20063	0.20081	0.20042	0.20017	0.20022	0.20037	80.02	0.720	0.90
	Corrected Conc (ppb)	161.85	159.04	160.94	159.08	161.12	158.25
	Fe content in ppm	80.925	79.52	80.47	79.54	80.56	79.13
Cd	Weight of sample in (gm)	0.20063	0.20081	0.20042	0.20017	0.20022	0.20037	2.01	0.030	1.50
	Corrected Conc (ppb)	4.06	3.92	4.08	3.97	4.03	4.04
	Co content in ppm	2.03	1.96	2.04	1.99	2.02	2.02
Ni	Weight of sample in (gm)	0.20063	0.20081	0.20042	0.20017	0.20022	0.20037	80.01	0.631	0.79
	Corrected Conc (ppb)	161.24	158.96	161.25	158.99	160.98	158.66
	Ni content in ppm	80.62	79.48	80.63	79.50	80.49	79.33
As	Weight of sample in (gm)	0.20063	0.20081	0.20042	0.20017	0.20022	0.20037	6.04	0.113	1.87
	Corrected Conc (ppb)	12.08	11.98	12.08	11.78	12.03	12.47
	As content in ppm	6.04	5.99	6.04	5.89	6.02	6.24
Hg	Weight of sample in (gm)	0.20063	0.20081	0.20042	0.20017	0.20022	0.20037	11.95	0.133	1.12
	Corrected Conc (ppb)	24.01	24.15	23.55	23.78	24.21	23.68
	Hg content in ppm	12.005	12.08	11.78	11.89	12.11	11.84
Pb	Weight of sample in (gm)	0.20063	0.20081	0.20042	0.20017	0.20022	0.20037	2.00	0.048	2.39
	Corrected Conc (ppb)	4.12	3.91	4.05	4.09	3.97	3.89
	Pb content in ppm	2.06	1.96	2.03	2.05	1.99	1.95

Table 12: Accuracy data of 8 elements

Standards		50% (Trails)			100%(Trails)				150%(Trails)
Standards		@-1	@-II	@-III	@-I	@-II		@-III	@-1	@-II	@-III
Al	Spl. Wt. in (gm)	0.20093	0.20086	0.20049	0.20003	0.20014		0.20028	0.20041	0.20051	0.20087
	Obtained Conc (ppb)	79.95	79.91	80.22	158.92	160.13		159.37	240.34	239.81	240.24
	Amount added (ppb)	80			160				240
	% Recovery	99.94	99.89	100.28	99.33	100.08	99.61		100.14	99.92	100.10
	Average % Recovery	100.03			99.67				100.05
V	Spl. Wt. in (gm)	0.20093	0.20086	0.20049	0.20003	0.20014	0.20028		0.20041	0.20051	0.20087
	Obtained Conc (ppb)	38.95	40.24	39.42	80.35	78.62	79.68		120.53	121.31	119.98
	Amount added (ppb)	40			80				120
	% Recovery	97.38	100.60	98.55	100.44	98.28	99.60		100.44	101.09	99.98
	Average % Recovery	98.84			99.44				100.51
Fe	Spl. Wt. in (gm)	0.20093	0.20086	0.20049	0.20003	0.20014	0.20028		0.20041	0.20051	0.20087
	Obtained Conc (ppb)	78.58	80.21	79.85	159.12	161.02	159.35		241.25	241.35	240.88
	Amount added (ppb)	80			160				240
	% Recovery	98.23	100.26	99.81	99.45	100.64	99.59		100.52	100.56	100.37
	Average % Recovery	99.43			99.89				100.48
Cd	Spl. Wt. in (gm)	0.20093	0.20086	0.20049	0.20003	0.20014	0.20028		0.20041	0.20051	0.20087
	Obtained Conc (ppb)	1.98	2.06	1.98	3.98	4.04	4.03		5.98	6.02	6.08
	Amount added (ppb)	2			4				6
	% Recovery	99.00	103.00	99.00	99.50	101.00	100.75		99.67	100.33	101.33
	Average % Recovery	100.33			100.42				100.44
Ni	Spl. Wt. in (gm)	0.20093	0.20086	0.20049	0.20003	0.20014	0.20028		0.20041	0.20051	0.20087
	Obtained Conc (ppb)	79.66	78.63	80.11	158.69	161.02	158.93		241.02	240.33	240.52
	Amount added (ppb)	80			160				240
	% Recovery	99.58	98.29	100.14	99.18	100.64	99.33		100.43	100.14	100.22
	Average % Recovery	99.33			99.72				100.26
As	Spl. Wt. in (gm)	0.20093	0.20086	0.20049	0.20003	0.20014	0.20028		0.20041	0.20051	0.20087
	Obtained Conc (ppb)	6.16	5.98	5.96	12.31	12.08	12.27		18.33	17.96	17.91
	Amount added (ppb)	6			12				18
	% Recovery	102.67	99.67	99.33	102.58	100.67	102.25		101.83	99.78	99.50
	Average % Recovery	100.56			101.83				100.37
Hg	Spl. Wt. in (gm)	0.20093	0.20086	0.20049	0.20003	0.20014	0.20028		0.20041	0.20051	0.20087
	Obtained Conc (ppb)	12.22	12.19	11.97	24.01	24.35	24.09		36.36	35.92	36.07
	Amount added (ppb)	12			24				36
	% Recovery	101.83	101.58	99.75	100.04	101.46	100.38		101.00	99.78	100.19
	Average % Recovery	101.06			100.63				100.32
Pb	Spl. Wt. in (gm)	0.20093	0.20086	0.20049	0.20003	0.20014	0.20028		0.20041	0.20051	0.20087
	Obtained Conc (ppb)	2.04	1.96	1.98	3.96	4.02	4.11		6.12	6.07	5.97
	Amount added (ppb)	2			4				6
	% Recovery	102.00	98.00	99.00	99.00	100.50	102.75		102.00	101.17	99.50
	Average % Recovery	99.67			100.75				100.89

