Introduction

In the pharmaceutical sector, analytical methods validation serves as proof that the procedures are appropriate for the task; these procedures must follow a plan that specifies acceptance limits, performance characteristics, and scopes. It is necessary to validate or revalidate analytical procedures before incorporating them into regular analysis¹. Chromatography is an analytical method that separates molecules according to structural or compositional variations. Chromatography typically entails passing a sample over a stationary phase inside the apparatus. Due to their interactions and varying affinities for the stationary support, the molecules in the samples will segregate. Analytical chemistry Investigates, detects, and quantifies matter using tools and techniques. In actuality, the analysis may consist solely of separation, identification, or quantification, or it may be paired with another technique^2,3. Analysis separates the analytes. Analytes are identified through qualitative examination, and the concentration or numerical amount is ascertained through quantitative analysis. Qualitative analysis can determine the presence or absence of a compound, but not its mass or concentration, as they are not quantitative in nature ⁴.

Drug profile

Scheme 1: Structure of Dronedarone5 Click here to view Scheme

Material andmethods Materials

Drug: Dronedarone

Drug is taken from Vidisha analytical.

Reagents: some chemicals and solvents are used,

Methanol from Merk

Acetonitrile from Merk

Water from siddhi laboratory

Instruments

Instruments that were utilized is UV – visible spectrophotometer

The Jasco Model 550 double beam UV-visible spectrophotometer is a reliable and efficient tool for analyzing various types of UV-visible data⁶.

HPLC system

Agilent’s 1260 Infinity II model number, DEAX02386 pump, and DEACX16446 detector are all in use.

KromasilC18 is a 250 x 4.6 mm, 5 µm column that runs on open lab EZ Chrome software.

Table 1: Trial of solution with their chromatographic condition of drug dronedarone 

Trial	Standar d dissolut ion	Colum n	Column dimensio n	Colum n oven temp.	detecto r	wav elen gth	Flo w rate	Mobile phase	Injection volume
1.	Droneda rone 100PPM	Pheno menex C18,	(250 mm X4.6                mm i.d.) 5μm	40°C	U.V.Detector	288nm	1.0ml/ min	Methanol: water (70:30)	20μl
2.	Droneda rone 100PPM	Pheno menex C18,	(250 mm X4.6                mm i.d.) 5μm	40°C	U.V.Detector	288nm	1.0ml/ min	Acetonitril e:            water (70:30)	20μl
3.	Droneda rone 100PPM	Pheno menex C18,	(250 mm X4.6                mm i.d.) 5μm	40°C	U.V.Detector	288nm	1.0ml/ min	Methanol: 0.05% OPAin            Water (70:30)	20μl
4.	Droneda rone 100PPM	Pheno menex C18,	(250 mm X4.6          mm i.d.) 5μm	40°C	U.V.Detector	288nm	1.0ml/ min	Methanol: 0.05% OPAin          Water (65:35)	20μl

Optimal Chromatographic Conditions:  Trial No. 4 is regarded as having optimal chromatography, and it looks like this,

Chromatographic Conditions

Column Dimensions: (250 mm x 4.6 mm i.d.) Column Type: Phenomenex C18 5 μm Temperature of column oven: 40 °C

The detector is a UVdetector. 288 nm is the wavelength. Rate of Flow: 1.0 ml/min

Phase of mobility: Methanol: 65:35 water with 0.05% OPA Injection 20 μl of volume

Sample preparation of Marketed test sample

After being weighed, twenty tablets were moved to a pestle and mortar and ground into a fine powder. Equally combine the ingredients with the butter paper. Once 50 mg of Dronedarone had been weighed out of the powder, it was placed to a 100 mL volumetric flask that had been cleaned and let to dry. After adding 70 milliliters of methanol, the liquid was sonicated by erratic shaking for ten minutes. Allow the solution to reach room temperature after ten minutes, then add methanol to bring the volume up to the proper level. Three to five milliliters of the first filtrate were thrown away after the mixture was filtered using an appropriate 0.45 µ syringe filter.

