Residual Solvents by GC-HS Procedure for Etoricoxib: Method Development and Validation Report

 

Komali Sivaprasad¹*, Vardhani Devi Duggirala Parvatha Venkata¹,

Kapavarapu Maruthi Venkata Narayanarao¹, Pulipaka Shyamala²

¹GVK Biosciences Pvt Ltd, Hyderabad, Telangana, India – 500076.

²Physical Chemistry Department, Andhra University, Visakhapatnam, Andhra Pradesh, India – 530003.

 

ABSTRACT:

The intent of this research paper was to describe a “headspace gas chromatography (HGC)” procedure development and its completely validation for the analysis of residuals of methanol (MTL), isopropyl alcohol (IPL), t-butanol (TBL), toluene (TLE) and dimethylformamide (DFL) simultaneously in Etoricoxib (EIB). The experimentations are done on HGC system fitting with flame ionization type detector employing DB-624 silica fused capillary column (stationary phase) and nitrogen gas (mobile phase). The injector port and detector port temperatures were kept at 200 ^oC and 260 ^oC, respectively. N-methyl pyrrolidone was diluent. The MTL, IPL, TBL, TLE, and DFL detection (LOD) and quantitation (LOQ) values were much smaller than their ICH specification level concentrations. The linear corelation evaluated through range of LOQ to 150% of ICH specification level concentrations for MTL, IPL, TBL, TLE, and DFL of ICH. The regression coefficients for MTL, IPL, TBL, TLE, and DFL were ≥0.9950, and the diagrams of theoretic residuals concentration versus gotten peak response are linear. The HGC procedure proposed was represented by great accuracy, precision, ruggedness and specificity. For a minimum of 48 hr, the EIB sample with MTL, IPL, TBL, TLE and DFL is stable while managed to keep at ambient temperature. The current developed and completely validated HGC procedure can run effectively for EIB residual solvents (MTL, IPL, TBL, TLE and DFL) assessing in active pharma ingredient production.

 

 

INTRODUCTION:

Organic solvents are often included in the formulation of drug ingredients, drug products and excipients as reaction media, for separation/purification, and clean-up of devices^1,2. The organic solvents are undesirable in the finished products due to its toxicity, impact on the nature of medication component crystals, and aroma or taste, that would be unsafe for patients^3,4. Numerous processing methodologies or strategies are utilized to eliminate organic solvents^5-7. Certain solvents are still existing after such operations, but in narrow amounts. Organic volatile contaminants (CVC) or residual solvents (ReS) are the terms given to such small amounts of organic solvents.

 

Multiple organic solvents are employed by multiple manufacturers to make the similar prescription drugs. As a consequence, CVC or ReS analysis becomes a complicated analytical activity in pharmaceutical evaluation and monitoring. During standard quality assurance tests, undisclosed CVC or ReS are often discovered. Consequently, we ought to devise a fast and sensitive approach for detecting and quantifying all CVC or RS in pharmaceuticals.

 

Etoricoxib (EIB) is a specific antagonist of cyclooxygenase-2, a pain as well as inflammation-related enzyme. EIB is a representative of cyclooxygenase-2-discriminatory family of nonsteroidal antiinflammatory medicines^8,9. In a range of illness and patient care situations, significant medical researches have established EIB’s analgesic and antiinflammatory potency is at best as effective as, and in few cases superior than, non discriminatory nonsteroidal antiinflammatory medicines. EIB is officially authorised in a majority of countries for a variety of conditions, including acute aching, intense gouty arthritis, chronic low back aching, dysmenorrhea, and chronic therapy for and rheumatoid arthritis osteoarthritis indications and symptoms^10-12. Due to EIB’s greatest clinical significance, the more it is manufactured by numerous companies. The organic solvents, methanol (MTL), isopropyl alcohol (IPL), t-butanol (TBL), toluene (TLE) and dimethylformamide (DFL) are employed during formulation of EIB drug. In accordance with “ICH Q3C (R6)”¹³, permissible limits of MTL, IPL, TBL, TLE and DFL are 3000 ppm, 5000 ppm, 5000 ppm, 890 ppm and 880 ppm, respectively.

 

Headspace gas chromatography (HSC) is a system that involves placing a solid sample or liquid sample in a sealed container till the volatile compounds in sample as well as gas volume achieve equilibrium¹⁴. HSC is recommended by governing authorities and pharmacopoeias for ReS monitoring of active pharma substances and pharma formulations^15-23.   HSC assessment of ReS is now a well-established process^24-28. HSC based evaluation of MTL, IPL, TBL, TLE and DFL in EIB drug was not hitherto available. The intention of this research paper was to develop and completely validate a HGC based procedure for analysis of residuals of MTL, IPL, TBL, TLE and DFL simultaneously in EIB drug.

