Research ArticleSimultaneous Determination of Drugs Affecting Central NervousSystem (CNS) in Bulk and Pharmaceutical Formulations UsingMultivariate Curve Resolution-Alternating LeastSquares (MCR-ALS)

Heba Shaaban Ahmed Mostafa Bushra Al-Zahrani Bushra Al-Jasserand Raghad Al-Ghamdi

Department of Pharmaceutical Chemistry College of Clinical Pharmacy Imam Abdulrahman Bin Faisal UniversityKing Faisal Road PO Box 1982 Dammam 31441 Saudi Arabia

Correspondence should be addressed to Heba Shaaban hsmohammediauedusa

Received 9 November 2019 Accepted 20 January 2020 Published 11 February 2020

Academic Editor Serban C Moldoveanu

Copyright copy 2020Heba Shaaban et alampis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

ampe quality of medications is important to maintain the overall health care of patients ampis study aims to develop and validate aspectrophotometric method using multivariate curve resolution-alternating least squares (MCR-ALS) with correlation constraintfor simultaneous resolution and quantification of selected drugs affecting the central nervous system (imipramine carba-mazepine chlorpromazine haloperidol and phenytoin) in different pharmaceutical dosage forms Figures of merit such as root-mean-square error of prediction bias standard error of prediction and relative error of prediction for the developedmethod werecalculated High values of correlation coefficients ranged between 09993 and 09998 reflected high predictive ability of thedeveloped method ampe results are linear in the concentration range of 03ndash5 μgmL for carbamazepine 03ndash15 μgmL forchlorpromazine 05ndash10 μgmL for haloperidol 05ndash10 μgmL for imipramine and 3ndash20 μgmL for phenytoin ampe optimizedmethod was successfully applied for the analysis of the studied drugs in their pharmaceutical products without any separation stepampe optimized method was also compared with a reported HPLCmethod using Studentrsquos t test and F ratio at 95 confidence leveland the results showed no significant difference regarding accuracy and precision ampe proposed chemometric method is fastreliable and cost-effective and can be used as an eco-friendly alternative to chromatographic techniques for the analysis of thestudied drugs in commercial pharmaceutical products

1 Introduction

Central nervous system (CNS) disorders are a growingmedical concern worldwide Many people suffer from CNSdisorders and this number is increasing ampus the use ofdrugs affecting CNS has been increased as well ampe studiedpharmaceuticals are among the most commonly used CNSdrugs and therefore developing fast simple and eco-friendlymethods for their simultaneous determination is needed

Chlorpromazine (CHZ) is used in suppressing excite-ment agitation and other psychomotor disorders and canbe also used as antiemetic and in the treatment of intractablehiccup [1] Carbamazepine (CRZ) is indicated to treatpartial seizures tonic-clonic seizures trigeminal neuralgia

pain and psychiatric disorders such as manic-depressiveillness [2] Phenytoin (PTN) is used for the control of certaintypes of seizures and prevention of seizures happening afterneurosurgeries [3] Haloperidol (HAL) is indicated for thetreatment of schizophrenia It is also the drug of choice ofTourette syndrome [4] Imipramine (IMP) inhibits seroto-nin and norepinephrine reuptake [5]

Several methods have been developed for the analysis ofthese drugs either individually or in combination For ex-ample partial least squares (PLS) and MCR-ALS were usedfor the simultaneous determination of carbamazepine alongwith diclofenac naproxen and other anti-inflammatorydrugs [6] HPLC-DAD was used for the analysis of carba-mazepine and phenobarbital in human serum samples and

HindawiJournal of Analytical Methods in ChemistryVolume 2020 Article ID 1684172 8 pageshttpsdoiorg10115520201684172

was further evaluated by the MCR-ALS method [7] MCRwas also used to obtain information about the polymorphictransformation of carbamazepine tablets during the heatingprocess [8] HPLC was employed for the determination ofHAL its three metabolites and two butyrophenone-typeneuroleptics in phosphate-buffered saline [9] PTN CRZprimidone phenobarbital and two active metabolites weredetermined simultaneously using HPLC [10] HPLC wasalso employed for the analysis of the studied analytes [11]

Greening analytical procedures is of paramount im-portance in order to minimize the negative environmentalimpacts [12 13] Green analytical chemistry aims atsubstituting nongreen analytical methods with more eco-friendly alternatives that consume and generate less toxicsolvents [14 15] In comparison with chromatographicmethods spectrophotometric methods utilize less sophis-ticated instruments and consume low volumes of organicsolvents making them functional alternatives [16] To thebest of authorsrsquo knowledge there is no reported spectro-photometric method in the literature for the simultaneousdetermination of CHZ CRZ HAL IMP and PTNamperefore a simple method based on chemometrics for theirsimultaneous determination was developed and validatedusing UV-Vis data

UV-Vis spectrophotometry is a well-established fastgreen and simple analytical technique that can be used fordirect analysis with no need to prior tedious separation stepsampe main challenge that might arise is the presence of highlyoverlapped spectra of the compounds to be analyzed as is thecase in multicomponent mixtures like the five drugs in thisstudy In such instances conventional spectrophotometrictechniques such as ratio spectra [17 18] cannot be used toresolve such spectra amperefore multivariate calibrationmodels such as multivariate curve resolution (MCR) may bethe method of choice to resolve such kind of severe spectraloverlap Such models have been reported to be a valid al-ternative to HPLC for pharmaceutical analysis [19 20] MCRis a mathematical algorithm first proposed in 1995 [21] Ithas been reported to be more advantageous over othermultivariate calibration techniques by being able to providedetailed information about concentration and spectralprofiles of the compounds analyzed in the mixtures studiedand has the ability of the quantitative analysis in the presenceof the unknown interference [22]

ampe algorithm has been successfully used in differentapplications such as spectrophotometric pharmaceuticalanalysis [13 23ndash25] For further information about MCRreaders can refer to [26]

In this study we developed and validated a spectro-photometric method for the simultaneous determination ofthe above mentioned CNS pharmaceuticals with severelyoverlapped spectra using MCR-ALS ampe method wasemployed for the analysis of different commercial dosageforms without any preliminary separation step

2 Experimental

21 Instrumentation and Software UV spectra were ac-quired using a UV-1800 Shimadzu double-beam

spectrophotometer (Shimadzu Kyoto Japan) using a 10 cmquartz cell Absorbances were automatically acquired in therange of 200ndash400 nm scanning speed of 2800 nmmin andbandwidth of 1 nm Data acquisition was conducted usingShimadzu UV-Probe 262 software ampe MCR-ALS modelwas developed via using MCR-ALS GUI 20 software withMatlab 2015a [27] freely accessible at httpwwwmcralsinfo MCR-ALS calculations have been performed andobtained

22 Chemicals and Reagents ampe supplied CNS pure stan-dards of CHZ CRZ HAL IMP and PTN were obtainedfrom SigmandashAldrich (Steinheim Germany) and confirmedto contain ge98 for all analytes HPLC-grade methanolpurchased from Merck (Darmstadt Germany) was alsoused Ultrapure water (182MΩ) was purified by the PureLab Ultra water system (ELGA High Wycombe UK) whichwas used for the entire sample preparation procedure

Phentyinreg capsules (El-Nile Co Egypt) labeled tocontain 50mg of PTN per capsule Haloperidolreg ampoule(Sunny Pharmaceuticals Egypt) each ampoule was labeledto contain 5mg of HAL per 1mL Imipraminereg tablets(ACDIMA Egypt) labeled to contain 25mg imipramine pertablet Carbapexreg tablets (Multi-Apex Pharma Egypt) la-beled to contain 200mg CRZ per tablet and Neurazineregtablets (Misr Company for Pharmaceuticals Egypt) labeledto contain 100mg CHZ per tablet were used

23 Standard Solutions and Calibration Standard stocksolutions were prepared individually in methanol by dis-solving 10mg of each standard in 10mL methanol (ie1000 μgmL) and stored in dark at 4degC Working standardsolutions were prepared by appropriate dilution in ultrapurewater A five-factor five-level experimental design [28] wasemployed to develop the calibration model in the concen-tration range of 03ndash5 μgmL for CHZ 03ndash15 μgmL forCRZ 05ndash10 μgmL for HAL 05ndash10 μgmL for IMP and3ndash20 μgmL for PTN A set of 25 calibration mixtures wereprepared ampe validation set was developed using the sameexperimental design used to build the calibration mixturesA validation set of further 15 samples containing the fiveanalytes with different concentrations within the calibrationrange were equivalently prepared Calibration and validationset concentration design are represented in Table 1

ampe UV spectra of all samples were scanned over thewavelength range of 200ndash400 nm with data points collectedevery 1 nm and the data were exported into Matlab for thefollowing handling for the MCR-ALS model Five compo-nents were used for MCR-ALS determination of all analytes

24Analysis of theCommercialPharmaceutical FormulationsTen tablets or the content of ten hard gelatin capsules of eachcommercial dosage form were separately mixed andweighed A weight portion of each product equivalent to50mg of CHZ CRZ IMP and PTN was dissolved indi-vidually in 35mLmethanol using ultrasonication for 30minthen the solution was left to cool down and the volume was

2 Journal of Analytical Methods in Chemistry

completed to 50mL with methanol All solutions were fil-tered through 045 μm membrane filters Appropriate di-lutions were carried out in ultrapure water to prepare theworking solutions

For Haloperidol ampules ten ampules were mixed to-gether in 50mL volumetric flask and the solution wascompleted to volume with methanol ampe solution was thenfiltered through 045 μm membrane filters and further di-lutions were made in ultrapure water to obtain workingsolutions

25 Multivariate Calibration Analysis (MCR-ALS) A briefdescription of MCR-ALS will be provided For more detailsabout the technique readers are referred to [29] MCRobtains significant information about pure compounds in amixture via mathematical bilinear model decomposition ofthe data matrix according to the following equation

D CST

+ E (1)

where D is the experimental data matrix containing all thespectra of all components of the mixture C is the pureconcentration profiles of each compound in the mixture STis the matrix of the corresponding pure spectra and E is theresiduals matrix (ie data that were not expressed by themodel or error matrix) [29]

ampe first step in MCR-ALS is to estimate the number ofcomponents which can be simply obtained using singularvalue decomposition An iterative ALS procedure is used toachieve resolution ampis procedure is initialized using an

initial estimation of the spectral or concentration profiles foreach analyte ampese initial estimates can be obtained usingdifferent algorithms such as evolving factor analysis (EFA)[30] or simple to use interactive self-modeling mixtureanalysis (SIMPLISMA) [31] In this work the known purespectra of each individual analyte were used for initialestimation

Several constraints can be applied for the optimization ofthe ALS such as correlation closure nonnegativity andunimodality constraints [32] In this work and during theALS optimization the nonnegativity constraint was appliedto spectral and concentration profiles

ampe nonnegativity constraint forces the concentrationandor spectral profiles to be gezero In addition correlationconstraint was applied during the optimization processCorrelation constraint helps to build the MCR-ALS cali-bration model that enables the prediction of all mixturecompounds even if unknown interfering compounds arethere [33]

Once the abovementioned steps are completed thedeveloped calibration model is then used to predict theconcentration in the validation and test set samples ALSiteration will be repeated after updating the predictionresults obtained till a certain convergence criterion isachieved Usually convergence is achieved when thedifference of the root-mean-square error of residual matrixE of two consecutive cycles is lower than a previously setthreshold value (usually gt01) ampe percentage of lack offit equation (2) can be used to evaluate the developedMCR-ALS model

Table 1 ampe concentration matrix used for the preparation of the calibration and validation sets of CHZ CRZ HAL IMP and PTN

Sample noCalibration set (μgmL) Validation set (μgmL)

HAL IMP CHZ CRZ PTN HAL IMP CHZ CRZ PTN1 53 53 27 77 115 90 70 05 130 1702 53 05 03 150 73 70 50 45 10 503 05 05 50 40 200 50 90 45 40 1354 05 100 15 150 115 90 90 05 100 505 10 29 50 77 73 90 10 35 40 1006 29 100 27 40 73 10 70 05 70 1357 100 53 15 40 158 70 10 25 100 1358 53 29 15 114 200 10 50 35 10 659 29 29 39 150 158 50 70 35 40 5010 29 77 50 114 115 70 70 15 10 6511 77 100 39 77 200 70 30 05 40 10012 100 77 27 150 200 30 10 15 70 5013 77 53 50 150 30 10 30 25 130 5014 53 100 50 03 158 30 50 05 40 17015 100 100 03 114 30 50 10 25 130 6516 100 05 39 03 11517 05 77 03 77 15818 77 05 27 114 15819 05 53 39 114 7320 53 77 39 40 3021 77 77 15 03 7322 77 29 03 40 11523 29 05 15 77 3024 05 29 27 03 3025 29 53 03 03 200

Journal of Analytical Methods in Chemistry 3

lack of fit() 100

1113936ije2i j

1113936ijd2i j

11139741113972

(2)

where eij is the difference between experimental data inputand data predicted by the model and dij is an element of thedata matrix D

26 Validation of the Model To evaluate the quality ofprediction of the developed MCR-ALS model a group ofexternal validation samples were used Several figures ofmerit were calculated according to the following equationsto describe the quality of validation results

Root-mean-square error of prediction (RMSEP)

RMSEP

1113936ni1 ci minus 1113954ci( 1113857

2

n

1113971

(3)

Bias

bias 1113936

ni1 ci minus 1113954ci( 1113857

n (4)

ampe standard error of prediction (SEP)

SEP

1113936ni1 ci minus 1113954ci minus bias( 1113857

2

n minus 1

1113971

(5)

Relative percentage error in the concentration predic-tions RE ()

RE() 100

1113936ni1 ci minus 1113954ci( 1113857

2

1113936ni1 c2i

1113971

(6)

where ci and ci are known and predicted analyte concen-trations in sample i respectively and n is the number ofvalidation samples

Moreover the slope intercept and correlation coeffi-cient were calculated for a linear regression fit performedbetween the known and predicted concentrations for eachcompound in the mixture