Table 13: Sensitivity data of 8 elements

S. No.	Element Name	LOD (ppm) with respect to sample concentration (ppm)	LOQ (ppm) with respect to sample concentration (ppm)	Blank response (cps)	LOD solution response (cps)
1	Al	10	20	1415.15	73374.84
2	As	0.75	1.5	658.28	1309.65
3	Cd	0.25	0.5	4.97	708.175
4	Fe	10	20	29609.52	931221.085
5	Hg	0.75	1.5	172.14	3301.275
6	Ni	10	20	386.44	37569.695
7	Pb	0.25	0.5	861.68	7369.85
8	V	5	10	118.25	43107.92

Table 14: Robustness data of 8 elements

Element Name	Preparations						Ave.	STD Dev.	% RSD
Element Name	P-1	P-2	P-3	P-4	P-5	P-6	Ave.	STD Dev.	% RSD
Preparation with 4.7ml of nitric acid (Low)
Al	145302.13	145314.24	145284.53	145223.84	145351.78	145334.08	145301.77	44.88	0.03
As	1958.78	1967.08	1961.45	1958.22	1959.45	1962.31	1961.22	3.28	0.17
Cd	1410.14	1411.38	1412.62	1413.86	1415.1	1416.34	1413.24	2.32	0.16
Fe	1832832.65	1832789.47	1832046.29	1832203.11	1838159.93	1832032.65	1833344.02	2386.10	0.13
Hg	6438.11	6431.25	6433.82	6431.08	6432.75	6432.56	6433.26	2.58	0.04
Ni	74752.12	74708.5	74664.74	74620.84	74576.15	74532.49	74642.47	82.27	0.11
Pb	13815.24	13835.15	13826.37	13808.02	13822.82	13855.68	13827.21	16.76	0.12
V	86097.57	86045.09	86092.51	86055.09	86117.54	86035.09	86073.82	33.17	0.04
Preparation with 5.0ml of nitric acid (Actual)
Al	145302.13	145314.24	145326.35	145338.46	145350.57	145362.68	145332.41	22.66	0.02
As	1972.71	1967.08	1961.45	1956.59	1951.73	1946.87	1959.41	9.63	0.49
Cd	1410.14	1411.38	1432.62	1413.86	1425.1	1416.34	1418.24	8.82	0.62
Fe	1862669.05	1856541.77	1850414.49	1844287.21	1838159.93	1832032.65	1847350.85	11463.09	0.62
Hg	6433.51	6433.32	6433.13	6482.94	6432.75	6439.58	6442.54	19.96	0.31
Ni	74752.12	74708.5	74664.88	74621.26	74577.64	74534.02	74643.07	81.61	0.11
Pb	13716.24	13830.22	13855.06	13874.97	13894.88	13914.79	13847.69	70.87	0.51
V	86107.24	86065.09	85922.61	85940.13	85887.65	85830.17	85958.82	106.39	0.12
Preparation with 5.3ml of nitric acid (High)
Al	145385.23	145304.21	145294.54	145254.82	145225.11	145195.4	145276.55	67.24	0.05
As	1967.91	1964.68	1961.45	1958.22	1954.99	1951.76	1948.53	6.04	0.31
Cd	1403.15	1415.38	1419.61	1417.08	1415.1	1412.04	1413.73	5.75	0.41
Fe	1831772.65	1831919.47	1832066.29	1832213.11	1832359.93	1832516.75	1832141.37	277.36	0.02
Hg	6433.51	6433.32	6434.13	6402.94	6371.75	6340.56	6402.70	39.23	0.61
Ni	74700.79	74707.13	74713.47	74719.81	74726.15	74732.49	74716.64	11.86	0.02
Pb	13843.93	13835.15	13826.37	13817.59	13808.81	13800.03	13821.98	16.43	0.12
V	86447.34	86364.89	86288.44	86199.09	86109.74	86020.39	86238.32	159.87	0.19

