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. 2026 Jul 30;20(1):167. doi: 10.1186/s13065-026-01823-z

Simultaneous spectroscopic analysis of methocarbamol with its impurity guaifenesin: assessment of greenness, blueness and whiteness applying different sustainability tools

Maram Attia 1,2, Ghada M Hadad 1, Randa A Abdel Salam 1, Mary E K Wahba 2,✉
PMCID: PMC13428443  PMID: 42538549

Abstract

This work introduces an eco-friendly spectrophotometric approach for the simultaneous quantification of methocarbamol (MET) and its impurity product guaifenesin (GUF), based on measuring the second derivative amplitudes of each drug in presence of the other, using zero-crossing technique. The second derivative amplitudes were measured at 208.0 nm and at 207.5 nm for MET and GUF, respectively. The proposed method showed good linearity over the concentration ranges of 1.0–110.0 and 1.0–90.0 µg/mL for MET and GUF, respectively with corresponding correlation coefficient of 0.9997 and 0.9999. The detection and quantitation limits for MET were found to be 0.021 and 0.064 µg/mL, respectively, while GUF corresponding values were 0.013 and 0.041 µg/mL. The method was successfully applied for determining MET and GUF in its dosage forms with high selectivity. The developed method produced comparable results to those obtained by the published reference methods in terms of precision and accuracy. A comprehensive assessment was carried out to evaluate the suggested method’s economic feasibility, practicality, and environmental sustainability compared to previously reported techniques. This comprehensive assessment leveraged several state-of-the-art tools, including the analytical Eco-scale, Green Analytical Procedure Index (GAPI), Analytical GREEnness (AGREE), Multi-Color Assessment, Analytical Green Star Area (AGSA) and Blueness Assessment Graphical Index tools. The suggested approach exhibited favorable quadrant profiles in GAPI assessment, along with higher AGREE, AGSA and Eco-scale scores, all of which confirmed their eco-friendliness.

Keywords: Methocarbamol, Guaifenesin, Derivative spectrophotometry, Green metric tools

Introduction

Green analytical chemistry (GAC) has received more interest in recent years as a way to minimize the environmental impact of analytical techniques. For more than 20 years, the prospect of GAC has been established in the literature. The prospect of incorporating green chemistry into analytical techniques has been presented and expanded upon in works published in 1999 by Anastas [1], 2006 by Koel and Kaljurand [2], and 2008 by Armenta et al. [3]. These articles provide a thorough discussion of the basic principles of GAC. The most significant tenets of GAC were developed in 2013 by Gałuszka et al. [4] in the form of twelve main principles that demonstrate a readiness to take human safety and the environment into consideration while developing and using analytical techniques.

Many measuring tools have been developed in recent years to quantify the degree of compliance of techniques with the GAC prospect in both qualitative and quantitative manners in tandem with the development of greener methods [5–8]. Notably, five potential tools for measuring greenness have been adopted: The Eco-Scale [9], the Green Analytical Procedure Index (GAPI) [10], the Analytical Greenness Calculator (AGREE) [11], Multi-Color Assessment tool (MA tool) [12] and the Analytical Green Star Area (AGSA) [13]. The Eco-Scale is a semiquantitative tool for evaluating how greenness analytical processes are. For any parameter that does not follow the ideal green analysis, the approach for this scale consists of subtracting penalty points (PPs) from a maximum score of 100 [9], while Green Analytical Procedure Index (GAPI) [10] symbolically express the greenness of individual aspects of the analytical procedure via three levels of color scale: green, yellow, or red, indicating high, medium, or low impact respectively [10]. The Analytical Greenness Calculator (AGREE) [11] uses of a pictogram that directly alludes to the twelve GAC criteria in addition to a simple algorithm that quantitatively represents the method's overall greenness on a 0–1 scale. The Multi-Color Assessment tool (MA tool) [12] is an improved version which includes four colors (green, blue, red and violet) to assess the greenness of the following elements: sample preparation, reagents and solvents, instrumentation, and quantification. The MA tool presents the first integrated and freely accessible digital platform that consolidates greenness, practicality, performance, and innovation into a unified, real-time sustainability scoring system for analytical methods [12]. Eventually, the Analytical Green Star Area (AGSA) [13] presents a thorough, integrated rating system that is easy to use. AGSA ensures objective evaluation while adhering to the 12 GAC Principles by integrating method classification, integrated scoring, and resistance to human prejudice [13].