3 Results and Discussion

31 Spectral Characteristics and Selection of the WavelengthRange Figure 1 demonstrates the pure UV absorption spectraof the five analytes CHZ CRZ HAL IMP and PTN at theconcentration of 5μgmL of each analyte As shown below thespectra are extremely overlapped along the entire range ofabsorption amperefore the use of univariate or conventionalspectrophotometric methods is not feasible for the quantitativeanalysis of such mixture ampus the proposed MCR-ALSmethod was utilized to resolve this complex mixture

ampe quality of multivariate analysis is highly dependenton the selection of the optimum wavelength range [34]Absorbance spectra in the range of 200ndash220 nm were ex-cluded as they contained noise In addition the range of270ndash320 nm was also excluded as HAL and PTN did notshow significant absorption bands in this region

Accordingly the wavelength range of 220ndash270 nm was se-lected employed for developing the model

32MCR-ALSModel Amultilevel multifactor experimentaldesign [28] was employed to build the calibrationmodel Forevery individual analyte five concentration levels were usedampe chosen design provided factors that are orthogonal toeach other and spanned each otherrsquos calibration spacesymmetrically

ampe initial estimation of the pure spectral profiles of thetarget analytes employed singular value decomposition andrevealed five major components in the data matrix In orderto test the MCR-ALS resolution and to decrease the rota-tional ambiguities effects the pure spectra of the targetanalytes were used as initial estimates to check the MCR-ALS resolution and reduce the model rotational ambiguityeffects [29] SIMPLISMA was used to calculate the initialspectral profiles estimatesampeMCR-ALSmodel was appliedto the data matrix using nonnegativity constraint in bothspectral and concentration profiles and a fast nonnegativityconstrained least squares algorithm (fnnls) [35] wasemployed Moreover a correlation constraint was also usedand the variable containing the quantitative information ofthe five target analytes was selected Satisfactory results wereobtained with a low lack of fit ( lof) of 03541 ampe con-vergence criterion was set at 01 and the maximum numberof iterations was 50 however only 7 iterations were requiredto achieve convergence in all tested mixtures

ampe scatter plot of the predicted MCR-ALS concentra-tions versus the actual concentrations is shown in Figure 2with correlation coefficients (r2gt 09993) for all analytesindicating the good perdition ability of the developed modelTable 2 shows the figures of merit of the regression model ofthe calibration set ampe results show excellent predictionpower with correlation coefficients (r2gt 09993) and low

30000nm

20000 25000 35000 40000

0722

0600

0400

0200

0000

ndash0066

Abs

CHZCRZHAL

IMPPTN

Figure 1 UV absorption spectra of 5 μgmL of chlorpromazine(CHZ) carbamazepine (CRZ) haloperidol (HAL) imipramine(IMP) and phenytoin (PTN)

4 Journal of Analytical Methods in Chemistry

relative error RE () 114 100 165 092 and 061 forHAL IMP CHZ CRZ and PTN respectively)

33 Method Validation ampe quantitative prediction capa-bility of the established model was tested by applying the

model for the prediction of the concentration of CHZ CRZHAL IMP and PTN in an external validation set of 15synthetic mixtures with different concentrations within thecalibration range of each analyte (Table 1) ampis was done bymeans of using the same identical constraints applied for thecalibration set Various parameters (RMSEP SEP RE ()

0123456

0 1 2 3 4 5 6Actual concentration (microgmiddotmLndash1)

CalVal

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

(a)

CalVal

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

02468

10121416

0 2 4 6 8 10 12 14 16Actual concentration (microgmiddotmLndash1)

(b)

02468

1012

0 2 4 6 8 10 12

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

Actual concentration (microgmiddotmLndash1)

CalVal

(c)

12

02468

10

0 2 4 6 8 10 12

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

CalVal

Actual concentration (microgmiddotmLndash1)

(d)

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

Actual concentration (microgmiddotmLndash1)

CalVal

0

5

10

15

20

25

0 5 10 15 20 25

(e)

Figure 2 Scatter plot of actual analytes concentration versus the MCR-ALS-predicted concentrations of (a) CHZ (b) CRZ (c) HAL(d) IMP and (e) PTN

Table 2 Figures of merit of the MCR-ALS regression model for the calibration set of HAL IMP CHZ CRZ and PTN

Parameters HAL IMP CHZ CRZ PTNCalibration range (μgmiddotmLminus 1) 05ndash10 05ndash10 03ndash5 03ndash15 3ndash20Intercept (a) minus 311times 10minus 14 minus 515times10minus 14 888times10minus 15 364times10minus 14 249times10minus 14

Standard error of intercept 29times10minus 2 29times10minus 2 17times10minus 2 33times10minus 2 37times10minus 2

Slope (b) 10000 10000 10000 10000 10000Standard error of slope 466 10minus 3 479times10minus 3 548times10minus 3 353times10minus 3 285times10minus 3

RMSECV 389times10minus 2 332times10minus 2 279times10minus 2 503times10minus 2 470times10minus 2

SEP 381times 10minus 2 325times10minus 2 274times10minus 2 493times10minus 2 460times10minus 2

Bias 721times 10minus 3 232times10minus 3 minus 481times 10minus 3 568times10minus 3 minus 144times10minus 3

RE () 114 1004 165 092 061LOD (μgmiddotmLminus 1) 013 014 009 006 072LOQ (μgmiddotmLminus 1) 038 042 028 019 218Correlation coefficient (r2) 09995 09995 09993 09997 09998

Journal of Analytical Methods in Chemistry 5

and r2) were calculated to judge the predictive behavior of theproposedmodelampe validation results are presented in Table 3

331 Linearity ampe absorption spectra of each drug and theirmixtures as well were checked for their linearityampe results arelinear in the concentration range of 03ndash5μgmL for CHZ03ndash15μgmL for CRZ 05ndash10μgmL for HAL 05ndash10μgmLfor IMP and 3ndash20μgmL for PTN ampe model showed ex-cellent prediction for the validation set represented in the goodcorrelation coefficients ranging between 09993 and 09998 forall analytes Figure 2 shows the regression plots of the MCR-ALS-predicted analyte concentrations versus the actual con-centrations In addition low relative errors (RE ()) between067 and 142were obtained expressing the quality of fit of theentire calibration data

332 Accuracy ampe accuracy of the developed method wasevaluated using the standard addition method ampe percentrecoveries results were satisfactory ranging from 993 to1001 with SDs not higher than 16 (Table 3) ampeseresults confirmed that the excipients in commercial for-mulations do not interfere with the determination of thestudied analytes

333 Precision ampe intraday precision and interday pre-cision of the proposed method were assessed by analyzingthree concentration levels low intermediate and high (asindicated in Table 3) of the studied drugs within the sameday for intraday precision and at three consecutive days forinterday precision ampe lower values of RSD (˂16) indi-cated good precision of the developed method (Table 3)

334 Limits of Detection (LOD) and Limits ofQuantifications Limits of detection (LODs) and limits ofquantifications (LOQs) were calculated following themethodology described in [36] In this work LODs were inthe range of 006 to 014 μgmiddotmLminus 1 while the LOQs rangedfrom 019 to 042 μgmiddotmLminus 1 Table 3 shows the values obtained

ampe developed model demonstrated satisfactory vali-dation results

34 Literature Comparison ampis study established a spec-trophotometric method using MCR-ALS for simultaneousdetermination of imipramine carbamazepine chlorprom-azine haloperidol and phenytoin in commercial formula-tions An overview of analytical methods reported for thedetermination of CNS affecting drugs in pharmaceuticaldosage forms revealed that all reported methods [6ndash11]either use or generate harmful solvents Moreover LODs ofthe proposed method were similar to or even better thanthose of the reported methods Overall the comparison ofthe results showed that the presented method is eco-friendlyandmore sensitive than the reportedmethods Furthermore

Table 3 Figures of merit of the MCR-ALS regression model for the validation set of CHZ CRZ HAL IMP and PTN

Parameters HAL IMP CHZ CRZ PNTAccuracy (meanplusmn SD)a 993plusmn 145 998plusmn 155 998plusmn 113 1001plusmn 145 999plusmn 065Precision repeatability (RSD)b 109 132 089 067 078Intermediate precision (RSD)c 146 156 113 144 065RMSEP 656times10minus 2 617times10minus 2 165times10minus 2 781times 10minus 2 554times10minus 2

SEP 634times10minus 2 596times10minus 2 159times10minus 2 754times10minus 2 535times10minus 2

Bias 696times10minus 3 minus 174times10minus 2 minus 236times10minus 3 207times10minus 2 674times10minus 3

RE () 133 135 075 142 067Correlation coefficient (r2) 09994 09995 09997 09996 09998aampe mean and standard deviation for 15 determinations bampe intraday relative standard deviation (n 3) an average of three different concentrationrepeated three times within the same day campe interday relative standard deviation (n 3) an average of three different concentration repeated three times inthree different days Low concentrations 1 μgmL for HAL IMP and CRZ 05 μgmL for CHZ and 5 μgmL for PTN Intermediate concentrations 5 μgmLfor HAL IMP and CRZ 25 μgmL for CHZ and 10 μgmL for PTN High concentration 10 μgmL for HAL IMP and CRZ 5 μgmL for CHZ and 20 μgmLfor PTN

Table 4 Determination of the studied drugs in commercialproducts by the MCR-ALS method the proposed method and thereported HPLC method

MCR-ALS HPLCAnalytesHAL (Haloperidol ampoule)Mean + SD 988plusmn 138 998plusmn 131

t 119 mdashF 112 mdash

IMP (Imipramine tablets)Mean + SD 982plusmn 082 998plusmn 071

t 129 mdashF 133 mdash

CHZ (Neurazibe tablets)Mean + SD 9906plusmn 096 999plusmn 083

t 161 mdashF 135 mdash

CompoundCRZ (Carbapex tablets)Mean + SD 996plusmn 039 998plusmn 049

T 051 mdashF 156 mdash

PTN (Phenytin capsules)Mean + SD 995plusmn 013 997plusmn 014

T 194 mdashF 113 mdash

ampe reference HPLC published method used the C8 (250times 46mm 50 μm)column at 30degC and the mobile phase was composed of acetonitrile andsodium dihydrogenophosphate buffer used in gradient elution mode at15mLmiddotminminus 1 flow rate SD standard deviation of the mean of the per-centage recovery from the label claim amount for 6 determinationsampeoretical values for t and F at (p 005) are 223 and 505 respectively

6 Journal of Analytical Methods in Chemistry

the developed method is economic due to saving in solventconsumption and minimizing in preparation time and thuscan be applied for the routine analysis of the studiedpharmaceuticals without harming the environment

35 Analysis of Pharmaceutical Products ampe developedmodel was applied for the analysis of the studied pharma-ceuticals in different commercial pharmaceutical dosageforms including tablets capsules and ampules Six replicatedeterminations were performed Satisfactory results wereobtained (Table 4) which were in good agreement with thelabel claims

Finally the obtained MCR-ALS results were statisticallycompared with a reported HPLC method [11] for the si-multaneous determination of the five target analytes usingStudentrsquos t test and F ratio at 95 confidence level amperesults showed no significant difference regarding accuracyand precision (Table 4)

4 Conclusion

ampis work presents a fast simple eco-friendly precise andaccurate method for the simultaneous spectrophotometricanalysis of five CNS pharmaceuticals in different dosageforms such as tablets capsules and ampoulesampe developedMCR-ALS model results were compared with a reportedHPLC method and there was no significant difference be-tween the proposed and the reference method regarding theaccuracy and precision ampe proposed chemometric methodhas demonstrated its efficiency to be a valid eco-friendlyalternative to the chromatographic techniques for the de-termination of pharmaceuticals in different dosage formsamperefore it can be used for quality control testing withoutthe need for sample preparation and costly solvents

Data Availability

ampe data used to support the findings of this study areavailable from the corresponding author upon request

Conflicts of Interest

ampe authors declare that they have no conflicts of interest

Acknowledgments

ampe authors gratefully acknowledge the College of ClinicalPharmacy Immam Abdel Rahman Bin Faisal University forproviding research facilities ampis work was supported by theDeanship of Scientific Research Imam Abdulrahman BinFaisal University Saudi Arabia (Grant No Pharm-2017-250)

References

[1] Y Yamini and M Faraji ldquoExtraction and determination oftrace amounts of chlorpromazine in biological fluids usingmagnetic solid phase extraction followed by HPLCrdquo Journalof Pharmaceutical Analysis vol 4 no 4 pp 279ndash285 2014

[2] S Ghafghazi T Zanjani M Vosough and M SabetkasaeialdquoInterference-free determination of carbamazepine in humanserum using high performance liquid chromatography acomprehensive research with three-way calibration methodsrdquoIranian Journal of Pharmaceutical Research vol 16 no 1pp 120ndash131 2017

[3] R Hanaya and K Arita ldquoampe new antiepileptic drugs theirneuropharmacology and clinical indicationsrdquo NeurologiaMedico-Chirurgica vol 56 pp 205ndash220 2016

[4] J Billups C Jones T L Jackson S Y Ablordeppey andS D Spencer ldquoSimultaneous RP-HPLC-DAD quantificationof bromocriptine haloperidol and its diazepane structuralanalog in rat plasma with droperidol as internal standard forapplication to drug-interaction pharmacokineticsrdquo Biomed-ical Chromatography vol 24 no 7 pp 699ndash705 2010

[5] J Zhao Y Shin K-H Chun H-R Yoon J Lee andA Simple ldquoA simple rapid and reliable method to determineimipramine and desipramine in mouse serum using ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometryrdquo Journal of ChromatographicScience vol 54 no 4 pp 561ndash568 2016

[6] H Parastar and H Shaye ldquoComparative study of partial leastsquares and multivariate curve resolution for simultaneousspectrophotometric determination of pharmaceuticals inenvironmental samplesrdquo RSC Advances vol 5 no 86pp 70017ndash70024 2015

[7] M Vosough S Ghafghazi and M Sabetkasaei ldquoChemo-metrics enhanced HPLC-DAD performance for rapidquantification of carbamazepine and phenobarbital in humanserum samplesrdquo Talanta vol 119 pp 17ndash23 2014