 

MATERIALS AND METHODS:

CHEMICALS:

The solvents MTL (batch no. SL8SA81985), IPL (batch no. DL76F673292), TBL (batch no. RM15050532), TLE (batch no. SJ8SA81667), DFL (batch no. SK7S670791) and N-Methyl pyrrolidone (batch no. SH8S680815) were make available by “Merck, Mumbai, India”. EIB drug (batch no. EB/A0012/STG-03/02/005) was offered from “GVK Biosciences Private Limited, Hyderabad, India”.

 

Equipments and Conditions for Mtl, Ipl, Tbl, Tle And Dfl Analysis:

HGC system (Aligent, model 7890B) equipped with head space (Aligent, model 1888 N), flame ionization mode detector, Empower Waters version 3 software, 0.45 microns filter membrane was made involved in the analysis of residuals of MTL, IPL, TBL, TLE and DFL simultaneously in EIB drug.

 

The MTL, IPL, TBL, TLE and DFL were separated and evaluated on DB-624 silica fused capillary column of length 30 m, film thickness 3.0 µm and identification 0.53 mm. The mobile phase (carrier gas) is nitrogen gas with a make-up stream of 25 ml/min and a column stream of 2.5 ml/min. Split ratio of 1:2 maintained. Flow of hydrogen and air was 40 and 400 ml/min, respectively. The injector port and detector port temperatures were kept at 200 ^oC and 260 ^oC, respectively. The oven temperature was arranged to 40 °C for 11 min (hold time), then gradually raised to 230 °C at a pace of 20 °C/min and continued at 230 °C for 5.5 min (hold time). The head space settings include maintaining temperatures of 90 °C, 100 °C and 110 °C at vial, loop and transfer line, respectively. The event times in head space settings include 35 min, 18 min, 0.2 min and 0.5 min for chromatography cycle, equilibration, vial pressurizing and injection, respectively. The diluent N-methyl pyrrolidone was employed in all solutions preparation.

 

Solvents Standard Solution:

A common stock solution in N-methyl pyrrolidone containing all selected solvents (MTL, IPL, TBL, TLE and DFL) of EIB drug was prepared to have an ultimate concentration of 15000 ppm for MTL, 25000 ppm for IPL, 25000 ppm for TBL, 4450 ppm for TLE and 4400 ppm for DFL.

 

Through proper dilution of common stock solution in N-methyl pyrrolidone, working solution containing all selected solvents (MTL, IPL, TBL, TLE and DFL) was prepared with an ultimate concentration of 3000 ppm for MTL, 5000 ppm for IPL, 5000 ppm for TBL, 890 ppm for TLE and 880 ppm for DFL. 

 

Six linearity solutions were made using common stock solution diluted with N-methyl pyrrolidone having concentrations span of 90.56 - 4497 ppm for MTL, 59.98 - 7506 ppm for IPL, 70.08 - 7506 ppm for TBL, 7.8 - 1347 ppm for TLE and 141.5 - 1329 ppm for DFL.

 

Blank Preparation:

Pipetted 1.0 ml of N-methyl pyrrolidone diluent into 20 mL head space vial, inserted the septum and then crimped the vial.

 

EIB Sample:

Transferred precisely weighed 100 mg of EIB sample and pipetted 1.0 ml of N-methyl pyrrolidone diluent into 20 mL head space vial, inserted the septum and then crimped the vial.

 

Procedure to Analyse Mtl, Ipl, Tbl, Tle and Dfl in Eib Drug:

Arranged the gas chromatograph to the circumstances stated in section “Equipments and conditions for MTL, IPL, TBL, TLE and DFL analysis” and provide one hour time for the column to equilibrate. Injected N-methyl pyrrolidone diluent (n=1), working standard solvents solution (n=6) and EIB sample (n=1) into the DB-624 silica fused capillary column and analysed the solvents using the HGC procedure proposed. The content of MTL, IPL, TBL, TLE and DFL in EIB sample can be achieved using formulary below:

 

Where, PAS = solvent peak response in EIB sample; APA = average solvent peak response; PAB = solvent peak response in N-methyl pyrrolidone diluent; SC = solvent concentration taken (mg level); SW = EIB sample weight taken (mg levels)

 

RESULTS AND DISCUSSION

HGC PROCEDURE DEVELOPMENT:

EIB was used in liquid and solid dose types. The ReS (MTL, IPL, TBL, TLE and DFL) in EIB should be enumerated in harmony with “ICH Q3C (R6)”¹³. Conferring to “ICH Q3C (R6)” recommendations on impurities, it is deemed those quantities of MTL, IPL, TBL, TLE and DFL that would be tolerable with no justification was 3000 ppm, 5000 ppm, 5000 ppm, 890 ppm and 880 ppm, respectively. The suggested HGC protocol was evaluated for ReS (MTL, IPL, TBL, TLE and DFL) separation and quantitation in EIB.

