VALIDATION OF GAS CHROMATOGRAPHY (GC) METHOD FOR RESIDUAL SOLVENT IN BROMPHENIRAMINE MALEATE (API)

VALIDATION OF GAS CHROMATOGRAPHY (GC) METHOD FOR RESIDUAL SOLVENT IN BROMPHENIRAMINE MALEATE (API)

Sunil B. Lakhmapure ¹, Seema Kothari ¹ and Manohar V. Lokhande ^{* 2}

Department of Chemistry ¹, Pacific University, Udaipur - 313003, Rajasthan, India.

Department of Chemistry ², Sathaye College, Mumbai - 400057, Maharashtra, India.

ABSTRACT: Active Pharmaceutical ingredient (API) of pharmaceutical bulk drug Brompheniramine Maleate (API) was validation by gas chromatography. Aim for this article was to check the Residual Solvents in Brompheniramine Maleate (API) by Gas Chromatographic technique. To validate a Gas Chromatographic method for detection and Quantification of Residual Solvents Methanol, Isopropyl Alcohol, DMSO and -O-Xylene. This technique was developed accurately, and validation parameters such as Accuracy, Specificity, Precision, Linearity and Range, Limit of detection (LOD), Limit of quantitation (LOQ), ruggedness, robustness and system suitability testing are explained. Gas chromatograph equipped with FID detector and headspace injection and column 30 m × 0.32 mm ID × 1.8 µm DB-624 capillary column with column temperature was 40 °C (hold 10 min) to 250 °C @ 40 °C/min, hold at 250 °C for 5 mins. Specificity was retention time for Methanol (2.13), Isopropyl Alcohol (3.45), DMSO (13.90), and -O-Xylene (13.74). The recovery for Methanol % RSD was 2.49, Isopropyl alcohol 1.18, and O-Xylene 1.91. All validation parameters are used in the routine and stability analysis.

GC, Validation, Brompheniramine Maleate, Accuracy and Retention time

INTRODUCTION: The recent analytical techniques normally require specific analytical measurements at very low concentrations, through a variety of instruments. Normally, high-resolution separations have to be achieved with selective chromatographic methods past to analytical purposes ¹. Thus, the data of instrumentation are used in chemical analysis nowadays is of principal status to guarantee future growth in various fields of scientific work.

The best usage of instrumentation with more expressive data generation that can be interpreted constantly is probable only by the improved information of the values of the instrumentations used for measurements well as those utilized to attain several separations ^2-3. Brompheniramine Maleate is the maleate salt form of brompheniramine, an alkylamine derivative, and a histamine antagonist with anticholinergic and sedative properties. Brompheniramine maleate competes with histamine for the H-1 receptor.

This diminishes the actions of histamine on effector cells and decreases the histamine-mediated symptoms of an allergic reaction such as broncho-constriction, vasodilation, increased capillary permeability, and spasmodic contractions of gastrointestinal smooth muscle.

Brompheniramine Maleate is a white to almost white, crystalline powder ⁴. It is soluble in water, freely soluble in ethanol (96 %), in methanol and in methylene chloride. Brompheniramine maleate is the maleic acid salt of brompheniramine. A histamine H-1 receptor antagonist, it is used for the symptomatic relief of allergic conditions, including rhinitis and conjunctivitis. It has a role as an anti-allergic agent. It contains a brompheniramine ⁵. The present study deals with the validation of Residual solvent in Brompheniramine maleate by Cas Chromatography.

MATERIALS AND METHODS:

Materials:

Chemical Name: (3RS)-3-(4-Bromophenyl)-N,N-dimethyl-3-(pyridin-2-yl)propan-1-amine(Z)- butenedioate.

Molecular Formula: C₂₀H₂₃BrN₂O_4,

Molecular Weight: 435.3.

Limits for Residual Solvents: Methanol: NMT 3000 ppm, Isopropyl alcohol: NMT 5000  ppm and O-Xylene: NMT  2170 ppm.

Reagents: Methanol (AR Grade); Isopropyl alcohol (AR Grade); O-Xylene (AR Grade); Dimethyl sulfoxide (AR Grade) and Brompheniramine Maleate sample available from Supriya Lifescience, Mumbai.

Method: Following Instruments/equipment‘ sand reagent was used for the validation studies.

INSTRUMENTS / EQUIPMENT’s

REAGENTS

CHROMATOGRAPHIC CONDITION

Preparation of Standard Stock Solution: Transfer 1275 µL isopropyl alcohol, 750 µL methanol and 505 µL o-xylene into a 100.0 mL of the volumetric flask containing about 80 mL of Dimethyl sulfoxide (DMSO) & mix. Dilute up to the mark with DMSO and mix.