[8] L A Terra and R J Poppi ldquoMonitoring the polymorphictransformation on the surface of carbamazepine tabletsgenerated by heating using near-infrared chemical imagingand chemometric methodologiesrdquo Chemometrics and Intel-ligent Laboratory Systems vol 130 pp 91ndash97 2014

[9] Y Higashi M Kitahara and Y Fujii ldquoSimultaneous analysisof haloperidol its three metabolites and two other butyro-phenone-type neuroleptics by high performance liquidchromatography with dual ultraviolet detectionrdquo BiomedicalChromatography vol 20 no 2 pp 166ndash172 2006

[10] L Budakova H Brozmanova M Grundmann and J FischerldquoSimultaneous determination of antiepileptic drugs and theirtwo active metabolites by HPLCrdquo Journal of SeparationScience vol 31 no 1 pp 1ndash8 2008

[11] I Hahirwa C Charlier C Karangwa and R DenoozldquoValidation of an analytical method for the determination inserum of psychotropic drugs by high-performance liquidchromatography with diode array detectionrdquo Rwanda Jour-nal vol 2 no 1 pp 13ndash23 2015

[12] H Shaaban and T Gorecki ldquoCurrent trends in green liquidchromatography for the analysis of pharmaceutically activecompounds in the environmental water compartmentsrdquoTalanta vol 132 no 15 pp 739ndash752 2015

[13] H Shaaban ldquoNew insights into liquid chromatography formore eco-friendly analysis of pharmaceuticalsrdquo Analyticaland Bioanalytical Chemistry vol 408 no 25 pp 6929ndash69442016

[14] H Shaaban and A Mostafa ldquoSustainable eco-friendly ultra-high-performance liquid chromatographic method for si-multaneous determination of caffeine and theobromine incommercial teas evaluation of greenness profile using NEMIand eco-scale assessment toolsrdquo Journal of AOAC Interna-tional vol 101 no 6 pp 1781ndash1787 2018

Journal of Analytical Methods in Chemistry 7

[15] H Shaaban A Mostafa W Alhajri L Almubarak andK AlKhalifah ldquoDevelopment and validation of an eco-friendly SPE-HPLC-MS method for simultaneous determi-nation of selected parabens and bisphenol A in personal careproducts evaluation of the greenness profile of the developedmethodrdquo Journal of Liquid Chromatography amp RelatedTechnologies vol 41 no 10 pp 621ndash628 2018

[16] H Shaaban ldquoHigh speed hydrophilic interaction liquidchromatographic method for simultaneous determination ofselected pharmaceuticals in wastewater using a cyano-bondedsilica columnrdquo Journal of Liquid Chromatography amp RelatedTechnologies vol 41 no 4 pp 180ndash187 2018

[17] A El-Gindy S Emara and H Shaaban ldquoDevelopment andvalidation of chemometrics-assisted spectrophotometric andliquid chromatographic methods for the simultaneous de-termination of two multicomponent mixtures containingbronchodilator drugsrdquo Journal of Pharmaceutical and Bio-medical Analysis vol 43 no 3 pp 973ndash982 2007

[18] A El-Gindy S Emara and H Shaaban ldquoValidation andapplication of chemometrics-assisted spectrophotometry andliquid chromatography for simultaneous determination oftwo ternary mixtures containing drotaverine hydrochloriderdquoJournal of AOAC International vol 93 no 2 pp 536ndash5482010

[19] H Shaaban M Ahmed Z Almatar R Alsheef and S AlrubhldquoSimultaneous determination of over-the-counter pain re-lievers in commercial pharmaceutical products utilizingmultivariate curve resolution-alternating least squares (MCR-ALS) multivariate calibration modelrdquo Journal of AnalyticalMethods in Chemistry vol 2019 Article ID 1863910 8 pages2019

[20] A Mostafa and H Shaaban ldquoQuantitative analysis and res-olution of pharmaceuticals in the environment using multi-variate curve resolution-alternating least squares (MCR-ALS)rdquo Acta Pharmaceutica vol 69 no 2 pp 217ndash231 2019

[21] R Tauler ldquoMultivariate curve resolution applied to secondorder datardquo Chemometrics and Intelligent Laboratory Systemsvol 30 no 1 pp 133ndash146 1995

[22] A de Juan J Jaumot and R Tauler ldquoMultivariate curveresolution (MCR) Solving the mixture analysis problemrdquoAnalytical Methods vol 6 no 14 pp 4964ndash4976 2014

[23] A Mostafa H Shaaban M Almousa M Al Sheqawi andM Almousa ldquoEco-friendly pharmaceutical analysis of mul-ticomponent drugs coformulated in different dosage formsusing multivariate curve resolution and partial least squares acomparative studyrdquo Journal of AOAC International vol 102no 2 pp 465ndash472 2019

[24] P Katsarov G Gergov A Alin et al ldquoAdvanced spectro-photometric chemometric methods for resolving the binarymixture of doxylamine succinate and pyridoxine hydro-chloriderdquo Acta Pharmaceutica vol 68 no 1 pp 61ndash73 2018

[25] M De Luca G Ioele C Spatari and G Ragno ldquoA singleMCR-ALS model for drug analysis in different formulationsapplication on diazepam commercial preparationsrdquo Journalof Pharmaceutical and Biomedical Analysis vol 134 no 5pp 346ndash351 2017

[26] M Garrido F X Rius andM S Larrechi ldquoMultivariate curveresolution-alternating least squares (MCR-ALS) applied tospectroscopic data from monitoring chemical reactionsprocessesrdquo Analytical and Bioanalytical Chemistry vol 390no 8 pp 2059ndash2066 2008

[27] J Jaumot A de Juan and R Tauler ldquoMCR-ALS GUI 20 newfeatures and applicationsrdquo Chemometrics and IntelligentLaboratory Systems vol 140 pp 1ndash12 2015

[28] R G Brereton ldquoMultilevel multifactor designs for multi-variatecalibrationrdquo e Analyst vol 122 no 12pp 1521ndash1529 1997

[29] R Tauler E Gorrochategui and J Jaumot ldquoA protocol forLC-MS metabolomic data processing using chemometrictoolsrdquo Protocol Exchange 2015

[30] M Maeder and A D Zuberbuehler ldquoampe resolution ofoverlapping chromatographic peaks by evolving factoranalysisrdquo Analytica Chimica Acta vol 181 pp 287ndash291 1986

[31] W Windig and J Guilment ldquoInteractive self-modelingmixture analysisrdquo Analytical Chemistry vol 63 no 14pp 1425ndash1432 1991

[32] T Azzouz and R Tauler ldquoApplication of multivariate curveresolution alternating least squares (MCR-ALS) to thequantitative analysis of pharmaceutical and agriculturalsamplesrdquo Talanta vol 74 no 5 pp 1201ndash1210 2008

[33] A de Juan and R Tauler ldquoMultivariate curve resolution(MCR) from 2000 progress in concepts and applicationsrdquoCritical Reviews in Analytical Chemistry vol 36 no 3-4pp 163ndash176 2006

[34] A de Carvalho M Sanchez J Wattoom and R BreretonldquoComparison of PLS and kinetic models for a second-orderreaction as monitored using ultraviolet visible and mid-in-frared spectroscopyrdquo Talanta vol 68 no 4 pp 1190ndash12002006

[35] M Blanco J Coello F Gonzalez H Iturriaga andS Maspoch ldquoSpectrophotometric analysis of a pharmaceu-tical preparation by principal component regressionrdquo Journalof Pharmaceutical Sciences vol 82 no 8 pp 834ndash837 1993

[36] J Saurina C Leal R Compantildeo M Granados M D Prat andR Tauler ldquoEstimation of figures of merit using univariatestatistics for quantitative second-order multivariate curveresolutionrdquo Analytica Chimica Acta vol 432 no 2pp 241ndash251 2001

8 Journal of Analytical Methods in Chemistry

lack of fit() 100

1113936ije2i j

1113936ijd2i j

11139741113972

(2)

where eij is the difference between experimental data inputand data predicted by the model and dij is an element of thedata matrix D

26 Validation of the Model To evaluate the quality ofprediction of the developed MCR-ALS model a group ofexternal validation samples were used Several figures ofmerit were calculated according to the following equationsto describe the quality of validation results

Root-mean-square error of prediction (RMSEP)

RMSEP

1113936ni1 ci minus 1113954ci( 1113857

2

n

1113971

(3)

Bias

bias 1113936

ni1 ci minus 1113954ci( 1113857

n (4)

ampe standard error of prediction (SEP)

SEP

1113936ni1 ci minus 1113954ci minus bias( 1113857

2

n minus 1

1113971

(5)

Relative percentage error in the concentration predic-tions RE ()

RE() 100

1113936ni1 ci minus 1113954ci( 1113857

2

1113936ni1 c2i

1113971

(6)

where ci and ci are known and predicted analyte concen-trations in sample i respectively and n is the number ofvalidation samples

Moreover the slope intercept and correlation coeffi-cient were calculated for a linear regression fit performedbetween the known and predicted concentrations for eachcompound in the mixture

3 Results and Discussion

31 Spectral Characteristics and Selection of the WavelengthRange Figure 1 demonstrates the pure UV absorption spectraof the five analytes CHZ CRZ HAL IMP and PTN at theconcentration of 5μgmL of each analyte As shown below thespectra are extremely overlapped along the entire range ofabsorption amperefore the use of univariate or conventionalspectrophotometric methods is not feasible for the quantitativeanalysis of such mixture ampus the proposed MCR-ALSmethod was utilized to resolve this complex mixture

ampe quality of multivariate analysis is highly dependenton the selection of the optimum wavelength range [34]Absorbance spectra in the range of 200ndash220 nm were ex-cluded as they contained noise In addition the range of270ndash320 nm was also excluded as HAL and PTN did notshow significant absorption bands in this region

Accordingly the wavelength range of 220ndash270 nm was se-lected employed for developing the model

32MCR-ALSModel Amultilevel multifactor experimentaldesign [28] was employed to build the calibrationmodel Forevery individual analyte five concentration levels were usedampe chosen design provided factors that are orthogonal toeach other and spanned each otherrsquos calibration spacesymmetrically

ampe initial estimation of the pure spectral profiles of thetarget analytes employed singular value decomposition andrevealed five major components in the data matrix In orderto test the MCR-ALS resolution and to decrease the rota-tional ambiguities effects the pure spectra of the targetanalytes were used as initial estimates to check the MCR-ALS resolution and reduce the model rotational ambiguityeffects [29] SIMPLISMA was used to calculate the initialspectral profiles estimatesampeMCR-ALSmodel was appliedto the data matrix using nonnegativity constraint in bothspectral and concentration profiles and a fast nonnegativityconstrained least squares algorithm (fnnls) [35] wasemployed Moreover a correlation constraint was also usedand the variable containing the quantitative information ofthe five target analytes was selected Satisfactory results wereobtained with a low lack of fit ( lof) of 03541 ampe con-vergence criterion was set at 01 and the maximum numberof iterations was 50 however only 7 iterations were requiredto achieve convergence in all tested mixtures

ampe scatter plot of the predicted MCR-ALS concentra-tions versus the actual concentrations is shown in Figure 2with correlation coefficients (r2gt 09993) for all analytesindicating the good perdition ability of the developed modelTable 2 shows the figures of merit of the regression model ofthe calibration set ampe results show excellent predictionpower with correlation coefficients (r2gt 09993) and low

30000nm

20000 25000 35000 40000

0722

0600

0400

0200

0000

ndash0066

Abs

CHZCRZHAL

IMPPTN

Figure 1 UV absorption spectra of 5 μgmL of chlorpromazine(CHZ) carbamazepine (CRZ) haloperidol (HAL) imipramine(IMP) and phenytoin (PTN)

4 Journal of Analytical Methods in Chemistry

relative error RE () 114 100 165 092 and 061 forHAL IMP CHZ CRZ and PTN respectively)

33 Method Validation ampe quantitative prediction capa-bility of the established model was tested by applying the

model for the prediction of the concentration of CHZ CRZHAL IMP and PTN in an external validation set of 15synthetic mixtures with different concentrations within thecalibration range of each analyte (Table 1) ampis was done bymeans of using the same identical constraints applied for thecalibration set Various parameters (RMSEP SEP RE ()

0123456

0 1 2 3 4 5 6Actual concentration (microgmiddotmLndash1)

CalVal

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

(a)

CalVal

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

02468

10121416

0 2 4 6 8 10 12 14 16Actual concentration (microgmiddotmLndash1)

(b)

02468

1012

0 2 4 6 8 10 12

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

Actual concentration (microgmiddotmLndash1)

CalVal

(c)

12

02468

10

0 2 4 6 8 10 12

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

CalVal

Actual concentration (microgmiddotmLndash1)

(d)

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

Actual concentration (microgmiddotmLndash1)

CalVal

0

5

10

15

20

25

0 5 10 15 20 25

(e)

Figure 2 Scatter plot of actual analytes concentration versus the MCR-ALS-predicted concentrations of (a) CHZ (b) CRZ (c) HAL(d) IMP and (e) PTN

Table 2 Figures of merit of the MCR-ALS regression model for the calibration set of HAL IMP CHZ CRZ and PTN

Parameters HAL IMP CHZ CRZ PTNCalibration range (μgmiddotmLminus 1) 05ndash10 05ndash10 03ndash5 03ndash15 3ndash20Intercept (a) minus 311times 10minus 14 minus 515times10minus 14 888times10minus 15 364times10minus 14 249times10minus 14

Standard error of intercept 29times10minus 2 29times10minus 2 17times10minus 2 33times10minus 2 37times10minus 2

Slope (b) 10000 10000 10000 10000 10000Standard error of slope 466 10minus 3 479times10minus 3 548times10minus 3 353times10minus 3 285times10minus 3

RMSECV 389times10minus 2 332times10minus 2 279times10minus 2 503times10minus 2 470times10minus 2

