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Online First                                                                                                                       Indian J Pharm Drug Studies | 1  

 

 

Original Article 

QBD Approach and Chemo metric Method Development for the estimation of 

Metoprolol succinate and Cilnidipine in combined solid dosage form 

G. K. Dyade1, R. B. Jadhav2, Sanket Repal3, Shital Uparwad3, Prashant Suryawanshi3, Aashish Taware3, 

Sonali Khapne3, Shweta Kokare3, Anuse Dnyaneshwar3 

From, 1Asso. Professor, 2Principal, 3M. Pharma Students, Dept of Post Graduate Studies in Pharmaceutical Quality Assurance, 

SVPM’S College of Pharmacy, Malegaon (BKII)-413115 Baramati Dist Pune, Maharashtra, India. 

ABSTRACT 

Background: Development of several pharmaceutical processes including analytical methods by applying Quality by design assists in 

ensuring the robustness of the method. USFDA and other regulatory agencies have recommended implementation of Quality by 

design (QbD) a systematic process for pharmaceutical development along with its significance. Objective: Chemo metric assisted 

UV-VIS spectrophotometric analytical method based on QbD was developed for the estimation of metoprolol succinate (MET) and 

cilnidipine (CIL) from the combined dosage forms. Method: Nature of spectra focused applicability of absorbance correction and 

amplitude modulation methods for estimation of both drugs from the formulations; and 50 % alcohol was being the common solvent. 

For both this method 221 nm and 242 nm was the wavelength for measurement of absorbance of metoprolol and cilnidipine 

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. Result and conclusion: Linearity of the drugs was ascertained over 

the conc range 1-36 μg/ml (microgram/ml) for MET and 1-16 μg/ml for CIL. The percentage purity of assay in method II was found 

103.773 % for MET and 96.825 % for CIL; and the accuracy study data of method I were varied 2.04859 for MET and 1.26321 for  

CIL. Precision study was shown acceptable data as % RSD in method I data varied 0.58894 for MET and 1.15116 for CIL. The 

developed method is rigid, robust and efficient for the estimation of MET and CIL from the composition of dosage form.  

Keywords: Metoprolol succinate, Cilnidipine, QbD, ICH, Absorbance correction method, Amplitude modulation method 

 

ilnidipine (CIL) chemically 1, 4-Dihydro-2,6-

dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic 

acid 2-methyloxyethyl (2E)-3-phenyl-2-propenyl ester 

[1] is a dihydropyridine calcium channel blocker given orally 

in the management of hypertension [2] Reported analytical 

methods for estimation of cilnidipine were includes alone by 

UV spectrophotometric method [3], UV spectrometric 

methods with metoprolol [4, 5] alone UV-HPLC method [6] , 

Stability indicating HPLC [7] QbD based HPLC [8] 

chromatographic methods [9-12] and have been found in the 

literature. Metoprolol succinate (MET) is a beta blocker; used 

in the treatment of hypertension, angina and to reduce 

myocardial infarction [2]. Chemically it is (RS)-1-(Isopropy 

Access this article online 

Received –  20th May 2024 

Initial Review –  13th June 2024 

Accepted – 15th July 2024 

Quick Response Code 

lamino)-3-[p-(2- Methoxyethyl) phenoxy]-2-propan-2-ol 

succinate [1].  

Literature survey revealed that various analytical methods 

have been reported for estimation of MET such as alone UV 

spectrophotometric method [13-16], with other drugs UV 

spectrophotometric method [17-22], bio analytical method 

[23], MET alone by RP-HPLC [24], with other drug by RP-

HPLC [25-30], stability indicating HPLC [31, 32], designed 

and eco-friendly TLC densitometry [33] and HPTLC [34] in 

combination with other drug. Cilnidipine and Metoprolol 

succinate are official in Indian Pharmacopoeia [35], whereas 

Metoprolol is official in BP [36]. Chemical structures of both 

drugs are shown in (Fig 1). Quality by design concept is 

applied for the development of pharmaceutical processes to 

assure a predefined product quality. 

__________________________________________________ 

Correspondence to: G. K. Dyade, Dept of Post Graduate 

studies in Pharmaceutical Quality Assurance, SVPM’S 

College of Pharmacy, Malegaon (BKII)-413115 Baramati Dist 

Pune, Maharashtra, India. 