Today, various metrics are available to evaluate the sustainability of analytical methods, including green metrics and models for assessing whiteness, blueness, or the practicality of the method. This study aims to develop an eco-friendly, simple, sensitive, selective, quick, accurate, and affordable derivative spectrophotometric method for simultaneous assay of MET and GUF in different dosage forms to apply these metrics and compare with its reference methods, highlighting their advantages and limitations.

Methocarbamol (MET); a guaiacol glyceryl ether (Fig. 1A), is chemically designated as [2-hydroxy-3-(2-methoxyphenoxy) propyl] carbamate [14], is a centrally-acting skeletal muscle relaxant with an unclear mode of action [15–17]. Methocarbamol is used to treat muscle spasms in individuals with pyramidal spine abnormalities, such as ruptured intervertebral discs [18].

Fig. 1.

Fig. 1

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Structural formulae of MET (A) and GUF (B)

Guaifenesin (GUF) which is marketed as a cold and cough cure, is an impurity product of methocarbamol (Fig. 1B), and chemically designated as 3-(2-methoxyphenoxy) propane-1,2-diol [14]. The respiratory symptoms of colds, asthma, sinusitis, allergies, bronchitis, and other disorders (coughing, congestion, runny/stuffy nose) are treated with GUF medicines [19]. The most popular GUF use for coughing is being an expectorant [20], since it is thought to reduce cough discomfort by increasing sputum volume and decreasing sputum viscosity, which in turn improves effective coughing [20].

Various analytical methods have been developed and optimized for the determination of MET and GUF either alone or in combination with other drugs in pure from, dosage forms and biological matrices. These methods included spectroscopic methods [21–25], chromatographic methods [26–31] and electrochemical methods [32–36].

Over the last few decades, derivative spectrophotometry has been employed extensively for multi-component analysis [37] and matrix background reduction [38]. Because of this, a variety of methods have been used to resolve overlapping derivative peaks. Among its various uses are chemical, pharmaceutical, dietary, clinical, and environmental analyses [37, 39], they have also been used to identify numerous medications in the presence of their impurity products or in mixtures of multiple components [37]. These facts gave us the motivation to carry out this work and because up to the moment, no analytical tool has been reported for the simultaneous determination of the concerned drugs using a derivative spectroscopic method which is advantageous by being rapid, sensitive, economic, and nondestructive requiring minimal sample preparation.

Experimental

Instrumentation

Spectrophotometric analyses were performed on a double beam UV–visible spectrophotometer (model 1900 Shimadzu, Tokyo-Japan) equipped with a pair of matched quartz cells with a path length one cm.

Materials and reagents

  • Methocarbamol (Batch# B/MC-IPA/12/20/010) was kindly supplied by (MUP); Medical Union Pharmaceuticals Co., Cairo, Egypt.

  • Guaifenesin was kindly provided by (MUP); Medical Union Pharmaceuticals Co., Cairo, Egypt.

  • Gufidrexn® tablets: 400 mg GUF per tablet, (Batch #2,501,102), manufactured by (Egyptian International Pharmaceutical Industries Company EPICO, Egypt), were obtained from local pharmacies.

  • Muslgix® capsules: 400 mg of MET and 200 mg ibuprofen /capsule, (Batch #241201A), manufactured by (Pharopharma & chemical industries, Egypt), were obtained from local pharmacies.

  • Methanol (99.9% purity, a product of Fisher scientific, UK) HPLC grade.