After adding 20 milligrams of Dronedarone to the mobile phase to dilute the filtered stock solution to a volume of 25 milliliters, the mixture was injected, and the chromatograms and outcomes were noted.

Table 2: The sample was prepared in duplicate and the summary of the preparation process is provided below

Sample	Sample (mg)	Diluted     to (mL)	Volume taken	Diluted     to (mL)
Sample 1	96.7	100	1	25
Sample 2	97.2	100	1	25

 Formula for % Assay calculation

Validation of Rp-Hplc Method

The Dronedarone estimate method has been validated for certain parameters in accordance with ICH guidelines.

Filtration Study

An analytical procedure’s filtration investigation evaluates a filter’s compatibility with the sample, its deposition on the filter bed, and interference from extraneous components⁷.

Stability of Analytical Solution

The stability analysis was conducted on both the test sample and standard solution in a typical laboratory setting, evaluating the solution under standard lighting conditions after 12 and 24 hours ⁸.

Specificity

Specificity is the ability to accurately detect an analyte in the presence of expected components.

The next step is to prepare and inject the solution to demonstrate the method’s specificity⁹.

(Peak purity for test sample and standard solution checked)

Blank (diluent: mobile phase)

Placebo

The standard dronedarone solution

Sample solution for tablet testing¹⁰.

Linearity and Range

Preparation of linearity solution

Linearity refers to an analytical procedure’s ability to produce test results proportionate to the analyte concentration within a given range, with five linearity levels tested ¹¹.

Linearity Dronedarone stock solution

20 milliliters of methanol were used to dissolve 21.30 milligrams of Dronedarone hydrochloride, which is equal to 20 milligrams of Dronedarone. To create 50 mL, 2.5 ml of the stock solution were further diluted with mobile phase ¹². (Parts per million of 50)

Table 3: Linearity levels preparation

Sr. No.	Level (%)	mL      of             stock solution	Diluted       to with mobile phase (mL)	Dronedarone Concentration(µg/mL)
1	10%	0.4	10	2.00
2	50%	2.0	10	10.00
3	100%	4.0	10	20.00
4	125%	5.0	10	25.00
5	150%	6.0	10	30.00

Determination

The mean area was calculated after each level was administered three times. The calibration curve was plotted as mean area on the y-axis against analyte concentration in µg/mL on the X- axis based on the results.

Acceptance criteria

NLT 0.98 is the correlation coefficient. Interception: To be documented

Slope: To be reported

Limit of Detection (LOD) and Limit of Quantitation (LOQ)

The detection limit of an analytical technique refers to the lowest concentration of analyte in a sample that can be identified but may not always be accurately measured ¹³.

Quantitation limit

The quantitation limit of an analytical technique is the lowest concentration in a sample that can be accurately identified, and LOD and LOQ are computed in accordance with ICH Q2R1 recommendations ¹⁴.

The calibration curve was utilized to determine the residual standard deviation of a regression line, and the LOD and LOQ were determined using the following formula ¹⁵.

LOD = 3.3 σ / S

LOQ = 10 σ / S

Were,

σ = represents the regression line’s residual standard deviation.

S = Slope of regression line

Accuracy (% Recovery)

The analytical procedure’s accuracy is determined by the degree of agreement between the discovered and recognized value, with a working concentration of 50-50% and three copies of each accuracy level ¹⁶.

Accuracy levels details

Refer Following table for each sample

Table 4: Accuracy levels

Level (%)	Dronedarone HCl Std (mg)	Placebo (mg)	Diluted to (mL)	Volume taken (mL)	Diluted to (mL)	Dronedarone Concentration (µg/mL)
50	26.8	43.9	100	1	25	10.07
	26.9	43.7	100	1	25	10.10
	26.7	44.2	100	1	25	10.03
100	53.4	44.1	100	1	25	20.06
	53.3	43.8	100	1	25	20.02
	53.4	44.3	100	1	25	20.06
150	79.9	43.9	100	1	25	30.01
	80.1	43.7	100	1	25	30.09
	80.0	44.1	100	1	25	30.05

 Acceptance criteria

The mean recovery and the percentage recovery for every sample should fall between 98 and 102%.