SEP 381times 10minus 2 325times10minus 2 274times10minus 2 493times10minus 2 460times10minus 2

Bias 721times 10minus 3 232times10minus 3 minus 481times 10minus 3 568times10minus 3 minus 144times10minus 3

RE () 114 1004 165 092 061LOD (μgmiddotmLminus 1) 013 014 009 006 072LOQ (μgmiddotmLminus 1) 038 042 028 019 218Correlation coefficient (r2) 09995 09995 09993 09997 09998

Journal of Analytical Methods in Chemistry 5

and r2) were calculated to judge the predictive behavior of theproposedmodelampe validation results are presented in Table 3

331 Linearity ampe absorption spectra of each drug and theirmixtures as well were checked for their linearityampe results arelinear in the concentration range of 03ndash5μgmL for CHZ03ndash15μgmL for CRZ 05ndash10μgmL for HAL 05ndash10μgmLfor IMP and 3ndash20μgmL for PTN ampe model showed ex-cellent prediction for the validation set represented in the goodcorrelation coefficients ranging between 09993 and 09998 forall analytes Figure 2 shows the regression plots of the MCR-ALS-predicted analyte concentrations versus the actual con-centrations In addition low relative errors (RE ()) between067 and 142were obtained expressing the quality of fit of theentire calibration data

332 Accuracy ampe accuracy of the developed method wasevaluated using the standard addition method ampe percentrecoveries results were satisfactory ranging from 993 to1001 with SDs not higher than 16 (Table 3) ampeseresults confirmed that the excipients in commercial for-mulations do not interfere with the determination of thestudied analytes

333 Precision ampe intraday precision and interday pre-cision of the proposed method were assessed by analyzingthree concentration levels low intermediate and high (asindicated in Table 3) of the studied drugs within the sameday for intraday precision and at three consecutive days forinterday precision ampe lower values of RSD (˂16) indi-cated good precision of the developed method (Table 3)

334 Limits of Detection (LOD) and Limits ofQuantifications Limits of detection (LODs) and limits ofquantifications (LOQs) were calculated following themethodology described in [36] In this work LODs were inthe range of 006 to 014 μgmiddotmLminus 1 while the LOQs rangedfrom 019 to 042 μgmiddotmLminus 1 Table 3 shows the values obtained

ampe developed model demonstrated satisfactory vali-dation results

34 Literature Comparison ampis study established a spec-trophotometric method using MCR-ALS for simultaneousdetermination of imipramine carbamazepine chlorprom-azine haloperidol and phenytoin in commercial formula-tions An overview of analytical methods reported for thedetermination of CNS affecting drugs in pharmaceuticaldosage forms revealed that all reported methods [6ndash11]either use or generate harmful solvents Moreover LODs ofthe proposed method were similar to or even better thanthose of the reported methods Overall the comparison ofthe results showed that the presented method is eco-friendlyandmore sensitive than the reportedmethods Furthermore

Table 3 Figures of merit of the MCR-ALS regression model for the validation set of CHZ CRZ HAL IMP and PTN

Parameters HAL IMP CHZ CRZ PNTAccuracy (meanplusmn SD)a 993plusmn 145 998plusmn 155 998plusmn 113 1001plusmn 145 999plusmn 065Precision repeatability (RSD)b 109 132 089 067 078Intermediate precision (RSD)c 146 156 113 144 065RMSEP 656times10minus 2 617times10minus 2 165times10minus 2 781times 10minus 2 554times10minus 2

SEP 634times10minus 2 596times10minus 2 159times10minus 2 754times10minus 2 535times10minus 2

Bias 696times10minus 3 minus 174times10minus 2 minus 236times10minus 3 207times10minus 2 674times10minus 3

RE () 133 135 075 142 067Correlation coefficient (r2) 09994 09995 09997 09996 09998aampe mean and standard deviation for 15 determinations bampe intraday relative standard deviation (n 3) an average of three different concentrationrepeated three times within the same day campe interday relative standard deviation (n 3) an average of three different concentration repeated three times inthree different days Low concentrations 1 μgmL for HAL IMP and CRZ 05 μgmL for CHZ and 5 μgmL for PTN Intermediate concentrations 5 μgmLfor HAL IMP and CRZ 25 μgmL for CHZ and 10 μgmL for PTN High concentration 10 μgmL for HAL IMP and CRZ 5 μgmL for CHZ and 20 μgmLfor PTN

Table 4 Determination of the studied drugs in commercialproducts by the MCR-ALS method the proposed method and thereported HPLC method

MCR-ALS HPLCAnalytesHAL (Haloperidol ampoule)Mean + SD 988plusmn 138 998plusmn 131

t 119 mdashF 112 mdash

IMP (Imipramine tablets)Mean + SD 982plusmn 082 998plusmn 071

t 129 mdashF 133 mdash

CHZ (Neurazibe tablets)Mean + SD 9906plusmn 096 999plusmn 083

t 161 mdashF 135 mdash

CompoundCRZ (Carbapex tablets)Mean + SD 996plusmn 039 998plusmn 049

T 051 mdashF 156 mdash

PTN (Phenytin capsules)Mean + SD 995plusmn 013 997plusmn 014

T 194 mdashF 113 mdash

ampe reference HPLC published method used the C8 (250times 46mm 50 μm)column at 30degC and the mobile phase was composed of acetonitrile andsodium dihydrogenophosphate buffer used in gradient elution mode at15mLmiddotminminus 1 flow rate SD standard deviation of the mean of the per-centage recovery from the label claim amount for 6 determinationsampeoretical values for t and F at (p 005) are 223 and 505 respectively

6 Journal of Analytical Methods in Chemistry

the developed method is economic due to saving in solventconsumption and minimizing in preparation time and thuscan be applied for the routine analysis of the studiedpharmaceuticals without harming the environment

35 Analysis of Pharmaceutical Products ampe developedmodel was applied for the analysis of the studied pharma-ceuticals in different commercial pharmaceutical dosageforms including tablets capsules and ampules Six replicatedeterminations were performed Satisfactory results wereobtained (Table 4) which were in good agreement with thelabel claims

Finally the obtained MCR-ALS results were statisticallycompared with a reported HPLC method [11] for the si-multaneous determination of the five target analytes usingStudentrsquos t test and F ratio at 95 confidence level amperesults showed no significant difference regarding accuracyand precision (Table 4)

4 Conclusion

ampis work presents a fast simple eco-friendly precise andaccurate method for the simultaneous spectrophotometricanalysis of five CNS pharmaceuticals in different dosageforms such as tablets capsules and ampoulesampe developedMCR-ALS model results were compared with a reportedHPLC method and there was no significant difference be-tween the proposed and the reference method regarding theaccuracy and precision ampe proposed chemometric methodhas demonstrated its efficiency to be a valid eco-friendlyalternative to the chromatographic techniques for the de-termination of pharmaceuticals in different dosage formsamperefore it can be used for quality control testing withoutthe need for sample preparation and costly solvents

Data Availability

ampe data used to support the findings of this study areavailable from the corresponding author upon request

Conflicts of Interest

ampe authors declare that they have no conflicts of interest

Acknowledgments

ampe authors gratefully acknowledge the College of ClinicalPharmacy Immam Abdel Rahman Bin Faisal University forproviding research facilities ampis work was supported by theDeanship of Scientific Research Imam Abdulrahman BinFaisal University Saudi Arabia (Grant No Pharm-2017-250)

References

[1] Y Yamini and M Faraji ldquoExtraction and determination oftrace amounts of chlorpromazine in biological fluids usingmagnetic solid phase extraction followed by HPLCrdquo Journalof Pharmaceutical Analysis vol 4 no 4 pp 279ndash285 2014

[2] S Ghafghazi T Zanjani M Vosough and M SabetkasaeialdquoInterference-free determination of carbamazepine in humanserum using high performance liquid chromatography acomprehensive research with three-way calibration methodsrdquoIranian Journal of Pharmaceutical Research vol 16 no 1pp 120ndash131 2017

[3] R Hanaya and K Arita ldquoampe new antiepileptic drugs theirneuropharmacology and clinical indicationsrdquo NeurologiaMedico-Chirurgica vol 56 pp 205ndash220 2016

[4] J Billups C Jones T L Jackson S Y Ablordeppey andS D Spencer ldquoSimultaneous RP-HPLC-DAD quantificationof bromocriptine haloperidol and its diazepane structuralanalog in rat plasma with droperidol as internal standard forapplication to drug-interaction pharmacokineticsrdquo Biomed-ical Chromatography vol 24 no 7 pp 699ndash705 2010

[5] J Zhao Y Shin K-H Chun H-R Yoon J Lee andA Simple ldquoA simple rapid and reliable method to determineimipramine and desipramine in mouse serum using ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometryrdquo Journal of ChromatographicScience vol 54 no 4 pp 561ndash568 2016

[6] H Parastar and H Shaye ldquoComparative study of partial leastsquares and multivariate curve resolution for simultaneousspectrophotometric determination of pharmaceuticals inenvironmental samplesrdquo RSC Advances vol 5 no 86pp 70017ndash70024 2015

[7] M Vosough S Ghafghazi and M Sabetkasaei ldquoChemo-metrics enhanced HPLC-DAD performance for rapidquantification of carbamazepine and phenobarbital in humanserum samplesrdquo Talanta vol 119 pp 17ndash23 2014

[8] L A Terra and R J Poppi ldquoMonitoring the polymorphictransformation on the surface of carbamazepine tabletsgenerated by heating using near-infrared chemical imagingand chemometric methodologiesrdquo Chemometrics and Intel-ligent Laboratory Systems vol 130 pp 91ndash97 2014

[9] Y Higashi M Kitahara and Y Fujii ldquoSimultaneous analysisof haloperidol its three metabolites and two other butyro-phenone-type neuroleptics by high performance liquidchromatography with dual ultraviolet detectionrdquo BiomedicalChromatography vol 20 no 2 pp 166ndash172 2006

[10] L Budakova H Brozmanova M Grundmann and J FischerldquoSimultaneous determination of antiepileptic drugs and theirtwo active metabolites by HPLCrdquo Journal of SeparationScience vol 31 no 1 pp 1ndash8 2008

[11] I Hahirwa C Charlier C Karangwa and R DenoozldquoValidation of an analytical method for the determination inserum of psychotropic drugs by high-performance liquidchromatography with diode array detectionrdquo Rwanda Jour-nal vol 2 no 1 pp 13ndash23 2015

[12] H Shaaban and T Gorecki ldquoCurrent trends in green liquidchromatography for the analysis of pharmaceutically activecompounds in the environmental water compartmentsrdquoTalanta vol 132 no 15 pp 739ndash752 2015

[13] H Shaaban ldquoNew insights into liquid chromatography formore eco-friendly analysis of pharmaceuticalsrdquo Analyticaland Bioanalytical Chemistry vol 408 no 25 pp 6929ndash69442016

[14] H Shaaban and A Mostafa ldquoSustainable eco-friendly ultra-high-performance liquid chromatographic method for si-multaneous determination of caffeine and theobromine incommercial teas evaluation of greenness profile using NEMIand eco-scale assessment toolsrdquo Journal of AOAC Interna-tional vol 101 no 6 pp 1781ndash1787 2018

Journal of Analytical Methods in Chemistry 7

[15] H Shaaban A Mostafa W Alhajri L Almubarak andK AlKhalifah ldquoDevelopment and validation of an eco-friendly SPE-HPLC-MS method for simultaneous determi-nation of selected parabens and bisphenol A in personal careproducts evaluation of the greenness profile of the developedmethodrdquo Journal of Liquid Chromatography amp RelatedTechnologies vol 41 no 10 pp 621ndash628 2018

[16] H Shaaban ldquoHigh speed hydrophilic interaction liquidchromatographic method for simultaneous determination ofselected pharmaceuticals in wastewater using a cyano-bondedsilica columnrdquo Journal of Liquid Chromatography amp RelatedTechnologies vol 41 no 4 pp 180ndash187 2018

[17] A El-Gindy S Emara and H Shaaban ldquoDevelopment andvalidation of chemometrics-assisted spectrophotometric andliquid chromatographic methods for the simultaneous de-termination of two multicomponent mixtures containingbronchodilator drugsrdquo Journal of Pharmaceutical and Bio-medical Analysis vol 43 no 3 pp 973ndash982 2007

[18] A El-Gindy S Emara and H Shaaban ldquoValidation andapplication of chemometrics-assisted spectrophotometry andliquid chromatography for simultaneous determination oftwo ternary mixtures containing drotaverine hydrochloriderdquoJournal of AOAC International vol 93 no 2 pp 536ndash5482010

[19] H Shaaban M Ahmed Z Almatar R Alsheef and S AlrubhldquoSimultaneous determination of over-the-counter pain re-lievers in commercial pharmaceutical products utilizingmultivariate curve resolution-alternating least squares (MCR-ALS) multivariate calibration modelrdquo Journal of AnalyticalMethods in Chemistry vol 2019 Article ID 1863910 8 pages2019

[20] A Mostafa and H Shaaban ldquoQuantitative analysis and res-olution of pharmaceuticals in the environment using multi-variate curve resolution-alternating least squares (MCR-ALS)rdquo Acta Pharmaceutica vol 69 no 2 pp 217ndash231 2019

[21] R Tauler ldquoMultivariate curve resolution applied to secondorder datardquo Chemometrics and Intelligent Laboratory Systemsvol 30 no 1 pp 133ndash146 1995

[22] A de Juan J Jaumot and R Tauler ldquoMultivariate curveresolution (MCR) Solving the mixture analysis problemrdquoAnalytical Methods vol 6 no 14 pp 4964ndash4976 2014

[23] A Mostafa H Shaaban M Almousa M Al Sheqawi andM Almousa ldquoEco-friendly pharmaceutical analysis of mul-ticomponent drugs coformulated in different dosage formsusing multivariate curve resolution and partial least squares acomparative studyrdquo Journal of AOAC International vol 102no 2 pp 465ndash472 2019