Preparation of System Suitability Solution: Take 5 ml of stock solution in a 100 ml volumetric flask and dilute up to the mark with DMSO.

Preparation of Test Solution: Take accurately about 500 mg of Brompheniramine Maleate 20ml Headspace Vial and add 5 ml of DMSO.

Procedure: Inject blank solution, and sample preparation (in duplicate) records the chromato-gram for all injections.

Calculation:

PPM = Area of sample µl in standard × 5 × 5 × Purity of STD. × Density × 1000000 / Area of Standard × 100 ml × 100 × Wt. of Sample, mg × 100  STD

RESULTS AND DISCUSSION: The resultant peaks of DMSO solvent Fig. 1, methanol solvent Fig. 2, isopropyl alcohol Fig. 3 and O-Xylene solvent, Fig. 4 are given below.

FIG. 1: CHROMATOGRAM OF DMSO SOLVENT

PEAK RESULTS

FIG. 2: CHROMATOGRAM OF METHANOL SOLVENT

PEAK RESULTS

FIG. 3: CHROMATOGRAM OF ISOPROPYL ALCOHOL SOLVENT

PEAK RESULTS

FIG. 4: CHROMATOGRAM OF O-XYLENE SOLVENT

PEAK RESULTS

Specificity: International Council for Harmonization (ICH) defines specificity as “the ability to assess the analyte unequivocally in the presence of components which may be expected to be present. This reserves the use of ‘specific’ for those procedures that produce a response for a single analyte only. Our goal is to distinguish and quantify the response of the target compounds from the responses of all other compounds in Table 1. Analytical techniques that can measure the analyte response in the presence of all potential sample components should be used for specificity validation. It is not always possible to demonstrate that a single analytical procedure is specific for a particular analyte. In this case, a combination of two or more analytical procedures is recommended to achieve the necessary level of discrimination ⁶.

Identification: The retention time of the Brompheniramine maleate peak in the chromatogram of the sample preparation corresponds to that of the Brompheniramine maleate peak in the chromatogram of the Standard preparation. Compare the retention times obtained for Methanol, Isopropyl alcohol, and o-Xylene peaks. Also, inject Diluents (Blank). The data will be processed for Methanol, Isopropyl alcohol, and O-Xylene peaks. Check for the interference from diluents (dimethyl sulfoxide) at the retention time of main peaks of solvents, respectively.

TABLE 1: SPECIFICITY

Precision: The precision of an analytical procedure expresses the closeness of agreement (degree of scattering) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions. Precision was considered at three levels, repeatability, intermediate, and reproductively precision ⁷.

A. System Precision: The system precision is checked by using a standard chemical substance to ensure that the analytical system is working properly. In this retention time and area of six determinations are measured, and % RSD should be calculated. In method precision, a homogenous sample of the single batch should be analyzed six times. This indicates whether a method is giving consistent results for a single batch. In this analysis, the sample six times and calculate known, unknown, and total impurities in the sample calculate the % RSD Table 2.

Experiment: Six replicate injections of the Standard preparation will be made into the GC using the method, and the standard deviation and relative standard deviation (% RSD) of the six replicate injections will be calculated and reported. The % RSD for NMT is 15%.

The % RSD should not be more than 15.0%. The RSD of system precision methanol is 48%, isopropyl alcohol 0.71%, and o-Xylene is 1.52%, respectively and it meets acceptance criteria. Therefore, the GC method for the determination of methanol, isopropyl alcohol, and o-xylene in Brompheniramine Maleate API is precise.

TABLE 2: SYSTEM PRECISION

B. Method Precision: method precision should be performed by determining % assay on six homogeneous samples at working concentration level on one single batch and determining the % RSD of assay value Table 3.

TABLE 3: METHOD PRECISION (SINGLE BATCH)

BDL-Below detection limit, NA – Not applicable

Experiment: Six sample preparations of Brompheniramine Maleate API are to be prepared and injected into the GC using the method as described under Methodology. Prepare six sample preparations, inject, and process as per the Methodology. Report the % RSD of each individual solvent present in the sample.

The % RSD should not be more than 15.0%. Therefore, the GC method for the determination of Methanol, Isopropyl alcohol, and o-Xylene in Brompheniramine Maleate API is reproducible.

Spike Study-1: Spike the Methanol, Isopropyl alcohol and o-Xylene at a 100% concentration of specification level in the sample and inject and process as per the methodology. Separately standard preparation containing a concentration of 100% specification level of Methanol, Isopropyl alcohol, and o-Xylene are also to be prepared and injected and used for quantification of impurities in the sample Table 4. Prepare six sample preparations, inject, and process as per the Methodology. Report the % RSD of each individual solvent present in the sample.