Robustness:

A test of the robustness of the developed ICP-MS technique was conducted. There were minor adjustments made to the microwave digestion settings regarding the acid concentration given to the samples. In compliance with the instrumental conditions outlined for the suggested approach, all samples were digested, dissolved, as well as then analysed using aforementioned technique that is ICP-MS. Table 14 presents the findings as the relative difference between the reference measurement (based on the results of repeatability measurement) and the measurements taken during the robustness test. The effects of reducing, increasing, and real nitric acid concentrations are revealed in Table 14. 8 elemental impurities results of the robustness test satisfied the acceptance standards, which state that there must be less than or equal to 1% of the relative deviations between the measurements of samples prepared under the prescribed conditions and those made with changed preparation. Every condition modification that was tested for each element under examination met the requirements and validated the robustness and resistance of the technique employed for the trace elements in the analysis of Etoricoxib.

Batch analysis:

A batch analysis was performed in accordance with the quality control methodology for the Etoricoxib API molecule, with results summarized in Table 15. The current study utilized ICP-MS to evaluate eight heavy metals from one batch, revealing that the results fell well within the specified limits.

Table 15: Batch analysis results of Elemental impurities by ICP-MS

S. No.	Elemental impurities	Results (ppm)	Limits (ppm)
1	Al	0.2	200ppm
2	As	Not Detected	1.5ppm
3	Cd	Not Detected	0.5ppm
4	Fe	1.9	200ppm
5	Hg	Not Detected	3.0ppm
6	Ni	0.01	20ppm
7	Pb	Not Detected	0.5ppm
8	V	Not Detected	10ppm

CONCLUSIONS:

The ultimate goal of this analytical research study was to evaluate trace elements in Etoricoxib properly through development of a new analytical methodology for ICP-MS direct solid analysis. A validated ICP-MS method was developed for the identification of heavy metals such as Mercury, Iron, Cadmium, Arsenic, Lead, Vanadium, Nickel, and Aluminium in Etoricoxib. Various parameters were evaluated for method validation, with detection limits ranging from 0.25 to 10ppm for the eight metals, which aligns with the required quantification limits of 0.5 to 20ppm. The method exhibited strong linearity, indicated by a correlation factor (R²) greater than 0.995. The analytical technique was found to be specific, accurate, precise, reproducible, rugged, linear, and robust. These characteristics ensure that the ICP-MS methodology can be effectively utilized in routine analytical laboratories for monitoring heavy metal content in the production of Etoricoxib. Ultimately, the method is recognized as simple, selective, and cost-efficient, with the capability to detect all eight metals associated with the active pharmaceutical ingredients in Etoricoxib. The use of ICP-MS for quantitative analysis has been validated as a powerful technique for the determination of elemental impurities, particularly relevant for this non-steroidal anti-inflammatory drug.

ABBREVIATIONS:

XRF: X-ray fluorescence spectrometry.

NSAIDs: Non-steroidal anti-inflammatory drugs

Q-TOF: Quadrupole time-of-flight.

ICP-AES: Inductively coupled plasma atomic emission spectrometry.

INAA: Instrumental neutron activation analysis.

AAS: Atomic absorption spectrometry

CONFLICT OF INTEREST:

According to the author of the article, there is no conflict of interest.

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Received on 01.05.2025 Revised on 30.08.2025

Accepted on 31.11.2025 Published on 16.03.2026

Available online from March 18, 2026

Research J. Pharmacy and Technology. 2026;19(3):1091-1101.

DOI: 10.52711/0974-360X.2026.00155

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