 

This HGC approach made use of flame ionization mode detector, which come up with an elevated sensitivity. Since it is inexpensive compared with helium, the gas was chosen as nitrogen with 2.5 ml flow stream. For its propensity to liquefy a large range of drug compounds, N-methyl pyrrolidone was considered as the specimen and standard solution preparation solvent. N-methyl pyrrolidone has a higher boiling point (202 °C), so N-methyl pyrrolidone doesn't mess with volatile solvent testing.

 

A DB-624 silica fused capillary column of length 30 m, film thickness 3.0 µm and identification 0.53 mm, which is extensively exercised for ReS determinations, was chosen since this work aim was to establish an effective HGC approach for ReS assessment in EIB drug. The ReS (MTL, IPL, TBL, TLE and DFL) contained in EIB were well segregated from each other and also from N-methyl pyrrolidone diluent, as realized in Figure 1 of indicative chromatogram for the HGC approach using said column. The above observations demonstrated that the DB-624 silica fused capillary column of length 30 m, film thickness 3.0 µm and identification 0.53 mm is the best option for separating all five MTL, IPL, TBL, TLE, and DFL constituents in EIB. The optimized oven temperature was arranged to 40 °C for 11 min (hold time), then gradually raised to 230 °C at a pace of 20 °C/min and continued at 230 °C for 5.5 min (hold time). Finally, with an overall run analysis cycle of around 24 minutes, the an effective HGC approach for ReS (MTL, IPL, TBL, TLE, and DFL) assessment in EIB drug was established.

 

Figure 1: Chromatogram of five MTL, IPL, TBL, TLE, and DFL solvents standard solution

 

VALIDATION:

Limit of detection, specificity, limit of quantitation, linearity, accuracy, robustness, device suitability, and process precision of ReS (MTL, IPL, TBL, TLE and DFL) were investigated as part of the proposed HGC protocol validation, as stated in the ICH synchronized tripartite recommendations^29-31.

 

 

System Suitability:

Using the HGC system (Aligent, model 7890B) equipped with head space (Aligent, model 1888 N) flame ionization mode detector and Empower Waters version 3 software, the resolution flanked by IPL and TBL was calculated. The criteria for device appropriateness was that the resolution (IPL and TBL) between the two could not be shorter than 1.5. It was revealed to be over (4.6 resolution value) the minimal passing threshold. Also %RSD for MTL, IPL, TBL, TLE and DFL peak response in five repeats of working standard solvents solution (3000 ppm - MTL, 5000 ppm - IPL, 5000 ppm - TBL, 890 ppm - TLE and 880 ppm - DFL) injections could not be above than 15%. The results (Table 1) displayed that the analytical HGC system has a passable precision.

 

Table 1: Suitability and specificity results of HGC system

Suitability results
INJ#	Peak response
	MTL	IPL		TBL	TLE		DFL
1	951.04	2107.56		2991.73	782.31		36.3
2	988.72	2169.87		3069.61	805.26		38.45
3	989.32	2122		3005.09	787.45		37.08
4	966.62	2053.49		2909.56	759.07		35.3
5	969.17	2052.19		2908.17	759.09		34.82
6	975.7	2066.41		2928.58	765.39		34.77
Avg.	973.4	2095.3		2968.8	776.4		36.1
STDEV	14.541	46.616		64.511	18.499		1.454
%RSD	1.5	2.2		2.2	2.4		4
Specificity results
Solvents	Retention times of ReS in					Resolution
	Solution A		Solution B
MTL	4.42		4.41			--
IPL	7.34		7.33			13.6
TBL	8.6		8.59			4.6
TLE	15.49		15.49			36.6
DFL	16.51		16.51			14.9

Avg. - average; STDEV – standard deviation; INJ# - injection number;

%RSD – percentile relative standard deviation

Solution A - working standard solvents solution; Solution B - EIB sample spiked with ReS

 

SPECIFICITY:

