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Vol 3 | Issue 1 | Jan – Mar 2024                                                                                     Indian J Pharm Drug Studies | 16  

Original Article 

Chemo metric assisted Spectrophotometric Method Development through 

Quality by design Approach for the estimation of Bilastine and Montelukast 

sodium in combined solid dosage form   

Bhagyashri D Kolekar1, Namrata N Gawade1, G K Dyade1, Nilesh Y Jadhav2 

From, 1Dept of Post Graduate Studies in Pharmaceutical Quality Assurance, SVPM’S College of Pharmacy, Malegaon (BKII), 

Baramati, Pune, 2SSPM’S Dr N. J. Paulbudhe College of Pharmacy, Survey No 45/1B, Vasant Tekadi, Savedi, Ahmednagar, 

Maharashtra, India      

ABSTRACT 

Objective: Quality by design (QbD) is a systematic process for pharmaceutical development recommended by regulatory agencies 

like USFDA. Development of various pharmaceutical processes including analytical methods by applying Quality by design aids in 

ensuring the robustness of the method. QbD approached chemo metric assisted UV-VIS spectrophotometric analytical method was 

developed for the estimation of Bilastine (BSE) and Montelukast sodium (MKS) from their combined dosage forms. Materials and 

Method: Simultaneous equation method was selected from the nature of spectra, solvent 50 % alcohol was utilised; and for method 

274.5 nm and 351.5 nm was the wavelength for measurement of absorbance of bilastine and montelukast sodium respectively. Effect 

of input variables on spectrum characteristics were studied for selection of critical parameters and developed method was validated as 

per ICH Q 2 R1 regulatory guidelines. Linearity of the drugs was ascertained over the conc range 1-32 mcg/ml (microgram/ml) for 

BSE and 1-20 mcg/ml for MKS. Results and Discussion: The percentage purity of assay was found 98.09 % for BSE and 103.62 % 

for MKS; and the accuracy study data were varied from 0.2523 to 0.5221 for BSE and 0.2512 to 1.2515 for MKS. Precision study was 

shown acceptable data as SD data varied from 0.1902 to 0.5773 for BSE and from 0.2828 to 0.5458 for MKS. Conclusion: The 

developed method is rigid, robust and efficient for the estimation of BSE and MKS from the composition of dosage form. QbD was 

applied to build rigid robust method through risk assessment at early stage and defining the design space at the later stage. 

Key Words: Bilastine, Montelukast Sodium, Qbd, ICH, Simultaneous Equation Method 

ilastine (BSE) chemically 4-[2-[4-[1-(2-Ethoxy 

ethyl)-1H-Benzimidazole-2-yl]-1-piperidinyl] ethyl]-

α, α-dimethyl benzene acetic acid [1] is an 

antihistamine, non-sedative histamine H1 receptor antagonist; 

by binding and preventing activation of H1 receptor bilastine 

reduces development of allergic symptoms due to release of 

histamine from mast cell [2]. Literature survey revealed that 

various analytical methods have been reported for estimation 

of BSE such as UV spectrophotometric methods lonely [3-6],  

UV spectrophotometric method with MKS or other drug [7], 

for estimation of BSE with MKS or other by RP-HPLC [8-14], 

stability indicating RP-HPLC [15-17], green QbD HPLC [18],  

LC-MS/MS [19], stability indicating UPLC [20] and RP-

UFLC [21] alone or in combination with other drugs.  