Email: pharmacyresearchsvpmcop@gmail.com 

C 

pharmacyresearchsvpmcop@gmail.com


Dyade et al.                                            QbD and Chemometric method for estimation of Metoprolol and Cilnidipine 

 

Online First                                                                                                                       Indian J Pharm Drug Studies | 2  

 

 

Fig 1: Chemical structure of Drug molecule 

QBD concepts are mentioned in ICH guidelines Q 8(R2) 

(Pharmaceutical development), Q9 (Quality risk 

management), and Q10 (Pharmaceutical quality system) [37-

39] shown in Fig 2. ICH guidelines Q8 (R2) [40] 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”. 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. QbD was applied to build rigid robust method 

through risk assessment at early stage and defining the design 

space at the later stage. 

 

Fig 2: Analytical QbD approach 

There are similar advantages of applying QbD principles to 

analytical methods as to manufacturing processes and product 

[41]. 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 [42, 43]. For analytical method validation ICH 

Q2 (R1) has given various method performance characteristics 

for an analytical method. Thus a QbD based UV 

spectrophotometric was developed, 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 1900i and 1700 

(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 sample of 

MET was procured from Macleods Pharmaceuticals Ltd. 

Mumbai and CIL from Swapnroop drugs and pharmaceuticals, 

Aurangabad, Maharashtra, India procured as a gift samples 

and the commercial formulation Cilacar-M manufactured by J 

B Chemicals and Pharmaceuticals containing cilnidipine 10 

and metoprolol 50 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 (Fig 3). 

Solvent selection: CIL is very soluble in N, N-Dimethyl 

acetamide, freely soluble in acetone, soluble in methanol and 

practically insoluble in water, whereas MET is freely soluble 

in water, ethanol, methanol and ethyl acetate;. 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 CIL is 

insoluble in both these solvents however MET is soluble in 

0.1 N NaOH. Alcohol 90% was selected as common solvent 

as both drugs have solubility. Each solution with known conc 

of analyte was scanned in UV range of 400 nm to 200 nm. It 



Dyade et al.                                            QbD and Chemometric method for estimation of Metoprolol and Cilnidipine 

 

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was found that suitable solvent is alcohol 90% with respect to 

stable, robust and precise in producing result. 

Fig 3: Diagram showing the relationship between input 

variable parameters and the spectrophotometric method 

performance characteristics 

Preparation of stock solutions and standard solutions: 10 

mg each of drug CIL and MET were separately and accurately 

weighed; and transferred into separate 25 ml volumetric flask. 

Dissolved into alcohol 90% solvent and volume was made to 

25 ml with solvent. Subsequent standard solution of drug 

MET with conc 16μg/ml and CIL with conc 8μg/ml were 

prepared by diluting aliquot of stock solution to 10 ml with 

50% alcohol into 10 ml capacity volumetric flask. 

Selection of method, wavelength and conc range: From UV 

spectra it was found that CIL has measurable absorbance at 

242 nm (Fig 4) and less interference was observed by MET; 

similarly MET has maximum absorbance at 221 nm (Fig 4) 

and measurable interference having constant absorptivity by 

CIL was accounted. Chemo metric method i.e. absorbance 

correction method was applied and which was reasonable 

remedy to overcome interference at each other’s absorbance, 

and other method was amplitude modulation method. From 

the nature of spectra to study linearity, working conc range 1 

to 16 μg/ml for CIL and 1 to 36μg/ml for MET was selected. 

Also combined drug solution was prepared simulated to 

marketed formulation. Selected critical parameters based upon 

above discussion, observations are listed in and by using 

these; method was validated as per ICH guidelines and by 

analysing marketed preparations. 

Experimental Method for estimation: From the overlain 

spectra absorbance correction method was applicable for 

estimation of both the analytes from the combined dosage 

form. 

Method-I: Absorbance correction method for estimation of 

MET and CIL: MET was shown maximum absorbance i.e. 

λmax at 221 nm where measurable interference with constant 

absorptivity by CIL found and CIL has maximum absorbance 

i.e. λmax at 242 nm where negligible interference observed by 

MET. At 242 nm the λmax of CIL, MET was shown 

consistency in the absorptivity; hence two wavelengths 221 

and 242 nm were considered as 1 and 2 respectively for the 

said method to estimate MET and CIL. The equation A= abc 

was applied for x (MET) and y (CIL) determination. Conc of 

working standard solutions of MET and CIL containing 28 

mcg/ml and 8 mcg/ml conc respectively were separately 

prepared and used for the method. 