The recommended relative standard deviation is no more than 2.0%.

Precision

Analytical method precision refers to the agreement between measurements from multiple samplings of a homogenous test, with intermediate precision and repeatability being the two types ¹⁷.

Repeatability

Table 5: Precision (Repeatability) Sample details are as follows 

Sample No.	Test powdermaterial (mg)	Diluted to (mL)	Volume taken(mL)	Diluted to (mL)
1	97.2	100	1	25
2	96.9	100	1	25
3	97.3	100	1	25
4	97.1	100	1	25
5	96.8	100	1	25
6	97.4	100	1	25

Acceptance criteria

Each sample’s 90% to 110% as well as the average assay value RSD percentage: NMT 2% for the six-sample assay

Intermediate precision

Analysis is done on a different day to confirm that the results are repeatable. Using the same process as the Repeatability parameter, six samples were created ¹⁸.

Table 6: Intermediate Precision Sample details are as follows

Sample No.	Test powder material (mg)	Diluted to (mL)	Volume taken(mL)	Diluted to (mL)
1	96.9	100	1	25
2	97.2	100	1	25
3	96.8	100	1	25
4	97.4	100	1	25
5	97.1	100	1	25
6	97.3	100	1	25

Acceptance criteria

90% to 110% for each sample and the average assay value

Percentage RSD for six samples of intermediate precision assay: NMT 2

% RSD for each of the 12 samples: 6 tests for intermediate precision and 6 tests for repeatability; NMT 2% for test outcomes.

Robustness

Robustness is a statistic that conveys how reliable an analytical procedure is under typical operating conditions and how resistant it is to tiny, intentional changes in method parameters ¹⁹.

Determination: The Blank and Standard solutions were injected using a variety of chromatographic conditions, as shown below ²⁰.

Variation of ±10% in the flow (± 0.1 ml/min)

Temperature of the column oven has (± 2ºC)

Wavelength variation (± 3 nm).

Results

Preliminary Characterization and Identification of Drug

Color, odour and appearance

Table 7: Color, odour and appearance of Drug

Sr. No	Name	Colour, odour and appearance of drug
1	Dronedarone hydrochloride	White, odorless and Crystalline powder

Melting point determination

Table 8: Melting point of Drug

Sr.No.	Name	Melting                    point                        std. value (°C)	Melting                                 point observed (°C)
1	Dronedarone hydrochloride	142-146 °C	144-148 °C

Solubility study

Table 9: Solubility study of Dronedarone hydrochloride

Sr.No.	Nameof Solvent	Observation	Conclusion	Summary
1	Water	Drug     Particles               seen	Drug was not	The stock solution is prepared using methanol as a diluent.
		after sonication	foundsoluble in water.
2	Methanol	No       Drug             Particles seen after sonication.	Drugwas found soluble in methanol.

Selection of solvent

Methanol was selected as the solvent for dissolving Dronedarone hydrochloride.

Table 10: Optimized Chromatographic Conditions:

Parameter	Description
Mode	Isocratic
Column Name	Phenomenex C18, 250mm*4.6mm, 5μ
Detector	UV Detector
Injection Volume	20 μl
wavelength	288nm
Column Oven temp	40ºC
Mobile Phase	Methanol: 0.05% OPA in Water (65:35 % V/V)
Flow Rate	1.0 ml/min
Run time	8 minutes