Access this article online 

Received – 21th Dec 2023 

Initial Review – 30th Dec 2023 

Accepted – 08th Jan 2024 Quick Response Code 

Montelukast sodium (MKS) chemically Sodium [1-[[[(1 

R)-1-(3-[(E) 2-(7-chloroquinoline-2-yl) ethenyl] phenyl)-3-[2-

(1-hydroxy-1-methylethyl) phenyl] propyl] sulfanyl] methyl] 

cyclopropyl] acetate [1] is an anti-asthmatic, leukotriene 

receptor antagonist. It can completely block the binding of 

CYSLT’S to receptor that they can inhibit the binding of 

inflammation mediator LTD4 [2]. Literature survey revealed 

that various analytical methods have been reported for 

estimation of MKS includes UV spectrophotometric method 

lonely [22-28],  UV spectrophotometric method with BSE or 

other drug [29-33], for estimation of MKS Qbd technique 

[34], RP-HPLC methods [35-40], stability indicating HPLC 

with other [41-43] and HPTLC [44] alone or in combination 

with other drugs. Montelukast sodium is official in Indian and 

British Pharmacopoeia [45, 46]. Chemical structure of both 

these drugs is shown in (Figure 1).  

_________________________________________ 

Correspondence to: G K Dyade, Department of PG Studies 

in Pharm Quality Assurance, SVPM’S College of Pharmacy, 

Malegaon (BKII), Baramati, Pune, Maharashtra, India. Email: 

pharmacyresearchsvpmcop@gmail.com  

B 

mailto:pharmacyresearchsvpmcop@gmail.com


D Kolekar et al.                    Chemometric assisted QbD method for estimation of bilastine and montelukast sodium 

Vol 3 | Issue 1 | Jan – Mar 2024                                                                                     Indian J Pharm Drug Studies | 17  

 
Figure 1: Chemical structure of Drug molecule 

Quality by design concept is applied for the development 

of pharmaceutical processes to assure a predefined product 

quality. QBD concepts are mentioned in ICH guidelines Q8 

(R2) (Pharmaceutical development), Q9 (Quality risk 

management), and Q10 (Pharmaceutical quality system) [47-

49] shown in (Figure 2). ICH guidelines Q8 (R2) defines 

QBD as a “a systematic approach to development that begins 

with predefined objectives and emphasizes product and 

process understanding and process control, based on sound 

science and quality risk management”[50]. QBD approach in 

analytical method summarizes a complete understanding of 

how the analytical technique attributes and operating 

conditions affect the analytical performance. Factors to study 

in analytical quality by design (AQbD) approach may include 

the type of analytical technique chosen, reagents used and 

instrument parameters. 

 
Fig No 2: Analytical QbD approach 

There are similar advantages of applying QbD principles 

to analytical methods as to manufacturing processes and 

product [51]. A QbD approach can be beneficial in the 

development of suitable, robust, low cost and eco-friendly 

(eco-friendly solvent, chemicals) method which is applicable 

at any stage of the lifecycle of the product. Also some 

regulatory guidelines have mentioned flexibility of changing 

analytical method without revalidation if the AQbD approach 

has been implemented during analytical method development. 

The first stage of AQbD approach is to fix an analytical target 

profile (ATP) for the method. ATP defines the goal of the 

analytical method development process and it is the sign of 

method performance [52, 53]. For analytical method 

validation ICH Q2 (R1) has given various method 

performance characteristics for an analytical method. In 

development of UV-VIS spectrophotometric method, QbD 

approach was implemented with the study of the effect of 

method input variables on spectral shape, intensity of 

absorbance, and absorbance maxima λmax and critical 

parameters were selected for the proposed method and method 

was validated as per ICH guidelines Q2 (R1).  

MATERIALS AND METHODS  

Instrumentation: Analysis was performed with a Shimadzu 

Double beam UV-Visible spectrophotometer (Shimadzu, 

Kyoto, Japan) with spectral bandwidth of 2 nm and 

wavelength accuracy of ± 1 nm with 10 mm matched Quartz 

cells was used. Electronic balance Afcoset balance (The 

Bombay Burmah Trading corpo Ltd) with accuracy ±0.1 mg 

Model No. ER 200A was utilised for weighing and for 

degassing the solution Digital Ultrasonic cleaner 1.8 Ltr 

(Labman scientific Instruments Chennai) was used. 