 

Where      CX = Conc of MPS in sample solution 

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

wavelength 

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

standard solution  

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

standard solution   

Cy = Conc of CIL in sample solution 

As = Absorbance of Sample solution at 2 wavelength 

Method-II:  Amplitude Modulation method: This method 

comprises the conversion of zero order/normal spectra to its 

first, second or higher derivative spectrum. The amplitude is 

directly proportional to the conc of solution provided Beer’s 

law is obeyed by spectrum. In derivative method zero crossing 

wave length for both drugs is found such that at the zero 

crossing of one drug the other drug should show substantial 

absorbance. 

Here standard solutions 16 µg/ml each of metoprolol and 

cilnidipine were prepared in 10 ml volumetric flask and 

scanned from 400 to 200 nm wavelength range against ethanol 

50% as blank. Absorption spectra of both drugs were recorded 

and the found λmax of MET and CIL were stated in earlier 

discussed method.  

From overlain spectra CIL has substantial interference due 

to absorption at wavelength 221 nm and MET shows 

negligible absorption at 242 nm, hence it was decided to apply 

derivative method.  



Dyade et al.                                            QbD and Chemometric method for estimation of Metoprolol and Cilnidipine 

 

Online First                                                                                                                       Indian J Pharm Drug Studies | 4  

 

 

Zero order spectra of both drug was modulated and converted 

to first order derivative spectra. From overlain spectra, it 

clearly shows that no interference or zero absorbance of MET 

was found at 263 nm hence it was selected λmax of CIL and 

229.5 nm was zero crossing of CIL, so it was selected as λmax 

of MET. Both drugs were obeying Beer’s law in first order 

derivative mode at the respective wavelength. 

Fig 4: UV spectra of Cilnidipine and Metoprolol succinate 

in ethanol  

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 conc16 μg/ml and 8 μg/ml 

each of MET and CIL respectively were prepared separately 

and absorbance was recorded, SD and % RSD of the response 

was calculated.    

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 1-36μg/ml for MET 

and 1-16  μg/ml for CIL 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. 221 for MET and 242 nm for CIL 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 absorbance correction and 

amplitude modulation method: Tablet powder equivalent to 

12.5 mg MET and 2.5 mg CIL was weighed and transferred 

into 25 ml volumetric flask. Dissolved into 90% 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 221 nm and 242 nm in spectrum order. Also 

spectrum converted to first order derivative and absorbance 

was recorded at 229.5 and 263 nm. 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 MET and CIL were prepared and standard 

solutions added in 100 % proportionate to the tablet solution. 

Three replicates at this level was prepared, absorbance 

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 MET and CIL 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  

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 221nm 



Dyade et al.                                            QbD and Chemometric method for estimation of Metoprolol and Cilnidipine 

 

Online First                                                                                                                       Indian J Pharm Drug Studies | 5  

 

 

(λmax of MET) and 242 nm (λmax of CIL) shown in Fig 5 for 

calculation of both drugs in combined solution shown.  

Fig 5: Overlaid spectra of MET and CIL 

System Suitability: The absorbances of six replicates of 

standard solutions of tabulated respective conc are reported in 

Table No 1. The SD and % RSD was found for MET and CIL 

and meets the system suitability requirements indicates 

method was suitable for analysis. 

Table No 1: System suitability study of MET and CIL 

Sr 

No 

Conc in 

μg /ml 

Absorbance 

of MET* 

Conc in 

μg /ml 

Absorbance 

of CIL* 

1 

 
16μg/ml 0.5157 8 μg /ml 0.6519 

2 

 

SD 

RSD % 

0.004676 

0.9060 

SD 

RSD 

0.004809 

0.73774 

*Mean of six determinations 

Linearity: The calibration curve of both drugs was found to 

be linear in the conc range of 1-36 μg/ml for MET and 1-16 

μg/ml for CIL in normal spectrum as shown in Fig 6 and in 

first order derivative mode Fig 7. The regression equation of 

line and its parameters slope, r2 value and intercept are 

tabulated in Table No 2, which proved the linear relationship 

between conc and obtained response.  

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

The overlaid spectra obtained in amplitude modulation 

method are shown in Fig 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 3. The results indicated applicability 

of the method for estimation of formulation. 

Fig 6: Normal spectrum kind Calibration curve of MET 

and CIL 

 

Fig 7: Calibration curve of MET and CIL in First order 

derivative  

Accuracy and Precision: The results of accuracy are 

summarised in Table No 4, 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 No 4. 