Table 11: Results for System Suitability Test of Dronedarone

Sr.no	Standard solution	Area	Asymmetry	Theoretical plates
1	Standard 1	8442067	1.21	7058
2	Standard 2	8463658	1.21	7043
3	Standard 3	8456980	1.21	7047
4	Standard 4	8420621	1.21	7064
5	Standard 5	8476790	1.21	7069
Mean		8452023	1.21	7056
STD Dev.		21555.49178
% RSD		0.26

Figure 1: The standard solution 1 of the system suitability solution is a typical chromatogram. Click here to view Figure

Table 12: Dilsave tablet assay result

Assay results  of Dilsave 400mg tab let sample	Area	% Assay	Mean assay
Sample 1	8269685	98.06	98.50
Sample 2	8386850	98.94

Figure 2: Typical chromatogram Dilsave 400 mg Tablet sample. Click here to view Figure

Table 13: Result of filter study

Results of Filter study Sample description	Area	% Absolute difference
Unfiltered	8453581	NA
0.45 μ PVDF filter	8416258	0.44
0.45 μ Nylon filter	8432560	0.25

 Table 14: Results of Solution stability.

Sample solution timepoint	Area	%Absolute difference	Standard solution timepoint	Area	%Absolute difference
Initial	8449658	NA	Initial	8465823	NA
12 Hours	8425260	0.29	12 Hours	8443582	0.26
24 Hours	8401704	0.57	24 Hours	8428060	0.45

 Table 15: Results of specificity description

Results of specificity description	Observation
Blank	Due to blank, there is no interference at R.T. of Dronedarone
Placebo	No placebo-induced interference at R.T. of Dronedarone
Standard solution	The highest purity was 0.987.
Test solution	The highest purity was 0.981.

 Table 16: Linearity data for dronedarone level

Linearity Data for Dronedarone Level	Concentration(μg/mL)	Area	Mean	% RSD
10%	2.00	826151827692 825207	826350	0.152
50%	10.00	42080754213620 4219894	4213853	0.140
100%	20.00	84390968427679 8450680	8439152	0.136
125%	25.00	1041317510438940 10420807	10424307	0.127
150%	30.00	1256548812540843 12578304	12561545	0.152

Chromatograms

Figure 3: Typical chromatogram of Linearity 10%.  Click here to view Figure

Figure 4: Typical chromatogram of Linearity 50%. Click here to view Figure

Figure 5: Typical chromatogram of Linearity 150%.  Click here to view Figure

Figure 6: Calibration curve of Dronedarone Click here to view Figure

Table 17: Data of linearity of Dronedarone

Sr no.	Parameter	Result value	Acceptance criteria
1	Beer’s linearity range	2.0 -30.0 µg/mL	NA
2	Correlation coefficient (R2)	0.99996	NLT 0.98
3	Intercept	13759.060	To be report
4	Slope	418334.9181	To be report
5	% RSD for area at each level	NA	NMT 2.0

Table 18: Result and statistical data of Accuracy of Dronedarone

Level (%)	Area	Recovered conc (µg/mL)	Added conc (µg/mL)	%Recovery	Mean Recovery	% RSD
50	4190251	9.92	10.07	98.51	98.94	0.589
	4250485	10.06	10.10	99.60
	4183840	9.90	10.03	98.70
100	8490256	20.09	20.06	100.15	99.27	0.858
	8330475	19.71	20.02	98.45
	8411823	19.90	20.06	99.20
150	1256405	29.73	30.01	99.07	99.07	0.636
	7
	12679430	30.00	30.09	99.70
	1250160	29.58	30.05	98.44
	9

Chromatograms

Figure 7: Typical chromatogram of Accuracy 50%. Click here to view Figure

Figure 8: Typical chromatogram of Accuracy 150%. Click here to view Figure

Table 19: Result of Intra- day and Inter- Day Precision for Dronedarone test sample assay