Reagents and Chemicals: Pharmaceutically pure samples of 

BSE and MKS from Glenmark Pharmaceuticals, Nashik, 

Maharashtra, India were procured as a gift sample and the 

commercial formulation Bilafav-M Tablet containing bilastine 

20 mg and montelukast sodium 10 mg was procured from the 

local market.  

AQbD approach application in method development: 

AQbD approach was applied to study the influence of input 

variable parameters on spectrophotometric analytical method 

performance shown in (Figure 3). 

 
Figure 3: Diagram showing the relationship between input 

variable parameters and the spectrophotometric method 

performance characteristics 



D Kolekar et al.                    Chemometric assisted QbD method for estimation of bilastine and montelukast sodium 

Vol 3 | Issue 1 | Jan – Mar 2024                                                                                     Indian J Pharm Drug Studies | 18  

Solvent selection: BSE is freely soluble in 10% acetic acid 

glacial, chloroform and in ethanol, slightly soluble in 1 N HCl 

and soluble in 1N NaOH and sparingly soluble in water; 

whereas MKS is very soluble in water, methylene chloride and 

ethanol. Although the solubility of the procured drugs were 

studied in alcohol 90%, 0.1 N HCl and 0.1 N NaOH 

separately; and found that BSE is soluble in ethanol, 0.1 N 

NaOH, slightly soluble in 0.1 HCl however MKS soluble in 

ethanol and insoluble in NaOH and HCl. Both drugs 

solubilises in 50% alcohol, hence selected as a common 

solvent. Each drugs solution with known conc was scanned in 

UV range of 400 nm to 200 nm. It was found that alcohol 50% 

is suitable with respect to stable, robust and precise in 

producing result. 

Preparation of stock solutions and standard solutions: 10 

mg each of drug BSE and MKS were separately and 

accurately weighed; and transferred into separate 25 ml 

volumetric flask. Dissolved into solvent alcohol 50% and 

volume was made to 25 ml with this solvent. Working 

standard solution was prepared by diluting 5 ml to 10 ml with 

50 % alcohol. Subsequent standard solution of each drug with 

conc 16μg/ml was prepared by diluting aliquot of stock 

solution to 10 ml with 50% alcohol into 10 ml capacity 

volumetric flask. 

Selection of wavelength and conc range: From UV spectra it 

was found that BSE has measurable absorbance at 274.5 nm 

and 281.5 nm (Figure 4) and less interference was observed 

by MKS; similarly MKS has maximum absorbance at 351.5 

nm and negligible interference by BSE was accounted. 

Chemometric method using simultaneous equation was 

applied and which was reasonable remedy to overcome 

interference at each other’s absorbance. To study linearity, 

working conc range 1 to 32μg/ml for BSE and 1 to 20μg/ml 

for MKS was selected. Also combined drug solution was 

prepared simulated to marketed formulation. Selected critical 

parameters based upon above discussion, observations were 

listed in (Table 1) and by using these; method was validated 

as per ICH guidelines and by analysing marketed preparations. 

Experimental Method for estimation: From the overlain 

spectra simultaneous equation method was applied for estima-

tion of both the analytes from their combined dosage form. 

 
Figure 4: Overlaid spectra of BSE and MKS 

Table No 1: Selected critical parameter for UV-VIS 

analytical method of BSE and MKS 

Parameter 

Selected variables for simultaneous 

equation method           

BSE MKS 

Wavelength 274.5 351.5 

Solvent 50% alcohol 50% alcohol 

Scan speed Fast Fast 

Sampling interval 0.2 nm 0.2 nm 

Simultaneous Equation Method for estimation of bilastine 

and montelukast sodium: BSE was shown maximum 

absorbance i.e. λmax at 274.5 nm where moderate interference 

by MKS found and MKS has maximum absorbance i.e. λmax at 

351.5 nm where negligible interference by BSE observed. At 

274.5 nm the λmax of BSE, the MKS was shown consistency in 

the absorptivity; hence two wavelengths 274.5 and 351.5 nm 

were considered as 1 and 2 respectively for the said method to 

estimate BSE and MKS. The equation A= abc was applied for 

x (BSE) and y (MKS) determination. Working standard 

solutions of BSE and MKS containing 12μg/ml conc were 

separately prepared and used for the method.   