[24] P Katsarov G Gergov A Alin et al ldquoAdvanced spectro-photometric chemometric methods for resolving the binarymixture of doxylamine succinate and pyridoxine hydro-chloriderdquo Acta Pharmaceutica vol 68 no 1 pp 61ndash73 2018

[25] M De Luca G Ioele C Spatari and G Ragno ldquoA singleMCR-ALS model for drug analysis in different formulationsapplication on diazepam commercial preparationsrdquo Journalof Pharmaceutical and Biomedical Analysis vol 134 no 5pp 346ndash351 2017

[26] M Garrido F X Rius andM S Larrechi ldquoMultivariate curveresolution-alternating least squares (MCR-ALS) applied tospectroscopic data from monitoring chemical reactionsprocessesrdquo Analytical and Bioanalytical Chemistry vol 390no 8 pp 2059ndash2066 2008

[27] J Jaumot A de Juan and R Tauler ldquoMCR-ALS GUI 20 newfeatures and applicationsrdquo Chemometrics and IntelligentLaboratory Systems vol 140 pp 1ndash12 2015

[28] R G Brereton ldquoMultilevel multifactor designs for multi-variatecalibrationrdquo e Analyst vol 122 no 12pp 1521ndash1529 1997

[29] R Tauler E Gorrochategui and J Jaumot ldquoA protocol forLC-MS metabolomic data processing using chemometrictoolsrdquo Protocol Exchange 2015

[30] M Maeder and A D Zuberbuehler ldquoampe resolution ofoverlapping chromatographic peaks by evolving factoranalysisrdquo Analytica Chimica Acta vol 181 pp 287ndash291 1986

[31] W Windig and J Guilment ldquoInteractive self-modelingmixture analysisrdquo Analytical Chemistry vol 63 no 14pp 1425ndash1432 1991

[32] T Azzouz and R Tauler ldquoApplication of multivariate curveresolution alternating least squares (MCR-ALS) to thequantitative analysis of pharmaceutical and agriculturalsamplesrdquo Talanta vol 74 no 5 pp 1201ndash1210 2008

[33] A de Juan and R Tauler ldquoMultivariate curve resolution(MCR) from 2000 progress in concepts and applicationsrdquoCritical Reviews in Analytical Chemistry vol 36 no 3-4pp 163ndash176 2006

[34] A de Carvalho M Sanchez J Wattoom and R BreretonldquoComparison of PLS and kinetic models for a second-orderreaction as monitored using ultraviolet visible and mid-in-frared spectroscopyrdquo Talanta vol 68 no 4 pp 1190ndash12002006

[35] M Blanco J Coello F Gonzalez H Iturriaga andS Maspoch ldquoSpectrophotometric analysis of a pharmaceu-tical preparation by principal component regressionrdquo Journalof Pharmaceutical Sciences vol 82 no 8 pp 834ndash837 1993

[36] J Saurina C Leal R Compantildeo M Granados M D Prat andR Tauler ldquoEstimation of figures of merit using univariatestatistics for quantitative second-order multivariate curveresolutionrdquo Analytica Chimica Acta vol 432 no 2pp 241ndash251 2001

8 Journal of Analytical Methods in Chemistry

relative error RE () 114 100 165 092 and 061 forHAL IMP CHZ CRZ and PTN respectively)

33 Method Validation ampe quantitative prediction capa-bility of the established model was tested by applying the

model for the prediction of the concentration of CHZ CRZHAL IMP and PTN in an external validation set of 15synthetic mixtures with different concentrations within thecalibration range of each analyte (Table 1) ampis was done bymeans of using the same identical constraints applied for thecalibration set Various parameters (RMSEP SEP RE ()

0123456

0 1 2 3 4 5 6Actual concentration (microgmiddotmLndash1)

CalVal

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

(a)

CalVal

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

02468

10121416

0 2 4 6 8 10 12 14 16Actual concentration (microgmiddotmLndash1)

(b)

02468

1012

0 2 4 6 8 10 12

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

Actual concentration (microgmiddotmLndash1)

CalVal

(c)

12

02468

10

0 2 4 6 8 10 12

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

CalVal

Actual concentration (microgmiddotmLndash1)

(d)

Pred

icte

d co

ncen

trat

ion

(microgmiddot

mLndash1

)

Actual concentration (microgmiddotmLndash1)

CalVal

0

5

10

15

20

25

0 5 10 15 20 25

(e)

Figure 2 Scatter plot of actual analytes concentration versus the MCR-ALS-predicted concentrations of (a) CHZ (b) CRZ (c) HAL(d) IMP and (e) PTN

Table 2 Figures of merit of the MCR-ALS regression model for the calibration set of HAL IMP CHZ CRZ and PTN

Parameters HAL IMP CHZ CRZ PTNCalibration range (μgmiddotmLminus 1) 05ndash10 05ndash10 03ndash5 03ndash15 3ndash20Intercept (a) minus 311times 10minus 14 minus 515times10minus 14 888times10minus 15 364times10minus 14 249times10minus 14

Standard error of intercept 29times10minus 2 29times10minus 2 17times10minus 2 33times10minus 2 37times10minus 2

Slope (b) 10000 10000 10000 10000 10000Standard error of slope 466 10minus 3 479times10minus 3 548times10minus 3 353times10minus 3 285times10minus 3

RMSECV 389times10minus 2 332times10minus 2 279times10minus 2 503times10minus 2 470times10minus 2

SEP 381times 10minus 2 325times10minus 2 274times10minus 2 493times10minus 2 460times10minus 2

Bias 721times 10minus 3 232times10minus 3 minus 481times 10minus 3 568times10minus 3 minus 144times10minus 3

RE () 114 1004 165 092 061LOD (μgmiddotmLminus 1) 013 014 009 006 072LOQ (μgmiddotmLminus 1) 038 042 028 019 218Correlation coefficient (r2) 09995 09995 09993 09997 09998

Journal of Analytical Methods in Chemistry 5

and r2) were calculated to judge the predictive behavior of theproposedmodelampe validation results are presented in Table 3

331 Linearity ampe absorption spectra of each drug and theirmixtures as well were checked for their linearityampe results arelinear in the concentration range of 03ndash5μgmL for CHZ03ndash15μgmL for CRZ 05ndash10μgmL for HAL 05ndash10μgmLfor IMP and 3ndash20μgmL for PTN ampe model showed ex-cellent prediction for the validation set represented in the goodcorrelation coefficients ranging between 09993 and 09998 forall analytes Figure 2 shows the regression plots of the MCR-ALS-predicted analyte concentrations versus the actual con-centrations In addition low relative errors (RE ()) between067 and 142were obtained expressing the quality of fit of theentire calibration data

332 Accuracy ampe accuracy of the developed method wasevaluated using the standard addition method ampe percentrecoveries results were satisfactory ranging from 993 to1001 with SDs not higher than 16 (Table 3) ampeseresults confirmed that the excipients in commercial for-mulations do not interfere with the determination of thestudied analytes

333 Precision ampe intraday precision and interday pre-cision of the proposed method were assessed by analyzingthree concentration levels low intermediate and high (asindicated in Table 3) of the studied drugs within the sameday for intraday precision and at three consecutive days forinterday precision ampe lower values of RSD (˂16) indi-cated good precision of the developed method (Table 3)

334 Limits of Detection (LOD) and Limits ofQuantifications Limits of detection (LODs) and limits ofquantifications (LOQs) were calculated following themethodology described in [36] In this work LODs were inthe range of 006 to 014 μgmiddotmLminus 1 while the LOQs rangedfrom 019 to 042 μgmiddotmLminus 1 Table 3 shows the values obtained

ampe developed model demonstrated satisfactory vali-dation results

34 Literature Comparison ampis study established a spec-trophotometric method using MCR-ALS for simultaneousdetermination of imipramine carbamazepine chlorprom-azine haloperidol and phenytoin in commercial formula-tions An overview of analytical methods reported for thedetermination of CNS affecting drugs in pharmaceuticaldosage forms revealed that all reported methods [6ndash11]either use or generate harmful solvents Moreover LODs ofthe proposed method were similar to or even better thanthose of the reported methods Overall the comparison ofthe results showed that the presented method is eco-friendlyandmore sensitive than the reportedmethods Furthermore

Table 3 Figures of merit of the MCR-ALS regression model for the validation set of CHZ CRZ HAL IMP and PTN

Parameters HAL IMP CHZ CRZ PNTAccuracy (meanplusmn SD)a 993plusmn 145 998plusmn 155 998plusmn 113 1001plusmn 145 999plusmn 065Precision repeatability (RSD)b 109 132 089 067 078Intermediate precision (RSD)c 146 156 113 144 065RMSEP 656times10minus 2 617times10minus 2 165times10minus 2 781times 10minus 2 554times10minus 2

SEP 634times10minus 2 596times10minus 2 159times10minus 2 754times10minus 2 535times10minus 2

Bias 696times10minus 3 minus 174times10minus 2 minus 236times10minus 3 207times10minus 2 674times10minus 3

RE () 133 135 075 142 067Correlation coefficient (r2) 09994 09995 09997 09996 09998aampe mean and standard deviation for 15 determinations bampe intraday relative standard deviation (n 3) an average of three different concentrationrepeated three times within the same day campe interday relative standard deviation (n 3) an average of three different concentration repeated three times inthree different days Low concentrations 1 μgmL for HAL IMP and CRZ 05 μgmL for CHZ and 5 μgmL for PTN Intermediate concentrations 5 μgmLfor HAL IMP and CRZ 25 μgmL for CHZ and 10 μgmL for PTN High concentration 10 μgmL for HAL IMP and CRZ 5 μgmL for CHZ and 20 μgmLfor PTN

Table 4 Determination of the studied drugs in commercialproducts by the MCR-ALS method the proposed method and thereported HPLC method

MCR-ALS HPLCAnalytesHAL (Haloperidol ampoule)Mean + SD 988plusmn 138 998plusmn 131

t 119 mdashF 112 mdash

IMP (Imipramine tablets)Mean + SD 982plusmn 082 998plusmn 071

t 129 mdashF 133 mdash

CHZ (Neurazibe tablets)Mean + SD 9906plusmn 096 999plusmn 083

t 161 mdashF 135 mdash

CompoundCRZ (Carbapex tablets)Mean + SD 996plusmn 039 998plusmn 049

T 051 mdashF 156 mdash

PTN (Phenytin capsules)Mean + SD 995plusmn 013 997plusmn 014

T 194 mdashF 113 mdash

ampe reference HPLC published method used the C8 (250times 46mm 50 μm)column at 30degC and the mobile phase was composed of acetonitrile andsodium dihydrogenophosphate buffer used in gradient elution mode at15mLmiddotminminus 1 flow rate SD standard deviation of the mean of the per-centage recovery from the label claim amount for 6 determinationsampeoretical values for t and F at (p 005) are 223 and 505 respectively

6 Journal of Analytical Methods in Chemistry

the developed method is economic due to saving in solventconsumption and minimizing in preparation time and thuscan be applied for the routine analysis of the studiedpharmaceuticals without harming the environment

35 Analysis of Pharmaceutical Products ampe developedmodel was applied for the analysis of the studied pharma-ceuticals in different commercial pharmaceutical dosageforms including tablets capsules and ampules Six replicatedeterminations were performed Satisfactory results wereobtained (Table 4) which were in good agreement with thelabel claims

Finally the obtained MCR-ALS results were statisticallycompared with a reported HPLC method [11] for the si-multaneous determination of the five target analytes usingStudentrsquos t test and F ratio at 95 confidence level amperesults showed no significant difference regarding accuracyand precision (Table 4)

4 Conclusion

ampis work presents a fast simple eco-friendly precise andaccurate method for the simultaneous spectrophotometricanalysis of five CNS pharmaceuticals in different dosageforms such as tablets capsules and ampoulesampe developedMCR-ALS model results were compared with a reportedHPLC method and there was no significant difference be-tween the proposed and the reference method regarding theaccuracy and precision ampe proposed chemometric methodhas demonstrated its efficiency to be a valid eco-friendlyalternative to the chromatographic techniques for the de-termination of pharmaceuticals in different dosage formsamperefore it can be used for quality control testing withoutthe need for sample preparation and costly solvents

Data Availability

ampe data used to support the findings of this study areavailable from the corresponding author upon request

Conflicts of Interest

ampe authors declare that they have no conflicts of interest

Acknowledgments

ampe authors gratefully acknowledge the College of ClinicalPharmacy Immam Abdel Rahman Bin Faisal University forproviding research facilities ampis work was supported by theDeanship of Scientific Research Imam Abdulrahman BinFaisal University Saudi Arabia (Grant No Pharm-2017-250)

References

[1] Y Yamini and M Faraji ldquoExtraction and determination oftrace amounts of chlorpromazine in biological fluids usingmagnetic solid phase extraction followed by HPLCrdquo Journalof Pharmaceutical Analysis vol 4 no 4 pp 279ndash285 2014

[2] S Ghafghazi T Zanjani M Vosough and M SabetkasaeialdquoInterference-free determination of carbamazepine in humanserum using high performance liquid chromatography acomprehensive research with three-way calibration methodsrdquoIranian Journal of Pharmaceutical Research vol 16 no 1pp 120ndash131 2017

[3] R Hanaya and K Arita ldquoampe new antiepileptic drugs theirneuropharmacology and clinical indicationsrdquo NeurologiaMedico-Chirurgica vol 56 pp 205ndash220 2016

[4] J Billups C Jones T L Jackson S Y Ablordeppey andS D Spencer ldquoSimultaneous RP-HPLC-DAD quantificationof bromocriptine haloperidol and its diazepane structuralanalog in rat plasma with droperidol as internal standard forapplication to drug-interaction pharmacokineticsrdquo Biomed-ical Chromatography vol 24 no 7 pp 699ndash705 2010

[5] J Zhao Y Shin K-H Chun H-R Yoon J Lee andA Simple ldquoA simple rapid and reliable method to determineimipramine and desipramine in mouse serum using ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometryrdquo Journal of ChromatographicScience vol 54 no 4 pp 561ndash568 2016