TABLE 4: 100% SPIKE STANDARD SOLUTION

The RSD should not be more than 15.0% and mean of recovery, mean recovery should be in the range of 90.0% to 110.0% for 100% levels. The Mean Recovery is within limits. Therefore, the GC method for the determination of Residual solvents in Brompheniramine Maleate is accurate.

Spike Study 2:

Experiment: Spike the methanol, isopropyl alcohol, and o-xylene a 100% concentration of specification level in the sample and inject and process as per the methodology Table 5.

TABLE 5: 100% SPIKE STANDARD SOLUTION

Mean recovery should be in the range of 90.0% to 110.0% for 100% levels. The mean recovery is within limits Table 6. Therefore, the GC method for the determination of Methanol, Isopropyl alcohol, and o-Xylene Brompheniramine Maleate is accurate.

TABLE 6: 100% OVERALL SPIKE STANDARD SOLUTION

The % RSD should not be more than 15.0%. Therefore, the GC method for the determination of methanol, isopropyl alcohol, and o-xylene in Brompheniramine Maleate API is reproducible.

LOD and LOQ: The highest point of discovery is the time when deliberate esteem is bigger than the liability related to it. It is the most minimal centralization of analyte in an example that can be identified, be that as it may, not evaluated. The farthest point of location is oftentimes mistaken for the affectability of policy ⁸. The affectability of an investigative strategy is the capacity of the technique to separate little contrasts in focus or mass of the test analyte. In down to earth terms, affectability is the incline of the adjustment bend that is gotten by plotting the reaction against the analyte focus or mass. In chromatography, as far as possible, is the infused sum that outcome in a top with size no less than a few times as high as the gauge commotion level. Moreover, this flag/clamor technique depicts three more policies (ICH) ⁹. The point of the limit of Quantification ¹⁰ is the base infused sum that produces quantitative estimations in the objective system with satisfactory precision in chromatography, commonly requiring top statures 10 to 20 times higher than the gauge commotion Fig. 5. Various specimens with diminishing measures of the analyte are infused six times. It is similarly vital to evaluate other technique approval parameters, for example, accuracy, reproducibility, and precision, near the cutoff points of recognition and quantitation. The point of confinement of quantitation to represents both the farthest point of recognition Table 7.

FIG. 5: GRAPH OF LIMIT OF DETECTION

PEAK RESULTS

FIG. 6: GRAPH OF LIMIT OF QUANTIFICATION STANDARD

PEAK RESULTS

Experiment:

Prediction of LOD: To determine LOD/LOQ and show precision at that level, Fig. 6.

Preparation of Stock Solution for LOD: (100 ppm):  Take 10 mg (12.60 µl) of methanol, 10 mg (12.80 µl) of isopropyl alcohol, and 10 mg (11.35 µl) of o-xylene into 100 ml of the volumetric flask, containing 80 ml of DMSO & mix. Dilute up to the mark with DMSO and mix.

TABLE 7: PREDICTION DILUTION SOLUTION FOR LOD

Determine the predicated LOD & LOQ from the above prediction solution. RSD for LOD to NMT is 15%, and RSD for LOQ to NMT is 15%.

Linearity and Range: ICH defines linearity of an analytical procedure as its ability (within a given range) to obtain test results that are directly proportional to the Curve concentration (amount) of analyte in the sample. Linearity may be demonstrated directly on the test substance (by dilution of a standard stock solution) or by separately weighing synthetic mixtures of the test product components ¹¹. The first is to plot the deviations from the regression line versus the concentration or versus the logarithm of the concentration if the concentration ranges over’s several decades, Table 8. For linear ranges, the deviations should be equally distributed between positive and negative values.

Experiment: Prepare six different concentrations of isopropyl alcohol, methanol, and o-xylene concentration values LOQ level, 50, 80, 100, 120, and 150% of the working levels. Prepared concentration at each level should be analyzed in duplicate, from the responses obtained for each conc. level, (y- value) should be plotted against conc. (x- value) using a least-squares of test results versus analyte conc. from regression data, calculate the following   parameters:

Preparation of Linearity Stock Solution: Take 1275 µL of isopropyl alcohol, 750 µl of methanol and 505 µl of o-xylene into 100.0 mL of the volumetric flask containing about 80 mL of dimethyl sulfoxide and mix. Dilute to the mark with dimethyl sulfoxide and mix properly.