 

Where      CX = Conc of BSE in sample solution 

A1 and A2 = absorbance of sample solution at 1 and 2 

wavelength 

ay1 and ay2 = absorptivity of MKS at 1 and 2 wavelength of 

standard solution  

ax1 and ax2 = absorptivity of BSE at 1 and 2 wavelength of 

standard solution   

Cy = Conc of MKS in sample solution 

As = Absorbance of Sample solution at 2 wavelength 

VALIDATION of the METHOD 

Selected critical parameters should meet the performance 

characteristics of the analytical method so as to attain 

analytical target profile of the method. An ICH guideline Q2 

R1 was applied to study methods performance with critical 

parameters in order to implement AQbD approach. The 

method was validated as per ICH guidelines 

System suitability: System suitability is studied to 

demonstrate the suitability of the developed procedure under 

consideration for the analytical method. Six replicates of 

working standard solutions with conc 20μg/ml and 16μg/ml of 

BSE and MKS respectively were prepared separately and 

absorbance was recorded, calculated SD and % RSD of the 

response. 



D Kolekar et al.                    Chemometric assisted QbD method for estimation of bilastine and montelukast sodium 

Vol 3 | Issue 1 | Jan – Mar 2024                                                                                     Indian J Pharm Drug Studies | 19  

Linearity: The linearity of an analytical method is its ability 

to obtain response i.e. absorbance which is directly 

proportional to the conc of analyte. Series of working standard 

solutions were prepared in conc. range of 1-32 μg/ml for BSE 

and 1-20 μg/ml for MKS and scanned in 400 to 200 nm range 

in spectrum mode of the spectrophotometer, absorbance of the 

standard solutions were recorded at their respective 

wavelength; i.e. 274.5 for BSE and 351.5 nm for MKS in 

spectrum order. Microsoft office excel software tool was used 

to obtain the standard regression curve and its analysis as 

slope, intercept, and correlation coefficient.  

Assay of formulation: Assay was carried out by proposed 

methods and assay was validated by statistical parameters. 

Estimation of formulations by simultaneous equation 

method: Tablet powder equivalent to 10 mg BSE and 5 mg 

MKS was weighed and transferred into 25 ml volumetric 

flask. Dissolved into 50% alcohol, mixed well for 10 mins and 

volume was made to 25 ml with the solvent. Solution was 

filtered through what man filter paper and aliquots of solution 

were further diluted with the 50% alcohol to obtain tablet 

sample solution. Solution was scanned in the range of 400 to 

200 nm to obtain absorbance of tablet solution at 274.5 nm 

and 351.5 nm in spectrum order. Obtained absorbance were 

utilised to estimate unknown conc of formulation; and results 

were statistically validated to obtain % of nominal conc, 

standard deviation and % of RSD.   

Accuracy and Precision: The accuracy of an analytical 

method expresses the closeness of an agreement between test 

result and true result. Accuracy study was performed by 

recovery study i.e. standard addition method; diluted standard 

solutions of BSE and MKS were prepared and standard 

solutions added in 80,100 and 120% proportionate to the 

tablet solution. Three replicates at each of these three levels 

were prepared, measured and % of conc, SD and RSD were 

calculated. The precision study was carried out by performing 

assay of tablet six times; also the reproducibility in result was 

studied by inter day and intraday precision.  

Limit of Detection (LOD) and Limit of Quantitation 

(LOQ): The LOD and LOQ of BSE and MKS by the 

proposed method were determined using calibration graph 

method and calculated as 3.3σ/s and 10 σ/s for LOD and LOQ 

respectively; σ is the standard deviation of calibration curve 

and s is the slope of regression line. 

Robustness and Ruggedness: It is measure of capacity of 

analytical procedure to remain unaffected by small but 

deliberate variations in method parameter. 