Limit of Detection (LOD) and Limit of Quantitation 

(LOQ) and Robustness and Ruggedness: The LOD and 

LOQ of CIL and MET were found in acceptable limits by the 

proposed method. Robustness was studied and capacity of 

analytical procedure to measure analyte was remain 

unaffected by small but deliberate variations in method 



Dyade et al.                                            QbD and Chemometric method for estimation of Metoprolol and Cilnidipine 

 

Online First                                                                                                                       Indian J Pharm Drug Studies | 6  

 

 

parameter. The analytical method was found rugged during 

development; similarity the result was produced by 

performing the analysis by different analyst. 

Table No 2: Parameters of regression equation obtained in 

Microsoft excel 

Parameters 

MET CIL MET CIL 

Linearity study in 

Normal 

Linearity in 

derivative  

Detection 

wavelength 221 242 

 

229.5 

 

263 

Beer’s law 

limit  

(μg/ml) 

1–36 

μg/ml 

1–16 

μg/ml 

1–36 

μg/ml 

1–16 

μg/ml 

Correlation 

coefficient 

(r2) 

0.9984 

 

 

0.9994 

 

 

0.9991 

 

0.9972 

Regression 

equation 

(y = mx + c) 

Y = 

0.0317X 

+ 0.0097 

Y = 

0.0797X 

+ 0.0145 

 

Y=-

0.0006X- 

0.0001 

 

Y=-

0.0015X-

0.0003 

 

Table No 3: Results of assay of formulation by proposed 

method 

Formula

tion 

Dr

ug 

Label 

Claim 

(mg/Ta

blet; 

n=6) 

Amou

nt 

found/

mg 

Drug 

Cont

ent    

% 

Std 

Deviat

ion 

% 

RSD 

Method-

I 

ME

T 50 47.084  

94.16

7 

4.1614

6 

4.419

2 

CI

L 10 9.681 

96.78

7 

1.7606

3 

1.809

67 

Method-

II 

ME

T 50 51.886 

103.7

73 

1.8865

1 

1.817

91 

CI

L 10 9.682 

96.82

5 

2.7493

4 

2.839

49 

Table No 4: Results of accuracy and precision  

Sr. 

No. 

Parame

ter 

Level 

of 

study 

Dru

g 

Na

me 

% 

Mean 
S.D. 

% 

RSD 

Meth

od  - I 

Precisi

on 

Intrada

y 

precisi

on 

ME

T 

94.877

% 

0.588

94 

0.620

74 

CIL 
97.744

% 

1.151

16 

1.177

12 

Accura

cy 
100% 

ME

T 

96.308

% 

2.048

59 

2.127

12 

CIL 
94.845

% 

1.263

21 

1.331

88 

Meth

od - 

II 

Precisi

on 

Intrada

y 

precisi

on 

ME

T 

102.06

6% 

1.665

33 

1.622

08 

CIL 
99.476

% 

2.260

24 

2.272

15 

Accura

cy 
100% 

ME

T 

97.646

% 

1.176

75 

1.205

11 

CIL 
96.667

% 

1.159

71 

1.194

52 

 

Fig 8: Overlaid spectra obtained in amplitude modulation 

method 



Dyade et al.                                            QbD and Chemometric method for estimation of Metoprolol and Cilnidipine 

 

Online First                                                                                                                       Indian J Pharm Drug Studies | 7  

 

 

DISCUSSION  

Both the drugs were estimated from the combined formulation 

by absorbance correction and amplitude modulation method. 

Results were found within acceptable limits, statistical data 

obtained were shown rigidity of the method. The validated 

method was employed alcohol as solvent thus become towards 

eco-friendly. 

CONCLUSION 

The proposed methods are precise, accurate, robust and 

reproducible hence can be routinely used for simultaneous 

estimation of cilnidipine and metoprolol succinate from 

combined dosage form. 

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Dyade et al.                                            QbD and Chemometric method for estimation of Metoprolol and Cilnidipine 

 

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How to cite this article: Dyade GK, Jadhav RB, Repal S, 

Uparwad S, Suryawanshi P, Taware A, Khapne S, Kokare S, 

Dnyaneshwar A. QBD Approach and Chemo metric Method 

Development for the estimation of Metoprolol succinate and 

Cilnidipine in combined solid dosage form. Indian J Pharm 

Drug Studies. 2024; Online First. 

Funding: None;                 Conflicts of Interest: None Stated 

 


	Keywords: Metoprolol succinate, Cilnidipine, QbD, ICH, Absorbance correction method, Amplitude modulation method