[6] H Parastar and H Shaye ldquoComparative study of partial leastsquares and multivariate curve resolution for simultaneousspectrophotometric determination of pharmaceuticals inenvironmental samplesrdquo RSC Advances vol 5 no 86pp 70017ndash70024 2015

[7] M Vosough S Ghafghazi and M Sabetkasaei ldquoChemo-metrics enhanced HPLC-DAD performance for rapidquantification of carbamazepine and phenobarbital in humanserum samplesrdquo Talanta vol 119 pp 17ndash23 2014

[8] L A Terra and R J Poppi ldquoMonitoring the polymorphictransformation on the surface of carbamazepine tabletsgenerated by heating using near-infrared chemical imagingand chemometric methodologiesrdquo Chemometrics and Intel-ligent Laboratory Systems vol 130 pp 91ndash97 2014

[9] Y Higashi M Kitahara and Y Fujii ldquoSimultaneous analysisof haloperidol its three metabolites and two other butyro-phenone-type neuroleptics by high performance liquidchromatography with dual ultraviolet detectionrdquo BiomedicalChromatography vol 20 no 2 pp 166ndash172 2006

[10] L Budakova H Brozmanova M Grundmann and J FischerldquoSimultaneous determination of antiepileptic drugs and theirtwo active metabolites by HPLCrdquo Journal of SeparationScience vol 31 no 1 pp 1ndash8 2008

[11] I Hahirwa C Charlier C Karangwa and R DenoozldquoValidation of an analytical method for the determination inserum of psychotropic drugs by high-performance liquidchromatography with diode array detectionrdquo Rwanda Jour-nal vol 2 no 1 pp 13ndash23 2015

[12] H Shaaban and T Gorecki ldquoCurrent trends in green liquidchromatography for the analysis of pharmaceutically activecompounds in the environmental water compartmentsrdquoTalanta vol 132 no 15 pp 739ndash752 2015

[13] H Shaaban ldquoNew insights into liquid chromatography formore eco-friendly analysis of pharmaceuticalsrdquo Analyticaland Bioanalytical Chemistry vol 408 no 25 pp 6929ndash69442016

[14] H Shaaban and A Mostafa ldquoSustainable eco-friendly ultra-high-performance liquid chromatographic method for si-multaneous determination of caffeine and theobromine incommercial teas evaluation of greenness profile using NEMIand eco-scale assessment toolsrdquo Journal of AOAC Interna-tional vol 101 no 6 pp 1781ndash1787 2018

Journal of Analytical Methods in Chemistry 7

[15] H Shaaban A Mostafa W Alhajri L Almubarak andK AlKhalifah ldquoDevelopment and validation of an eco-friendly SPE-HPLC-MS method for simultaneous determi-nation of selected parabens and bisphenol A in personal careproducts evaluation of the greenness profile of the developedmethodrdquo Journal of Liquid Chromatography amp RelatedTechnologies vol 41 no 10 pp 621ndash628 2018

[16] H Shaaban ldquoHigh speed hydrophilic interaction liquidchromatographic method for simultaneous determination ofselected pharmaceuticals in wastewater using a cyano-bondedsilica columnrdquo Journal of Liquid Chromatography amp RelatedTechnologies vol 41 no 4 pp 180ndash187 2018

[17] A El-Gindy S Emara and H Shaaban ldquoDevelopment andvalidation of chemometrics-assisted spectrophotometric andliquid chromatographic methods for the simultaneous de-termination of two multicomponent mixtures containingbronchodilator drugsrdquo Journal of Pharmaceutical and Bio-medical Analysis vol 43 no 3 pp 973ndash982 2007

[18] A El-Gindy S Emara and H Shaaban ldquoValidation andapplication of chemometrics-assisted spectrophotometry andliquid chromatography for simultaneous determination oftwo ternary mixtures containing drotaverine hydrochloriderdquoJournal of AOAC International vol 93 no 2 pp 536ndash5482010

[19] H Shaaban M Ahmed Z Almatar R Alsheef and S AlrubhldquoSimultaneous determination of over-the-counter pain re-lievers in commercial pharmaceutical products utilizingmultivariate curve resolution-alternating least squares (MCR-ALS) multivariate calibration modelrdquo Journal of AnalyticalMethods in Chemistry vol 2019 Article ID 1863910 8 pages2019

[20] A Mostafa and H Shaaban ldquoQuantitative analysis and res-olution of pharmaceuticals in the environment using multi-variate curve resolution-alternating least squares (MCR-ALS)rdquo Acta Pharmaceutica vol 69 no 2 pp 217ndash231 2019

[21] R Tauler ldquoMultivariate curve resolution applied to secondorder datardquo Chemometrics and Intelligent Laboratory Systemsvol 30 no 1 pp 133ndash146 1995

[22] A de Juan J Jaumot and R Tauler ldquoMultivariate curveresolution (MCR) Solving the mixture analysis problemrdquoAnalytical Methods vol 6 no 14 pp 4964ndash4976 2014

[23] A Mostafa H Shaaban M Almousa M Al Sheqawi andM Almousa ldquoEco-friendly pharmaceutical analysis of mul-ticomponent drugs coformulated in different dosage formsusing multivariate curve resolution and partial least squares acomparative studyrdquo Journal of AOAC International vol 102no 2 pp 465ndash472 2019

[24] P Katsarov G Gergov A Alin et al ldquoAdvanced spectro-photometric chemometric methods for resolving the binarymixture of doxylamine succinate and pyridoxine hydro-chloriderdquo Acta Pharmaceutica vol 68 no 1 pp 61ndash73 2018

[25] M De Luca G Ioele C Spatari and G Ragno ldquoA singleMCR-ALS model for drug analysis in different formulationsapplication on diazepam commercial preparationsrdquo Journalof Pharmaceutical and Biomedical Analysis vol 134 no 5pp 346ndash351 2017

[26] M Garrido F X Rius andM S Larrechi ldquoMultivariate curveresolution-alternating least squares (MCR-ALS) applied tospectroscopic data from monitoring chemical reactionsprocessesrdquo Analytical and Bioanalytical Chemistry vol 390no 8 pp 2059ndash2066 2008

[27] J Jaumot A de Juan and R Tauler ldquoMCR-ALS GUI 20 newfeatures and applicationsrdquo Chemometrics and IntelligentLaboratory Systems vol 140 pp 1ndash12 2015

[28] R G Brereton ldquoMultilevel multifactor designs for multi-variatecalibrationrdquo e Analyst vol 122 no 12pp 1521ndash1529 1997

[29] R Tauler E Gorrochategui and J Jaumot ldquoA protocol forLC-MS metabolomic data processing using chemometrictoolsrdquo Protocol Exchange 2015

[30] M Maeder and A D Zuberbuehler ldquoampe resolution ofoverlapping chromatographic peaks by evolving factoranalysisrdquo Analytica Chimica Acta vol 181 pp 287ndash291 1986

[31] W Windig and J Guilment ldquoInteractive self-modelingmixture analysisrdquo Analytical Chemistry vol 63 no 14pp 1425ndash1432 1991

[32] T Azzouz and R Tauler ldquoApplication of multivariate curveresolution alternating least squares (MCR-ALS) to thequantitative analysis of pharmaceutical and agriculturalsamplesrdquo Talanta vol 74 no 5 pp 1201ndash1210 2008

[33] A de Juan and R Tauler ldquoMultivariate curve resolution(MCR) from 2000 progress in concepts and applicationsrdquoCritical Reviews in Analytical Chemistry vol 36 no 3-4pp 163ndash176 2006

[34] A de Carvalho M Sanchez J Wattoom and R BreretonldquoComparison of PLS and kinetic models for a second-orderreaction as monitored using ultraviolet visible and mid-in-frared spectroscopyrdquo Talanta vol 68 no 4 pp 1190ndash12002006

[35] M Blanco J Coello F Gonzalez H Iturriaga andS Maspoch ldquoSpectrophotometric analysis of a pharmaceu-tical preparation by principal component regressionrdquo Journalof Pharmaceutical Sciences vol 82 no 8 pp 834ndash837 1993

[36] J Saurina C Leal R Compantildeo M Granados M D Prat andR Tauler ldquoEstimation of figures of merit using univariatestatistics for quantitative second-order multivariate curveresolutionrdquo Analytica Chimica Acta vol 432 no 2pp 241ndash251 2001

8 Journal of Analytical Methods in Chemistry

and r2) were calculated to judge the predictive behavior of theproposedmodelampe validation results are presented in Table 3

331 Linearity ampe absorption spectra of each drug and theirmixtures as well were checked for their linearityampe results arelinear in the concentration range of 03ndash5μgmL for CHZ03ndash15μgmL for CRZ 05ndash10μgmL for HAL 05ndash10μgmLfor IMP and 3ndash20μgmL for PTN ampe model showed ex-cellent prediction for the validation set represented in the goodcorrelation coefficients ranging between 09993 and 09998 forall analytes Figure 2 shows the regression plots of the MCR-ALS-predicted analyte concentrations versus the actual con-centrations In addition low relative errors (RE ()) between067 and 142were obtained expressing the quality of fit of theentire calibration data

332 Accuracy ampe accuracy of the developed method wasevaluated using the standard addition method ampe percentrecoveries results were satisfactory ranging from 993 to1001 with SDs not higher than 16 (Table 3) ampeseresults confirmed that the excipients in commercial for-mulations do not interfere with the determination of thestudied analytes

333 Precision ampe intraday precision and interday pre-cision of the proposed method were assessed by analyzingthree concentration levels low intermediate and high (asindicated in Table 3) of the studied drugs within the sameday for intraday precision and at three consecutive days forinterday precision ampe lower values of RSD (˂16) indi-cated good precision of the developed method (Table 3)

334 Limits of Detection (LOD) and Limits ofQuantifications Limits of detection (LODs) and limits ofquantifications (LOQs) were calculated following themethodology described in [36] In this work LODs were inthe range of 006 to 014 μgmiddotmLminus 1 while the LOQs rangedfrom 019 to 042 μgmiddotmLminus 1 Table 3 shows the values obtained

ampe developed model demonstrated satisfactory vali-dation results

34 Literature Comparison ampis study established a spec-trophotometric method using MCR-ALS for simultaneousdetermination of imipramine carbamazepine chlorprom-azine haloperidol and phenytoin in commercial formula-tions An overview of analytical methods reported for thedetermination of CNS affecting drugs in pharmaceuticaldosage forms revealed that all reported methods [6ndash11]either use or generate harmful solvents Moreover LODs ofthe proposed method were similar to or even better thanthose of the reported methods Overall the comparison ofthe results showed that the presented method is eco-friendlyandmore sensitive than the reportedmethods Furthermore

Table 3 Figures of merit of the MCR-ALS regression model for the validation set of CHZ CRZ HAL IMP and PTN

Parameters HAL IMP CHZ CRZ PNTAccuracy (meanplusmn SD)a 993plusmn 145 998plusmn 155 998plusmn 113 1001plusmn 145 999plusmn 065Precision repeatability (RSD)b 109 132 089 067 078Intermediate precision (RSD)c 146 156 113 144 065RMSEP 656times10minus 2 617times10minus 2 165times10minus 2 781times 10minus 2 554times10minus 2

SEP 634times10minus 2 596times10minus 2 159times10minus 2 754times10minus 2 535times10minus 2

Bias 696times10minus 3 minus 174times10minus 2 minus 236times10minus 3 207times10minus 2 674times10minus 3

RE () 133 135 075 142 067Correlation coefficient (r2) 09994 09995 09997 09996 09998aampe mean and standard deviation for 15 determinations bampe intraday relative standard deviation (n 3) an average of three different concentrationrepeated three times within the same day campe interday relative standard deviation (n 3) an average of three different concentration repeated three times inthree different days Low concentrations 1 μgmL for HAL IMP and CRZ 05 μgmL for CHZ and 5 μgmL for PTN Intermediate concentrations 5 μgmLfor HAL IMP and CRZ 25 μgmL for CHZ and 10 μgmL for PTN High concentration 10 μgmL for HAL IMP and CRZ 5 μgmL for CHZ and 20 μgmLfor PTN

Table 4 Determination of the studied drugs in commercialproducts by the MCR-ALS method the proposed method and thereported HPLC method

MCR-ALS HPLCAnalytesHAL (Haloperidol ampoule)Mean + SD 988plusmn 138 998plusmn 131

t 119 mdashF 112 mdash

IMP (Imipramine tablets)Mean + SD 982plusmn 082 998plusmn 071

t 129 mdashF 133 mdash

CHZ (Neurazibe tablets)Mean + SD 9906plusmn 096 999plusmn 083

t 161 mdashF 135 mdash

CompoundCRZ (Carbapex tablets)Mean + SD 996plusmn 039 998plusmn 049

T 051 mdashF 156 mdash

PTN (Phenytin capsules)Mean + SD 995plusmn 013 997plusmn 014

T 194 mdashF 113 mdash

ampe reference HPLC published method used the C8 (250times 46mm 50 μm)column at 30degC and the mobile phase was composed of acetonitrile andsodium dihydrogenophosphate buffer used in gradient elution mode at15mLmiddotminminus 1 flow rate SD standard deviation of the mean of the per-centage recovery from the label claim amount for 6 determinationsampeoretical values for t and F at (p 005) are 223 and 505 respectively

6 Journal of Analytical Methods in Chemistry

the developed method is economic due to saving in solventconsumption and minimizing in preparation time and thuscan be applied for the routine analysis of the studiedpharmaceuticals without harming the environment

35 Analysis of Pharmaceutical Products ampe developedmodel was applied for the analysis of the studied pharma-ceuticals in different commercial pharmaceutical dosageforms including tablets capsules and ampules Six replicatedeterminations were performed Satisfactory results wereobtained (Table 4) which were in good agreement with thelabel claims

Finally the obtained MCR-ALS results were statisticallycompared with a reported HPLC method [11] for the si-multaneous determination of the five target analytes usingStudentrsquos t test and F ratio at 95 confidence level amperesults showed no significant difference regarding accuracyand precision (Table 4)