RESULTS AND DISCUSSION 

Method development comprises numerous steps, and of which 

solvent selection, selection of method for measurement are 

significant one. Uses of aqueous solvents, eco-friendly 

solvents like hydrotropic have got remarkable weightage due 

to low cost, readily available and environmentally sound. 

Drugs underlying analysis must have appreciable solubility in 

the selected solvent. Chemical structure of the drug and 

physico-chemical properties available in the literature guides 

about use of appropriate solvent in the method.  

From UV spectra two wavelengths were selected as 274.5 

nm (λmax of BSE) and 351.5 nm (λmax of MKS) for calculation 

of both drugs in combined solution shown in (Fig No 4).  

System Suitability: The absorbances of six replicates of 

standard solutions of respective drugs conc are reported in 

(Table No 2). The SD and % RSD was found for BSE and 

MKS and meets the system suitability requirements indicate 

method was suitable for analysis.  

Table No 2: System suitability study of BSE and MKS 

Conc in 

μg /ml 

Absorbance 

of BSE 

Conc in μg 

/ml 

Absorbance of 

MKS 

20 μg /ml 0.3124 16 μg /ml 0.5269 

20 μg /ml 0.3110 16 μg /ml 0.5443 

20 μg /ml 0.3281 16 μg /ml 0.5146 

20 μg /ml 0.3115 16 μg /ml 0.5156 

20 μg /ml 0.3395 16 μg /ml 0.5332 

20 μg /ml 0.3292 16 μg /ml 0.5581 

SD 

RSD 

0.006662 

0.41972 

SD 

RSD 

0.01281 

0.29142 

Linearity: The calibration curve of both drugs was found to 

be linear shown in (Figure 5) in the conc range of 1-32 μg/ml 

for BSE and 1-20 μg/ml for MKS as shown in (Figure 6). The 

regression equation of line and parameters slope, r2 value and 

intercept (Figure 7) are tabulated in (Table 3), which proved 

the linear relationship between conc and obtained response.  

Assay: The assay was carried out by the proposed method. 

The spectrum of formulation by method was shown in (Fig No 

8). The assay of formulation was carried out by proposed 

method and calculated % of nominal conc and RSD was found 

within acceptable limits are summarized in (Table No 4). The 

results indicated applicability of the method for estimation of 

formulation. 

Accuracy and Precision: The accuracy study was carried out 

at 3 levels; and the results of accuracy are summarised in 

(Table 5), the obtained results were within acceptable limit; 

and methods accuracy was justified by calculating % drug 

content. The precision study was carried out by performing 

assay of solutions; further the reproducibility in result was 

studied by interday and intraday precision. The values 

obtained SD and % RSD was shown methods precision and 

are summarised in (Table 5). 



D Kolekar et al.                    Chemometric assisted QbD method for estimation of bilastine and montelukast sodium 

Vol 3 | Issue 1 | Jan – Mar 2024                                                                                     Indian J Pharm Drug Studies | 20  

Limit of Detection (LOD) and Limit of Quantitation 

(LOQ): The LOD and LOQ of BSE and MKS by the 

proposed method were calculated and shown in (Table 6).  

Robustness and Ruggedness: Robustness was studied and 

capacity of analytical procedure to measure analyte was 

remain unaffected by small but deliberate variations in method 

parameter. The analytical method was found rugged during 

development; similarly the result was produced shown in 

(Table 6) by performing the analysis by different analyst. 