Repeatability	Sample		Test              Sample (mg)	Area	% Assay
	Sample 1		97.2	8330682	98.28
	Sample 2		96.9	8430648	99.76
	Sample 3		97.3	8306720	97.89
	Sample 4		97.1	8352358	98.63
	Sample 5		96.8	8478516	100.43
	Sample 6		97.4	8315835	97.90
	Mean				98.82
	STD DEV				1.050195
	% RSD				1.063
Intermediate precision (Inter-Day)	Sample 1	96.9		8482361	100.38
	Sample 2	97.2		8313504	98.07
	Sample 3	96.8		8242860	97.64
	Sample 4	97.4		8413692	99.05
	Sample 5	97.1		8283025	97.81
	Sample 6	97.3		8467921	99.79
	Mean				98.79
	STD DEV				1.131106
	% RSD				1.145
Repeatability Plus Inter-day	Mean				98.803
	STD DEV				1.04069
	% RSD				1.053

 Table 20: Result of Robustness study of Dronedarone

Change in Parameter	R.T.	Standard area	Asymmetry	Theoretical plates
Wavelength by +3 NM (291 NM)	4.05	7938226	1.22	7289
Wavelength by -3 NM (285 NM)	4.03	7844385	1.19	7281
Flow rate by +10% (1.1 mL/min)	3.66	7336241	1.18	6743
Flow rate by -10% (0.9 mL/min)	4.48	9010416	1.21	7566
Column oven temp by +2ºC (42 ºC)	4.13	8410892	1.23	6936
Column oven temp by -2ºC (38 ºC)	4.12	8435691	1.21	7083

Discussion 

System suitability test

System Suitability Acceptance Criteria

The analyte peak area’s relative standard deviation in standard chromatograms shouldn’t be more than 2.0%.

There should be at least 2000 theoretical plates of analyte peak in standard

The analyte peaks’ tailing factor (asymmetry) in standard chromatograms should be less than 2.0.

Data interpretation

As can be seen from the data given above, the procedure conforms to the requirements for system appropriateness. Therefore, it may be said that the intended analysis can be conducted using the chromatographic method.

Analysis of Marketed Test samples (Assay)

Dilsave 400 mg Tablet

Weight of 20 tablets = 15.5060 gm.

Average weight of tablet = 15.5060 /20 = 0.7753 gm. = 775.3 mg

Acceptance criteria

The assay found should fall within the 90-110% range.

Data interpretation

Based on the aforementioned findings, it can be said that the sample can be utilized for validation because the assay result for the chosen commercial test sample is within the acceptable range.

Validation of Rp-Hplc Method

Filtration Study

The analytical technique’s filtration inquiry assesses the filter’s compatibility with the sample, deposition on the filter bed, and interference from extraneous components on a tablet test sample.

Acceptance criteria

The absolute difference between filtered samples and unfiltered samples is calculated using NMT 2.0.

Data interpretation

PVDF and Nylon filters are both suitable for use as they meet the requirements for filter studies. Since nylon showed smaller absolute difference than PVDF filter, we chose to utilize it.

Solution Stability

The stability analysis was conducted on both test and standard samples in a typical laboratory setting, examining the solution after six, twelve, and twenty four hours under standard laboratory lighting.

Acceptance criteria

NMT 2.0’s absolute stability solution differs from the first solution in percentage terms.

Data interpretation

Testing and standard solutions were proven to be steady for a whole day. Therefore, you can use both solutions for up to 24 hours.

Specificity

Specificity is the ability to accurately detect an analyte in the presence of expected components.

A standard solution was prepared and injected to ensure peak purity.

Acceptance criteria

Blank: There shouldn’t be any disruption at Dronedarone’s R.T. Placebo: At R.T. of Dronedarone, there shouldn’t be any interference. Sample solutions for testing and standards: Maximum purity: 0.95 NLT

Interpretation of the data

The chromatographic technique for Dronedarone met specificity requirements, with both standard and test solutions’ purity peaks within acceptable bounds, without interference from blank or placebo.