4 Conclusion

ampis work presents a fast simple eco-friendly precise andaccurate method for the simultaneous spectrophotometricanalysis of five CNS pharmaceuticals in different dosageforms such as tablets capsules and ampoulesampe developedMCR-ALS model results were compared with a reportedHPLC method and there was no significant difference be-tween the proposed and the reference method regarding theaccuracy and precision ampe proposed chemometric methodhas demonstrated its efficiency to be a valid eco-friendlyalternative to the chromatographic techniques for the de-termination of pharmaceuticals in different dosage formsamperefore it can be used for quality control testing withoutthe need for sample preparation and costly solvents

Data Availability

ampe data used to support the findings of this study areavailable from the corresponding author upon request

Conflicts of Interest

ampe authors declare that they have no conflicts of interest

Acknowledgments

ampe authors gratefully acknowledge the College of ClinicalPharmacy Immam Abdel Rahman Bin Faisal University forproviding research facilities ampis work was supported by theDeanship of Scientific Research Imam Abdulrahman BinFaisal University Saudi Arabia (Grant No Pharm-2017-250)

References

[1] Y Yamini and M Faraji ldquoExtraction and determination oftrace amounts of chlorpromazine in biological fluids usingmagnetic solid phase extraction followed by HPLCrdquo Journalof Pharmaceutical Analysis vol 4 no 4 pp 279ndash285 2014

[2] S Ghafghazi T Zanjani M Vosough and M SabetkasaeialdquoInterference-free determination of carbamazepine in humanserum using high performance liquid chromatography acomprehensive research with three-way calibration methodsrdquoIranian Journal of Pharmaceutical Research vol 16 no 1pp 120ndash131 2017

[3] R Hanaya and K Arita ldquoampe new antiepileptic drugs theirneuropharmacology and clinical indicationsrdquo NeurologiaMedico-Chirurgica vol 56 pp 205ndash220 2016

[4] J Billups C Jones T L Jackson S Y Ablordeppey andS D Spencer ldquoSimultaneous RP-HPLC-DAD quantificationof bromocriptine haloperidol and its diazepane structuralanalog in rat plasma with droperidol as internal standard forapplication to drug-interaction pharmacokineticsrdquo Biomed-ical Chromatography vol 24 no 7 pp 699ndash705 2010

[5] J Zhao Y Shin K-H Chun H-R Yoon J Lee andA Simple ldquoA simple rapid and reliable method to determineimipramine and desipramine in mouse serum using ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometryrdquo Journal of ChromatographicScience vol 54 no 4 pp 561ndash568 2016

[6] H Parastar and H Shaye ldquoComparative study of partial leastsquares and multivariate curve resolution for simultaneousspectrophotometric determination of pharmaceuticals inenvironmental samplesrdquo RSC Advances vol 5 no 86pp 70017ndash70024 2015

[7] M Vosough S Ghafghazi and M Sabetkasaei ldquoChemo-metrics enhanced HPLC-DAD performance for rapidquantification of carbamazepine and phenobarbital in humanserum samplesrdquo Talanta vol 119 pp 17ndash23 2014

[8] L A Terra and R J Poppi ldquoMonitoring the polymorphictransformation on the surface of carbamazepine tabletsgenerated by heating using near-infrared chemical imagingand chemometric methodologiesrdquo Chemometrics and Intel-ligent Laboratory Systems vol 130 pp 91ndash97 2014

[9] Y Higashi M Kitahara and Y Fujii ldquoSimultaneous analysisof haloperidol its three metabolites and two other butyro-phenone-type neuroleptics by high performance liquidchromatography with dual ultraviolet detectionrdquo BiomedicalChromatography vol 20 no 2 pp 166ndash172 2006

[10] L Budakova H Brozmanova M Grundmann and J FischerldquoSimultaneous determination of antiepileptic drugs and theirtwo active metabolites by HPLCrdquo Journal of SeparationScience vol 31 no 1 pp 1ndash8 2008

[11] I Hahirwa C Charlier C Karangwa and R DenoozldquoValidation of an analytical method for the determination inserum of psychotropic drugs by high-performance liquidchromatography with diode array detectionrdquo Rwanda Jour-nal vol 2 no 1 pp 13ndash23 2015

[12] H Shaaban and T Gorecki ldquoCurrent trends in green liquidchromatography for the analysis of pharmaceutically activecompounds in the environmental water compartmentsrdquoTalanta vol 132 no 15 pp 739ndash752 2015

[13] H Shaaban ldquoNew insights into liquid chromatography formore eco-friendly analysis of pharmaceuticalsrdquo Analyticaland Bioanalytical Chemistry vol 408 no 25 pp 6929ndash69442016

[14] H Shaaban and A Mostafa ldquoSustainable eco-friendly ultra-high-performance liquid chromatographic method for si-multaneous determination of caffeine and theobromine incommercial teas evaluation of greenness profile using NEMIand eco-scale assessment toolsrdquo Journal of AOAC Interna-tional vol 101 no 6 pp 1781ndash1787 2018

Journal of Analytical Methods in Chemistry 7

[15] H Shaaban A Mostafa W Alhajri L Almubarak andK AlKhalifah ldquoDevelopment and validation of an eco-friendly SPE-HPLC-MS method for simultaneous determi-nation of selected parabens and bisphenol A in personal careproducts evaluation of the greenness profile of the developedmethodrdquo Journal of Liquid Chromatography amp RelatedTechnologies vol 41 no 10 pp 621ndash628 2018

[16] H Shaaban ldquoHigh speed hydrophilic interaction liquidchromatographic method for simultaneous determination ofselected pharmaceuticals in wastewater using a cyano-bondedsilica columnrdquo Journal of Liquid Chromatography amp RelatedTechnologies vol 41 no 4 pp 180ndash187 2018

[17] A El-Gindy S Emara and H Shaaban ldquoDevelopment andvalidation of chemometrics-assisted spectrophotometric andliquid chromatographic methods for the simultaneous de-termination of two multicomponent mixtures containingbronchodilator drugsrdquo Journal of Pharmaceutical and Bio-medical Analysis vol 43 no 3 pp 973ndash982 2007

[18] A El-Gindy S Emara and H Shaaban ldquoValidation andapplication of chemometrics-assisted spectrophotometry andliquid chromatography for simultaneous determination oftwo ternary mixtures containing drotaverine hydrochloriderdquoJournal of AOAC International vol 93 no 2 pp 536ndash5482010

[19] H Shaaban M Ahmed Z Almatar R Alsheef and S AlrubhldquoSimultaneous determination of over-the-counter pain re-lievers in commercial pharmaceutical products utilizingmultivariate curve resolution-alternating least squares (MCR-ALS) multivariate calibration modelrdquo Journal of AnalyticalMethods in Chemistry vol 2019 Article ID 1863910 8 pages2019

[20] A Mostafa and H Shaaban ldquoQuantitative analysis and res-olution of pharmaceuticals in the environment using multi-variate curve resolution-alternating least squares (MCR-ALS)rdquo Acta Pharmaceutica vol 69 no 2 pp 217ndash231 2019

[21] R Tauler ldquoMultivariate curve resolution applied to secondorder datardquo Chemometrics and Intelligent Laboratory Systemsvol 30 no 1 pp 133ndash146 1995

[22] A de Juan J Jaumot and R Tauler ldquoMultivariate curveresolution (MCR) Solving the mixture analysis problemrdquoAnalytical Methods vol 6 no 14 pp 4964ndash4976 2014

[23] A Mostafa H Shaaban M Almousa M Al Sheqawi andM Almousa ldquoEco-friendly pharmaceutical analysis of mul-ticomponent drugs coformulated in different dosage formsusing multivariate curve resolution and partial least squares acomparative studyrdquo Journal of AOAC International vol 102no 2 pp 465ndash472 2019

[24] P Katsarov G Gergov A Alin et al ldquoAdvanced spectro-photometric chemometric methods for resolving the binarymixture of doxylamine succinate and pyridoxine hydro-chloriderdquo Acta Pharmaceutica vol 68 no 1 pp 61ndash73 2018

[25] M De Luca G Ioele C Spatari and G Ragno ldquoA singleMCR-ALS model for drug analysis in different formulationsapplication on diazepam commercial preparationsrdquo Journalof Pharmaceutical and Biomedical Analysis vol 134 no 5pp 346ndash351 2017

[26] M Garrido F X Rius andM S Larrechi ldquoMultivariate curveresolution-alternating least squares (MCR-ALS) applied tospectroscopic data from monitoring chemical reactionsprocessesrdquo Analytical and Bioanalytical Chemistry vol 390no 8 pp 2059ndash2066 2008

[27] J Jaumot A de Juan and R Tauler ldquoMCR-ALS GUI 20 newfeatures and applicationsrdquo Chemometrics and IntelligentLaboratory Systems vol 140 pp 1ndash12 2015

[28] R G Brereton ldquoMultilevel multifactor designs for multi-variatecalibrationrdquo e Analyst vol 122 no 12pp 1521ndash1529 1997

[29] R Tauler E Gorrochategui and J Jaumot ldquoA protocol forLC-MS metabolomic data processing using chemometrictoolsrdquo Protocol Exchange 2015

[30] M Maeder and A D Zuberbuehler ldquoampe resolution ofoverlapping chromatographic peaks by evolving factoranalysisrdquo Analytica Chimica Acta vol 181 pp 287ndash291 1986

[31] W Windig and J Guilment ldquoInteractive self-modelingmixture analysisrdquo Analytical Chemistry vol 63 no 14pp 1425ndash1432 1991

[32] T Azzouz and R Tauler ldquoApplication of multivariate curveresolution alternating least squares (MCR-ALS) to thequantitative analysis of pharmaceutical and agriculturalsamplesrdquo Talanta vol 74 no 5 pp 1201ndash1210 2008

[33] A de Juan and R Tauler ldquoMultivariate curve resolution(MCR) from 2000 progress in concepts and applicationsrdquoCritical Reviews in Analytical Chemistry vol 36 no 3-4pp 163ndash176 2006

[34] A de Carvalho M Sanchez J Wattoom and R BreretonldquoComparison of PLS and kinetic models for a second-orderreaction as monitored using ultraviolet visible and mid-in-frared spectroscopyrdquo Talanta vol 68 no 4 pp 1190ndash12002006

[35] M Blanco J Coello F Gonzalez H Iturriaga andS Maspoch ldquoSpectrophotometric analysis of a pharmaceu-tical preparation by principal component regressionrdquo Journalof Pharmaceutical Sciences vol 82 no 8 pp 834ndash837 1993

[36] J Saurina C Leal R Compantildeo M Granados M D Prat andR Tauler ldquoEstimation of figures of merit using univariatestatistics for quantitative second-order multivariate curveresolutionrdquo Analytica Chimica Acta vol 432 no 2pp 241ndash251 2001

8 Journal of Analytical Methods in Chemistry

the developed method is economic due to saving in solventconsumption and minimizing in preparation time and thuscan be applied for the routine analysis of the studiedpharmaceuticals without harming the environment

35 Analysis of Pharmaceutical Products ampe developedmodel was applied for the analysis of the studied pharma-ceuticals in different commercial pharmaceutical dosageforms including tablets capsules and ampules Six replicatedeterminations were performed Satisfactory results wereobtained (Table 4) which were in good agreement with thelabel claims

Finally the obtained MCR-ALS results were statisticallycompared with a reported HPLC method [11] for the si-multaneous determination of the five target analytes usingStudentrsquos t test and F ratio at 95 confidence level amperesults showed no significant difference regarding accuracyand precision (Table 4)

4 Conclusion

ampis work presents a fast simple eco-friendly precise andaccurate method for the simultaneous spectrophotometricanalysis of five CNS pharmaceuticals in different dosageforms such as tablets capsules and ampoulesampe developedMCR-ALS model results were compared with a reportedHPLC method and there was no significant difference be-tween the proposed and the reference method regarding theaccuracy and precision ampe proposed chemometric methodhas demonstrated its efficiency to be a valid eco-friendlyalternative to the chromatographic techniques for the de-termination of pharmaceuticals in different dosage formsamperefore it can be used for quality control testing withoutthe need for sample preparation and costly solvents

Data Availability

ampe data used to support the findings of this study areavailable from the corresponding author upon request

Conflicts of Interest

ampe authors declare that they have no conflicts of interest

Acknowledgments

ampe authors gratefully acknowledge the College of ClinicalPharmacy Immam Abdel Rahman Bin Faisal University forproviding research facilities ampis work was supported by theDeanship of Scientific Research Imam Abdulrahman BinFaisal University Saudi Arabia (Grant No Pharm-2017-250)

References

[1] Y Yamini and M Faraji ldquoExtraction and determination oftrace amounts of chlorpromazine in biological fluids usingmagnetic solid phase extraction followed by HPLCrdquo Journalof Pharmaceutical Analysis vol 4 no 4 pp 279ndash285 2014

[2] S Ghafghazi T Zanjani M Vosough and M SabetkasaeialdquoInterference-free determination of carbamazepine in humanserum using high performance liquid chromatography acomprehensive research with three-way calibration methodsrdquoIranian Journal of Pharmaceutical Research vol 16 no 1pp 120ndash131 2017

[3] R Hanaya and K Arita ldquoampe new antiepileptic drugs theirneuropharmacology and clinical indicationsrdquo NeurologiaMedico-Chirurgica vol 56 pp 205ndash220 2016

[4] J Billups C Jones T L Jackson S Y Ablordeppey andS D Spencer ldquoSimultaneous RP-HPLC-DAD quantificationof bromocriptine haloperidol and its diazepane structuralanalog in rat plasma with droperidol as internal standard forapplication to drug-interaction pharmacokineticsrdquo Biomed-ical Chromatography vol 24 no 7 pp 699ndash705 2010

[5] J Zhao Y Shin K-H Chun H-R Yoon J Lee andA Simple ldquoA simple rapid and reliable method to determineimipramine and desipramine in mouse serum using ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometryrdquo Journal of ChromatographicScience vol 54 no 4 pp 561ndash568 2016