The EIB sample spiked with ReS (3000 ppm - MTL, 5000 ppm - IPL, 5000 ppm - TBL, 890 ppm - TLE and 880 ppm - DFL), EIB sample, working standard solvents solution (3000 ppm - MTL, 5000 ppm - IPL, 5000 ppm - TBL, 890 ppm - TLE and 880 ppm - DFL) and blank N-methyl pyrrolidone diluent was chromatographed to inspect interference, if any, with N-methyl pyrrolidone, EIB and of the peaks of ReS with each other. Table 1 lists the specificity specifications. At the retention time of either ReS, the N-methyl pyrrolidone diluent and EIB display no interference. MTL, IPL, TBL, TLE and DFL solvents were eluted at diverse retention times. The resolutions between the ReS were above than 1.5. The results (Table 1 and Figure 2) displayed that the analytical HGC procedure proposed has a decent specificity.

 

METHOD PRECISION:

Precision of HGC procedure was determined by injecting 6 EIB samples spiked with ReS (3000 ppm - MTL, 5000 ppm - IPL, 5000 ppm - TBL, 890 ppm - TLE and 880 ppm - DFL) and analysed for the contents of ReS investigated. The content RSD determined data of investigated ReS were MTL – 1.3% RSD, IPL – 1.5% RSD, TBL – 1.2% RSD, TLE – 1.5% RSD and DFL – 4.7% RSD. Since the values are well below the defined limits (the %RSD was fewer than 15%), the HGC procedure is precise in determining the investigated ReS (MTL, IPL, TBL, TLE, and DFL) in EIB drug.

 

Figure 2. [A] Specificity - blank N-methyl pyrrolidone diluent chromatogram; [B] Specificity – EIB sample chromatogram; [C] Specificity – working standard solvents solution chromatogram; [D] Specificity - EIB sample spiked with ReS chromatogram

Detection Limit and Quantitation Limit:

The signal/noise relation was considered to establish the detection and quantitation limits for the investigated ReS (MTL, IPL, TBL, TLE, and DFL) in EIB drug. Signal/noise relation values ≥3 and ≥ 10 were considered as detection and quantitation limits, respectively, of MTL, IPL, TBL, TLE, and DFL. The values of investigated ReS detection (MTL – 27.13 ppm, IPL – 17.99 ppm, TBL – 21.02 ppm, TLE – 2.39 ppm, and DFL – 44.22 ppm) and quantitation (MTL – 90.56 ppm, IPL – 59.98 ppm, TBL – 70.08 ppm, TLE – 7.8 ppm, and DFL – 141.5 ppm) limits are far beneath the ICH prescribed limits. The HGC procedure is, therefore sensitive in determining the investigated ReS (MTL, IPL, TBL, TLE, and DFL) in EIB drug.

 

Linearity:

By injecting investigated ReS linearity solutions well over scope LOQ–150% of specification limit, the linearity of HGC procedure proposed was established. The concentration scope investigated was 90.56 - 4497 ppm for MTL, 59.98 - 7506 ppm for IPL, 70.08 - 7506 ppm for TBL, 7.8 - 1347 ppm for TLE and 141.5 - 1329 ppm for DFL.  The calibration curves for MTL, IPL, TBL, TLE, and DFL were attained with their corresponding peak response. Table 2 displays the linearity records.  The linearity of HGC protocol proposed for MTL, IPL, TBL, TLE, and DFL is confirmed over the whole concentration spectrum (LOQ–150%) relying on the data.

 

Table 2: Linearity results of HGC procedure

Solvents	Range (ppm)	Regression equation	Correlation coefficient
MTL	90.56 - 4497	y = 0.2961 x + 1.2758	0.9997
IPL	59.98 - 7506	y = 0.3069 x - 6.8832	0.9994
TBL	70.08 - 7506	y = 0.4639 x - 8.9255	0.9995
TLE	7.8 - 1347	y = 0.6709 x - 1.9627	0.9995
DFL	141.5 - 1329	y = 0.0380 x - 0.4871	0.9950

y = peak responses of MTL/IPL/TBL/TLE/DFL; x  - concentration (ppm) of MTL/IPL/TBL/TLE/DFL

 

Accuracy:

Through testing three duplicate injections containing EIB drug spiked with studied ReS at 50% of specification level limit, 100% of specification level limit, and 150% of specification level limit, the accuracy of the HGC procedure was resolved. The recovery findings for the examined ReS were in spectrum 100.9 to 103.4% for MTL, 104.4 to 1006.5% for IPL, 105.3 to 106.8% for TBL, 101.2 to 102.7% for TLE, and 99.0 to 103.1% for DFL. Given that the recovery values are well inside the defined limits (80% to 120% recovery), the HGC procedure is accurate in determining the investigated ReS in EIB drug.