 
Figure 5: Overlaid spectra of Bilastine obtained in 

linearity study 

 
Figure 6: Overlaid spectra of Montelukast obtained in 

linearity study 

 
Fig No 7: Calibration curve of BSE and MKS  

Table 3: Parameters of regression equation obtained in 

Microsoft excel 

Parameters BSE MKS 

Detection wavelength 274.5 351.5 

Beer’s law limit  (μg/ml) 1–32 μg/ml 1–20 μg/ml 

Correlation coefficient (r2) 0.9967 0.9998 

Regression equation 

(y = mx + c) 

Y = 0.0203X 

- 0.0037 

 

Y = 0.0302X 

- 0.0013 

 

 
Fig No 8: Spectra of formulation obtained in the assay 

Table 4: Results of assay of formulation by proposed method 

Name of the Formulation - BILAFAV M (Bilastine 20 mg,   Montelukast sodium 10 mg)  B No -23S2GTB843, MFG  Date- Jul 

2023,  EXP  Date–Jun 2025 

Formulation 

 

 

Drug 

 

 

Label Claim 

(mg/Tablet; n=6) 

 

Amount 

found/mg 

 

Drug 

Content    % 

 

Std 

Deviation 

 

% RSD 

 

Method 
BSE 20 19.618 98.092 0.15702 0.16092 

MKS 10 10.362 103.62 0.21932 0.24942 

Table No 5: Results of accuracy and precision  

Parameter Level of study Drug Name S.D. % RSD 

Precision 

Intraday Precision 
BSE 0.19025 3.9635 

MKS 0.28281 0.2828 

Inter day precision 
BSE 0.57732 0.83165 

MKS 0.54582 0.64584 

Accuracy study of BSE and 

MKS 

80% 
BSE 

 

0.25236 0.21612 

100% 0.28842 0.24982 

120% 0.52218 0.44192 

80% MKS 0.25123 0.34451 



D Kolekar et al.                    Chemometric assisted QbD method for estimation of bilastine and montelukast sodium 

Vol 3 | Issue 1 | Jan – Mar 2024                                                                                     Indian J Pharm Drug Studies | 21  

100% 0.68602 0.88492 

120% 1.25152 1.81023 

Table No.6: Results of LOD and LOQ, robustness  

Parameters BSE MKS 

LOD μg/ml 0.7253 0.6726 

LOQ μg/ml 1.1761 0.8458 

Robustness 

(conc 20 BSE and 16 μg/ml 

MKS)  0.3724 -to- 0.3973  (± 2 nm) 0.5308 -to- 0.5229 (± 2 nm) 

Ruggedness 

Analyst 1 
SD ± 0.20681 

RSD ± 3.53719 

SD ± 0.64246 

RSD ± 2.9893 

Analyst 2 
SD ± 0.20167 

RSD ± 5.16971 

SD ± 0.062412 

RSD ± 2.55771 

 

CONCLUSION 

Both the drugs were estimated from their combined 

formulation by simultaneous equation method. Results were 

found within acceptable limits, statistical data obtained were 

shown rigidity of the method. The validated method was 

employed 50% alcohol as solvent thus become economical. 

The proposed method is precise, accurate, robust and 

reproducible hence can be routinely used for simultaneous 

estimation of bilastine and montelukast sodium from combined 

dosage form 

ACKNOWLEDGEMENT 

Authors are thankful to Glenmark Pharmaceuticals, Nashik, 

Maharashtra. India for providing drugs as gift sample and 

Management, Principal of SVPM’S College of Pharmacy 

Malegaon (BKII),Baramati Dist. Pune, Maharashtra, India for 

providing necessary facilities, chemicals, instruments etc. for 

research. 

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D Kolekar et al.                    Chemometric assisted QbD method for estimation of bilastine and montelukast sodium 

Vol 3 | Issue 1 | Jan – Mar 2024                                                                                     Indian J Pharm Drug Studies | 23  

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How to cite this article: Bhagyashri D Kolekar, Namrata 

N Gawade, G K Dyade, Nilesh Y Jadhav. Chemo metric 

assisted Spectrophotometric Method Development through 

QBD Approach for the estimation of Bilastine and 

Montelukast sodium in combined solid dosage form. Indian 

J Pharm Drug Studies. 2024; 3(1):16-23. 

Funding: None                  Conflict of Interest: None Stated 

 


	Key Words: Bilastine, Montelukast Sodium, Qbd, ICH, Simultaneous Equation Method