[6] H Parastar and H Shaye ldquoComparative study of partial leastsquares and multivariate curve resolution for simultaneousspectrophotometric determination of pharmaceuticals inenvironmental samplesrdquo RSC Advances vol 5 no 86pp 70017ndash70024 2015

[7] M Vosough S Ghafghazi and M Sabetkasaei ldquoChemo-metrics enhanced HPLC-DAD performance for rapidquantification of carbamazepine and phenobarbital in humanserum samplesrdquo Talanta vol 119 pp 17ndash23 2014

[8] L A Terra and R J Poppi ldquoMonitoring the polymorphictransformation on the surface of carbamazepine tabletsgenerated by heating using near-infrared chemical imagingand chemometric methodologiesrdquo Chemometrics and Intel-ligent Laboratory Systems vol 130 pp 91ndash97 2014

[9] Y Higashi M Kitahara and Y Fujii ldquoSimultaneous analysisof haloperidol its three metabolites and two other butyro-phenone-type neuroleptics by high performance liquidchromatography with dual ultraviolet detectionrdquo BiomedicalChromatography vol 20 no 2 pp 166ndash172 2006

[10] L Budakova H Brozmanova M Grundmann and J FischerldquoSimultaneous determination of antiepileptic drugs and theirtwo active metabolites by HPLCrdquo Journal of SeparationScience vol 31 no 1 pp 1ndash8 2008

[11] I Hahirwa C Charlier C Karangwa and R DenoozldquoValidation of an analytical method for the determination inserum of psychotropic drugs by high-performance liquidchromatography with diode array detectionrdquo Rwanda Jour-nal vol 2 no 1 pp 13ndash23 2015

[12] H Shaaban and T Gorecki ldquoCurrent trends in green liquidchromatography for the analysis of pharmaceutically activecompounds in the environmental water compartmentsrdquoTalanta vol 132 no 15 pp 739ndash752 2015

[13] H Shaaban ldquoNew insights into liquid chromatography formore eco-friendly analysis of pharmaceuticalsrdquo Analyticaland Bioanalytical Chemistry vol 408 no 25 pp 6929ndash69442016

[14] H Shaaban and A Mostafa ldquoSustainable eco-friendly ultra-high-performance liquid chromatographic method for si-multaneous determination of caffeine and theobromine incommercial teas evaluation of greenness profile using NEMIand eco-scale assessment toolsrdquo Journal of AOAC Interna-tional vol 101 no 6 pp 1781ndash1787 2018

Journal of Analytical Methods in Chemistry 7

[15] H Shaaban A Mostafa W Alhajri L Almubarak andK AlKhalifah ldquoDevelopment and validation of an eco-friendly SPE-HPLC-MS method for simultaneous determi-nation of selected parabens and bisphenol A in personal careproducts evaluation of the greenness profile of the developedmethodrdquo Journal of Liquid Chromatography amp RelatedTechnologies vol 41 no 10 pp 621ndash628 2018

[16] H Shaaban ldquoHigh speed hydrophilic interaction liquidchromatographic method for simultaneous determination ofselected pharmaceuticals in wastewater using a cyano-bondedsilica columnrdquo Journal of Liquid Chromatography amp RelatedTechnologies vol 41 no 4 pp 180ndash187 2018

[17] A El-Gindy S Emara and H Shaaban ldquoDevelopment andvalidation of chemometrics-assisted spectrophotometric andliquid chromatographic methods for the simultaneous de-termination of two multicomponent mixtures containingbronchodilator drugsrdquo Journal of Pharmaceutical and Bio-medical Analysis vol 43 no 3 pp 973ndash982 2007

[18] A El-Gindy S Emara and H Shaaban ldquoValidation andapplication of chemometrics-assisted spectrophotometry andliquid chromatography for simultaneous determination oftwo ternary mixtures containing drotaverine hydrochloriderdquoJournal of AOAC International vol 93 no 2 pp 536ndash5482010

[19] H Shaaban M Ahmed Z Almatar R Alsheef and S AlrubhldquoSimultaneous determination of over-the-counter pain re-lievers in commercial pharmaceutical products utilizingmultivariate curve resolution-alternating least squares (MCR-ALS) multivariate calibration modelrdquo Journal of AnalyticalMethods in Chemistry vol 2019 Article ID 1863910 8 pages2019

[20] A Mostafa and H Shaaban ldquoQuantitative analysis and res-olution of pharmaceuticals in the environment using multi-variate curve resolution-alternating least squares (MCR-ALS)rdquo Acta Pharmaceutica vol 69 no 2 pp 217ndash231 2019

[21] R Tauler ldquoMultivariate curve resolution applied to secondorder datardquo Chemometrics and Intelligent Laboratory Systemsvol 30 no 1 pp 133ndash146 1995

[22] A de Juan J Jaumot and R Tauler ldquoMultivariate curveresolution (MCR) Solving the mixture analysis problemrdquoAnalytical Methods vol 6 no 14 pp 4964ndash4976 2014

[23] A Mostafa H Shaaban M Almousa M Al Sheqawi andM Almousa ldquoEco-friendly pharmaceutical analysis of mul-ticomponent drugs coformulated in different dosage formsusing multivariate curve resolution and partial least squares acomparative studyrdquo Journal of AOAC International vol 102no 2 pp 465ndash472 2019

[24] P Katsarov G Gergov A Alin et al ldquoAdvanced spectro-photometric chemometric methods for resolving the binarymixture of doxylamine succinate and pyridoxine hydro-chloriderdquo Acta Pharmaceutica vol 68 no 1 pp 61ndash73 2018

[25] M De Luca G Ioele C Spatari and G Ragno ldquoA singleMCR-ALS model for drug analysis in different formulationsapplication on diazepam commercial preparationsrdquo Journalof Pharmaceutical and Biomedical Analysis vol 134 no 5pp 346ndash351 2017

[26] M Garrido F X Rius andM S Larrechi ldquoMultivariate curveresolution-alternating least squares (MCR-ALS) applied tospectroscopic data from monitoring chemical reactionsprocessesrdquo Analytical and Bioanalytical Chemistry vol 390no 8 pp 2059ndash2066 2008

[27] J Jaumot A de Juan and R Tauler ldquoMCR-ALS GUI 20 newfeatures and applicationsrdquo Chemometrics and IntelligentLaboratory Systems vol 140 pp 1ndash12 2015

[28] R G Brereton ldquoMultilevel multifactor designs for multi-variatecalibrationrdquo e Analyst vol 122 no 12pp 1521ndash1529 1997

[29] R Tauler E Gorrochategui and J Jaumot ldquoA protocol forLC-MS metabolomic data processing using chemometrictoolsrdquo Protocol Exchange 2015

[30] M Maeder and A D Zuberbuehler ldquoampe resolution ofoverlapping chromatographic peaks by evolving factoranalysisrdquo Analytica Chimica Acta vol 181 pp 287ndash291 1986

[31] W Windig and J Guilment ldquoInteractive self-modelingmixture analysisrdquo Analytical Chemistry vol 63 no 14pp 1425ndash1432 1991

[32] T Azzouz and R Tauler ldquoApplication of multivariate curveresolution alternating least squares (MCR-ALS) to thequantitative analysis of pharmaceutical and agriculturalsamplesrdquo Talanta vol 74 no 5 pp 1201ndash1210 2008

[33] A de Juan and R Tauler ldquoMultivariate curve resolution(MCR) from 2000 progress in concepts and applicationsrdquoCritical Reviews in Analytical Chemistry vol 36 no 3-4pp 163ndash176 2006

[34] A de Carvalho M Sanchez J Wattoom and R BreretonldquoComparison of PLS and kinetic models for a second-orderreaction as monitored using ultraviolet visible and mid-in-frared spectroscopyrdquo Talanta vol 68 no 4 pp 1190ndash12002006

[35] M Blanco J Coello F Gonzalez H Iturriaga andS Maspoch ldquoSpectrophotometric analysis of a pharmaceu-tical preparation by principal component regressionrdquo Journalof Pharmaceutical Sciences vol 82 no 8 pp 834ndash837 1993

[36] J Saurina C Leal R Compantildeo M Granados M D Prat andR Tauler ldquoEstimation of figures of merit using univariatestatistics for quantitative second-order multivariate curveresolutionrdquo Analytica Chimica Acta vol 432 no 2pp 241ndash251 2001

8 Journal of Analytical Methods in Chemistry

[15] H Shaaban A Mostafa W Alhajri L Almubarak andK AlKhalifah ldquoDevelopment and validation of an eco-friendly SPE-HPLC-MS method for simultaneous determi-nation of selected parabens and bisphenol A in personal careproducts evaluation of the greenness profile of the developedmethodrdquo Journal of Liquid Chromatography amp RelatedTechnologies vol 41 no 10 pp 621ndash628 2018

[16] H Shaaban ldquoHigh speed hydrophilic interaction liquidchromatographic method for simultaneous determination ofselected pharmaceuticals in wastewater using a cyano-bondedsilica columnrdquo Journal of Liquid Chromatography amp RelatedTechnologies vol 41 no 4 pp 180ndash187 2018

[17] A El-Gindy S Emara and H Shaaban ldquoDevelopment andvalidation of chemometrics-assisted spectrophotometric andliquid chromatographic methods for the simultaneous de-termination of two multicomponent mixtures containingbronchodilator drugsrdquo Journal of Pharmaceutical and Bio-medical Analysis vol 43 no 3 pp 973ndash982 2007

[18] A El-Gindy S Emara and H Shaaban ldquoValidation andapplication of chemometrics-assisted spectrophotometry andliquid chromatography for simultaneous determination oftwo ternary mixtures containing drotaverine hydrochloriderdquoJournal of AOAC International vol 93 no 2 pp 536ndash5482010

[19] H Shaaban M Ahmed Z Almatar R Alsheef and S AlrubhldquoSimultaneous determination of over-the-counter pain re-lievers in commercial pharmaceutical products utilizingmultivariate curve resolution-alternating least squares (MCR-ALS) multivariate calibration modelrdquo Journal of AnalyticalMethods in Chemistry vol 2019 Article ID 1863910 8 pages2019

[20] A Mostafa and H Shaaban ldquoQuantitative analysis and res-olution of pharmaceuticals in the environment using multi-variate curve resolution-alternating least squares (MCR-ALS)rdquo Acta Pharmaceutica vol 69 no 2 pp 217ndash231 2019

[21] R Tauler ldquoMultivariate curve resolution applied to secondorder datardquo Chemometrics and Intelligent Laboratory Systemsvol 30 no 1 pp 133ndash146 1995

[22] A de Juan J Jaumot and R Tauler ldquoMultivariate curveresolution (MCR) Solving the mixture analysis problemrdquoAnalytical Methods vol 6 no 14 pp 4964ndash4976 2014

[23] A Mostafa H Shaaban M Almousa M Al Sheqawi andM Almousa ldquoEco-friendly pharmaceutical analysis of mul-ticomponent drugs coformulated in different dosage formsusing multivariate curve resolution and partial least squares acomparative studyrdquo Journal of AOAC International vol 102no 2 pp 465ndash472 2019

[24] P Katsarov G Gergov A Alin et al ldquoAdvanced spectro-photometric chemometric methods for resolving the binarymixture of doxylamine succinate and pyridoxine hydro-chloriderdquo Acta Pharmaceutica vol 68 no 1 pp 61ndash73 2018

[25] M De Luca G Ioele C Spatari and G Ragno ldquoA singleMCR-ALS model for drug analysis in different formulationsapplication on diazepam commercial preparationsrdquo Journalof Pharmaceutical and Biomedical Analysis vol 134 no 5pp 346ndash351 2017

[26] M Garrido F X Rius andM S Larrechi ldquoMultivariate curveresolution-alternating least squares (MCR-ALS) applied tospectroscopic data from monitoring chemical reactionsprocessesrdquo Analytical and Bioanalytical Chemistry vol 390no 8 pp 2059ndash2066 2008

[27] J Jaumot A de Juan and R Tauler ldquoMCR-ALS GUI 20 newfeatures and applicationsrdquo Chemometrics and IntelligentLaboratory Systems vol 140 pp 1ndash12 2015

[28] R G Brereton ldquoMultilevel multifactor designs for multi-variatecalibrationrdquo e Analyst vol 122 no 12pp 1521ndash1529 1997

[29] R Tauler E Gorrochategui and J Jaumot ldquoA protocol forLC-MS metabolomic data processing using chemometrictoolsrdquo Protocol Exchange 2015

[30] M Maeder and A D Zuberbuehler ldquoampe resolution ofoverlapping chromatographic peaks by evolving factoranalysisrdquo Analytica Chimica Acta vol 181 pp 287ndash291 1986

[31] W Windig and J Guilment ldquoInteractive self-modelingmixture analysisrdquo Analytical Chemistry vol 63 no 14pp 1425ndash1432 1991

[32] T Azzouz and R Tauler ldquoApplication of multivariate curveresolution alternating least squares (MCR-ALS) to thequantitative analysis of pharmaceutical and agriculturalsamplesrdquo Talanta vol 74 no 5 pp 1201ndash1210 2008

[33] A de Juan and R Tauler ldquoMultivariate curve resolution(MCR) from 2000 progress in concepts and applicationsrdquoCritical Reviews in Analytical Chemistry vol 36 no 3-4pp 163ndash176 2006

[34] A de Carvalho M Sanchez J Wattoom and R BreretonldquoComparison of PLS and kinetic models for a second-orderreaction as monitored using ultraviolet visible and mid-in-frared spectroscopyrdquo Talanta vol 68 no 4 pp 1190ndash12002006

[35] M Blanco J Coello F Gonzalez H Iturriaga andS Maspoch ldquoSpectrophotometric analysis of a pharmaceu-tical preparation by principal component regressionrdquo Journalof Pharmaceutical Sciences vol 82 no 8 pp 834ndash837 1993

[36] J Saurina C Leal R Compantildeo M Granados M D Prat andR Tauler ldquoEstimation of figures of merit using univariatestatistics for quantitative second-order multivariate curveresolutionrdquo Analytica Chimica Acta vol 432 no 2pp 241ndash251 2001

8 Journal of Analytical Methods in Chemistry