TABLE 8: DILUTIONS FOR LINEARITY

A least-square fit graph of the individual area counts against the concentration of methanol Fig. 7, isopropyl alcohol Fig. 8, and o-xylene Fig. 9 will be plotted and the correlation coefficient, slope, and intercept reported Table 9. The range of the analytical method in concentration (µg per ml) will be reported. Correlation coefficient: Not less than 0.99.

TABLE 9: LINEARITY AND RANGE

FIG. 7: LINEARITY GRAPH OF METHANOL

FIG. 8: LINEARITY GRAPH OF ISOPROPYL ALCOHOL                  

FIG. 9: LINEARITY GRAPH OF O-XYLENE

The correlation coefficient should not be less than 0.99. The correlation coefficient meets acceptance criteria. Therefore, the GC method for the determination of methanol, isopropyl alcohol, and o-xylene is linear.

Accuracy (Recovery): ICH defines the accuracy of an analytical procedure as the closeness of agreement between the actual conventional value or an accepted reference value and the value found. Efficiency can also be described as the extent to which test results generated by the method and the true value agree Table 10. The true value for accuracy assessment can be obtained in several ways.

Experiment: Brompheniramine Maleate API will be spiked with methanol, isopropyl alcohol (IPA), and o-Xylene at three different levels 80%, 100%, 120% and 150% of specification limit of solvents in triplicate (in total nine determinations). They will be prepared according to the sample preparation mentioned below.

Preparation of Solvent Recovery Stock Solution: Take 1275 µL of isopropyl alcohol, 750 µl of methanol and 505 µl of o-xylene into 100.0 mL of the volumetric flask containing about 80 mL of dimethyl sulfoxide and mix. Dilute to the mark with dimethyl sulfoxide and mix properly.

TABLE 10: PREPARATION OF 80, 100, 120 AND 150% STANDARD SOLUTION

Preparation of Sample without Spiking (Control Sample): Take accurately about 500 mg of Brompheniramine Maleate in 20ml Headspace Vial and add 5 ml of dimethyl sulfoxide.

Preparation of Sample with Spiking:  Weigh 500 mg of Brompheniramine Maleate in 20 ml Headspace vial and add 5 ml of 80% std. solution. Inject 1.0 ml using Headspace instruments. Calculate the residual solvents of methanol, isopropyl alcohol and o-xylene. Apply correction if required (Prepared in triplicate) same procedure for 100%, 120%, and 150%.

Data Evaluation: For each level and each replicate, the following will be calculated:

(i) Amount added in mg

(ii) % Recovery = Amount recovered/Amount added × 100.

The Mean, Standard deviation, and RSD % will be computed for the twelve determinations and reported along with the above (i) and (ii).

(iii) Amount of recovered calculation formula

PPM = Area of Sample µl in standard × 5 × 5 × Purity of STD. × Density × 1000000 / Area of Standard × 100 ml × 100 × Wt. of Sample, mg × 100 STD

Brompheniramine Maleate was spiked with methanol, isopropyl alcohol, and o-xylene at three different levels 80%, 100%, 120%, and 150% of the specifications in triplicate (in total twelve determinations) and preceded according to the sample preparation described in methodology Table 11, 12 and 13.

TABLE 11:  RECOVERY OF METHANOL

TABLE 12: RECOVERY OF ISOPROPYL ALCOHOL

TABLE 13: RECOVERY OF O-XYLENE

The mean recovery should be in the range of 90.0% to 110.0% for 80%, 100%, and 150% levels.

The mean recovery for all components is within limits. Therefore, the GC method for the determination of residual solvents in brompheniramine maleate is accurate.

Ruggedness:   Ruggedness is not addressed in the ICH documents -4.5 ^12-13. Its definition has been replaced by reproducibility, which has the same meaning. Ruggedness is defined by the USP as the degree of reproducibility of results obtained under a variety of conditions, such as different laboratories, analysts, instruments, environmental conditions, operators, and materials ¹⁴. Ruggedness is a measure of the reproducibility of test results under normal, expected operational conditions from laboratory to laboratory and from analyst to analyst Table 14.

Experiment: Six sample preparations of Brompheniramine Maleate API are to be prepared and injected into the GC using the different column on a different day and injected into a different GC using the method and spike the samples at a 100% concentration of specification level in the sample and inject and process as per the methodology. Separately standard preparation containing a concentration of 100% specification level of methanol, isopropyl alcohol, and o-xylene are also to be prepared and injected and used for quantification of impurities in the sample.

Prepare six sample preparations, inject, and process as per the Methodology. Report the % RSD of each impurity present in the sample.