 

Robustness:

The robustness of HGC procedure was established by adjusting purposely the experimental settings such as temperatures at column (± 5 ^oC), injector port (± 5 ^oC) and detector port (± 5 ^oC) while holding all other HGC procedure settings constant as mentioned above. EIB samples spiked with ReS (3000 ppm - MTL, 5000 ppm - IPL, 5000 ppm - TBL, 890 ppm - TLE and 880 ppm - DFL) were analysed for the retention times of ReS investigated with the adjusted experimental settings and compared with retention times of ReS investigated obtained with optimised HGC procedure settings. The modified temperatures at column (± 5 ^oC), injector port (± 5 ^oC) and detector port (± 5 ^oC) did not drastically influence the retention time outcomes of ReS. Therefore, the HGC procedure is robust with in ±5 ^oC modifications in temperatures.

 

Stability of Res Solution:

Measurements of the percentage variation of studied ReS (MTL, IPL, TBL, TLE, and DFL) contents were performed with optimised HGC procedure settings at 12 hr, 24 hr and 48 hr for the EIB samples spiked with ReS (3000 ppm - MTL, 5000 ppm - IPL, 5000 ppm - TBL, 890 ppm - TLE and 880 ppm - DFL). The percentage variation (-3.7 to 0.9% for MTL, -4.4 to 1.1% for IPL, -3.8 to 1.5 for TBL, -2.5 to 3.2% for TLE, and -4.7 to 3.9% for DFL) for the examined ReS were inside 15%. The findings presented that when held the ReS solution at room temperature, the examined ReS were sustainable for up to 48 hours in the EIB sample.

 

Ruggedness/Intermediate Precision:

By delivering six EIB samples spiked with ReS (3000 ppm - MTL, 5000 ppm - IPL, 5000 ppm - TBL, 890 ppm - TLE and 880 ppm - DFL) on separate days, columns, HCG systems, and analysts, the intermediate precision being established. Table 3 lists the content assessed data for the investigated ReS (MTL, IPL, TBL, TLE, and DFL) during ruggedness investigation. Since the values are well below the defined limits (i.e., %RSD was fewer than 15%), the HGC procedure proposed is rugged in assessing the investigated ReS (MTL, IPL, TBL, TLE, and DFL) in EIB drug.

 

Table 3: Ruggedness results of HGC procedure

Condition	INJ#	Content (ppm) determined for
		MTL	IPL	TBL	TLE	DFL
Day 1 Column 1 Analyst 1 System 1	1	3056.18	5345.4	5161.64	909.05	867.01
	2	3058.38	5278.62	5094.59	895.53	873.03
	3	3050.59	5250.2	5054.21	889.69	921.35
	4	3025.1	5417.03	5112.23	885.4	811.03
	5	3045.13	5223.43	5039.26	885.72	853.38
	6	3137.92	5396.71	5190.94	914.57	917.52
Day 2 Column 2 Analyst 2 System 2	1	3036.75	5560.13	5187.85	908.24	887.59
	2	3193.05	5912.44	5503.53	965.67	998.07
	3	3246.31	5982.45	5556	971.38	920.61
	4	3059.91	5610.61	5218.54	913.69	881.56
	5	3003.66	5455.04	5077.88	886.17	842.6
	6	3173.07	5767.89	5363.53	937.42	891.16
Avg.		3090.5	5516.7	5213.4	913.5	888.7
STDEV		77.085	255.578	172.241	29.986	47.727
%RSD		2.5	4.6	3.3	3.3	5.4

Avg. - average; STDEV – standard deviation; INJ# - injection number; %RSD – percentile relative standard deviation

 

 

CONCLUSION:

An HGC procedure was proposed in assessing the ReS (MTL, IPL, TBL, TLE, and DFL) in EIB drug. ReS by HGC procedure for EIB drug was realised as specific, rugged, accurate, linear, and precise. Limit of detection, limit of quantification ascertained for all ReS examined (MTL, IPL, TBL, TLE, and DFL) and beneath specification concentration levels. At ambient temperature, ReS stability in EIB solution was identified and maintained constant for up to 48 hr. As a whole, this procedure would be included to determine ReS examined (MTL, IPL, TBL, TLE, and DFL) in EIB samples for common analysis using HGC system.

 

ACKNOWLEDGEMENTS:

Authors are thankful to GVK Bioscience to provide the samples and providing the support for the research work.

 

CONFLICTS OF INTEREST:

Authors declare none.

 

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Accepted on 15.03.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(11):5043-5049.