Linearity and Range

Linearity is an analytical method’s ability to produce test results directly proportional to the concentration of the analyte in the samples.

The respective linear equation for Dronedarone

Y = M X + C

Y = 418334.9181 x + 13759.060

Where, x = concentration of Analyte in µg/mL

y = is area of peak.

M = Slope C=Intercept

Conclusion

The Dronedarone demonstrated a linear response within the 2.0-30.0 μg/ml range, with a regression value within the limit.

Limit of Detection (LOD) and Limit of Quantitation (LOQ)

σ = 40611.40658 (Residual standard deviation of a regression line)

s = 418334.9181

Detection limit (LOD)

LOD = 3.3 σ / S

LOD = 3.3 x 40611.40658 / 418334.9181

LOD = 0.320 µg/mL

Quantitation limit (LOQ)

LOQ = 10 σ / S

LOQ = 10 x 40611.40658 / 418334.9181

LOQ = 0.971 µg/mL

ACCURACY (RECOVERY)

An analytical method’s accuracy is determined by its closeness to the true value, achieved by applying the method to samples with known analyte amounts.

Overall Recovery: 99.09 %

% RSD for Overall Recovery: 0.627

Acceptance criteria

The recovery rate for each level and overall recovery ranges from 98.0 to 102.0%. The percentage RSD for each level and overall recovery rate for NMT 2.0 is provided. Data interpretation:

The analytical procedure’s recovery was found to be within acceptable criteria at all three levels, and the recovery was not affected by changes in analyte concentration.

Precision

The precision of an analytical method refers to the agreement among individual test results when applied to multiple samplings of a homogenous sample, usually expressed as standard deviation or relative standard deviation.

Acceptance criteria

% Assay: The mean assay value for precision (6 samples), intermediate precision (6 samples), and precision plus intermediate precision (12 samples) ranges from 90-110%.

% RSD: The NMT 2.0 was utilized to calculate the % RSD for precision, intermediate, and precision plus intermediate precision samples.

Data interpretation: The method was found tobe precise and reproducible, with the % Assay and % RSD falling within the acceptance limit.

Robustness

An analytical method’s robustness signifies its ability to withstand minor parameter changes, indicating its reliability during normal usage.

The following modifications have been made under the category of Robustness.

Change in Wavelength

Change in flow rate

Change in column oven temperature

Acceptance criteria

The system suitability acceptance criteria for chromatography should not be failed.

Data interpretation

The system suitability test results were found to be within the limits, indicating a robust analytical method.

Conclusion

The current work’s objective was to create a suitable, accurate, precise, and simple RP-HPLC method.

A survey of the literature revealed that several methods for quantifying dronedarone in bulk or prescription dosage forms have been reported.

In the current work, a new, sensitive, and suitable reversed-phase high performance liquid chromatography method was developed and validated in order to determine dronedarone in bulk dosage form. The developed RP-HPLC technique resolved the analyte using an isocratic procedure.

Acknowledgment

I take this opportunity with pride and enormous gratification to express the feelings of thanks and gratitude from the core of my heart to all individuals who abided with me directly and indirectly throughout the lean and lush phases during the materialization of this thesis.

I would like to thank to our Divine College of pharmacy, Satana for is valuable guidance.

I am also thankful to Vidisha analytical lab providing support and platform for project work.

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

The authors do not have any conflict of interest.

Data Availability Statement

This statement does not apply to this article.

Ethics Statement

This research did not involve human participants, animal subjects, or any material that requires ethical approval.

Informed Consent Statement

This study did not involve human participants, and therefore, informed consent was not required.

Clinical Trial Registration

This research does not involve any clinical trials.

Authors contribution

Rutika B. waghchaure: Data collection, writing original draft, methodology Shivraj P. Jadhav: Project administration, Analysis, writing review and editing Khemchand R. surana: Visualization

Darshan S. sonawane: Data collection, editing of data. Sunil K. Mahajan: Resource and supervision.

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