TABLE 14: RUGGEDNESS

The RSD should not be more than 15.0%. The RSD of system precision methanol is 1.03%, isopropyl alcohol is 1.10, and o-xylene is 1.45%, respectively, and it meets acceptance criteria. Therefore, the GC method for the determination of methanol, isopropyl alcohol, and o-xylene in Brom-pheniramine Maleate API is precise.

Robustness: ICH defines the robustness of an analytical procedure as a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters. Robustness refers to a change of parameters and stress to test a particular analytical method. The importance of demonstrating robustness in a particular analytical method is to meet regulatory and manufacturing standards ¹⁵.

Three sample preparations of Brompheniramine Maleate API are to be prepared and injected into the GC using the method and spike the three samples at a 100% concentration of specification level in sample and inject and process as per the methodology. Separately standard preparation containing a concentration of 100% specification level of methanol, isopropyl alcohol, and o-xylene Table 15 are also to be prepared and injected and used for quantification of impurities in the sample. The blank solution, system suitability solution, and sample preparation will be injected into GC under different chromatographic conditions as mentioned below.

1. Change in flow rate (± 2%)
2. Change in oven temperature.

Experiment: Spike the three samples at a 100% concentration of specification level in the sample and inject and process as per the methodology. Separately standard preparation containing a concentration of 100% specification level of methanol, isopropyl alcohol, and o-xylene are also to be prepared and injected and used for quantification of impurities in the sample. A)  As such a method, B) Change temperature and C) Change in flow rate (±2%).

TABLE 15: OVERALL RSD OF ROBUSTNESS STUDY

The % RSD should not be more than 15%. Robustness of the methods done on the same instruments with a change in temperature and carrier gas flow. Therefore, the GC method for the determination of methanol, isopropyl alcohol, and o-xylene in Brompheniramine Maleate robust. Methanol, isopropyl alcohol, and o-xylene will be calculated & reported along with Standard deviation.

System Suitability: The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was formed to provide a uniform set of guidelines for international use by the pharmaceutical industry.

1. Resolution: The resolution factor between any two peaks should not be less than 2.0.
2. Relative Standard Deviation: Not more than 15%, a standard solution of each standard.
3. Tailing Factor: Should not be greater than 2 for each peak of interest

%RSD of six replicates injections, retention time and area for methanol, isopropyl alcohol, and o-xylene. Standard solution and was recorded as per method on every day Fig. 9, 10, and Table 16.

FIG. 9: CHROMATOGRAM OF STANDARD SOLUTION

PEAK RESULTS

FIG. 10: CHROMATOGRAM OF SAMPLE SOLUTION

PEAK RESULTS

RT= Retention Time, RSD = Relative standard deviation

The relative standard deviation should not be more than 15%. And tailing and experimentation factor should not more than 2, and resolution should not less than 2. System suitability complies with Table 17, 18, 19, and 20.

TABLE 17: ACCEPTANCE CRITERIA

TABLE 18: SUMMARY REPORT OF METHANOL

TABLE 19: SUMMARY REPORT OF ISOPROPYL ALCOHOL

TABLE 20: SUMMARY REPORT OF O- XYLENE

CONCLUSION: This procedure is to validate by Gas Chromatography (GC) method of analysis for detection and Quantification of Residual Solvents methanol, isopropyl alcohol, and o-xylene in Brompheniramine Maleate. This method is applicable for quantifying & monitoring the traces of residual solvents methanol, isopropyl alcohol, and o-xylene simultaneously on a routine basis using Gas chromatograph in Brompheniramine Maleate. The recovery of % RSD for Methanol was 2.49, Isopropyl Alcohol 1.18 and O-Xylene 1.91. The residual solvent test method is validated for specificity, the limit of detection, the limit of quantification, linearity, and range, precision, recovery, ruggedness, and robustness are found to be meeting the pre-determined acceptance criteria. The validated method is Specific, LOD, LOQ, Linear, Precise, Accurate, Rugged, and Robust for Residual solvents of Brompheniramine Maleate. On the basis of the above, it was concluded that the developed method of assay for candidate drug was validated as per the ICH guideline

ACKNOWLEDGEMENT: The author, thanks to Mr. Satish Wagh, MD, Dr. Saloni Wagh, and Dr. Prashant Zate, Supriya Life Science Ltd, Mumbai for their cooperation and help to carry out this research work.

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    How to cite this article:

    Lakhmapure SB, Kothari S and Lokhande MV: Validation of gas chromatography (GC) method for residual solvent in brompheniramine maleate (API). Int J Pharm Sci & Res 2020; 11(10): 5039-52. doi: 10.13040/IJPSR.0975-8232.11(10).5039-52.

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