Standard stock and working solutions

The stock standard solutions of MET and GUF were prepared with a concentration of 200.0 μg/mL in methanol since MET is sparingly soluble in water [40]. After further diluting to reach a final concentration of 100.0 μg/mL, working solutions were created for more precise solution transfer, and volumes were adjusted with distilled water.

Construction of calibration curves

The stock solutions' proper volumes have been transferred to 10.0 mL volumetric flasks using distilled water as a diluent to bring the volume up to the mark which permitted preparation of various concentrations covering the linearity ranges of 1.0–110.0 and 1.0–90.0 µg/mL for MET and GUF, respectively. The zero-order absorption spectrum of each sample was obtained versus distilled water as a blank in the UV range of 200–500 nm. Shimadzu Lab Solution software was then used to derivatize the resulting spectra. Methocarbamol was measured selectively at 208.0 nm (zero crossing point for GUF), while GUF could be estimated at 207.5 nm (zero crossing point for MET) in the obtained second derivative spectra. By plotting the resultant peaks amplitudes versus the final drug concentrations (µg/mL), the calibration graph was established, or the appropriate regression equation was determined.

Analysis of laboratory prepared mixtures

Laboratory-synthetic mixtures were prepared by adding various ratios of MET and GUF along their linearity ranges and then scanned spectrophotometrically. Their absorption spectra were scanned over a wavelength range of 200–500 nm, using water as a blank. The steps described in " Construction of calibration curves " were then carried out. The percentage recoveries were calculated using the appropriate regression equations.

Analysis of dosage forms

Gufidrexn® tablets and Muslgix® capsules were precisely weighed. For both commercial formulations, about 30 mL of methanol was added to a conical flask containing an amount of the properly ground tablets or evacuated capsules content equivalent to 400 mg of GUF or MET in Gufidrexn® tablets or Muslgix® capsules respectively. Filtration was carried out after 20 min of sonicating the contents of the flask, and the filtrate was quantitatively transferred to a volumetric flask (100.0 mL). Two additions of 30 mL of methanol were performed to complete the extraction procedures. The stock volume was then completed to the appropriate level using the same solvent to reach a final concentration of 200 µg/mL. Appropriate volume was transferred to volumetric flask (100.0 mL) and complete to the mark with distilled water to prepare a working standard solution of final concentration 100 µg/mL. After that, the steps described under " Construction of calibration curves " were carried out, and the relevant regression equation was used to determine the content of MET and GUF in their dosage forms.

Results and discussion

A significant overlap between MET and GUF zero order UV spectra (Fig. 2) was observed. First derivative spectra was scanned but a reproducible zero crossing point could not be found. Consequently, second derivative spectrophotometry was applied to overcome such overlap (Fig. 3). Methocarbamol and guaifenesin were analyzed simultaneously in their binary mixtures using the second derivative technique, using wavelength interval = 0.5 nm, smoothing level ˟10 and scaling factor = 1, where MET was analyzed at 208.0 nm (zero-crossing of GUF) and GUF was analyzed at 207.5 nm (zero-crossing of MET).

Fig. 2.

Fig. 2

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Zero order UV spectra of 40.0 µg/mL MET and 40.0 µg/mL GUF

Fig. 3.

Fig. 3

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Second derivative spectroscopy of 40.0 µg/mL MET and 40.0 µg/mL GUF

Method validation

Full analytical validation of the proposed spectrophotometric method was followed as per ICH guidelines [41]. The method was tested for linearity, specificity, accuracy and precision, as well as detection and quantitation limits; LOD and LOQ.

Linearity and range

Upon applying the proposed method MET and GUF responses were linear over the concentration ranges of 1.0–110.0 µg/mL and 1.0–90.0 µg/mL, respectively. Plotting the peak amplitudes versus the final concentration of each drug in µg/mL led to the construction of calibration curves, which in turn permitted the deduction of partial last square regression equations (Table 1). Low scattering of the data points around the calibration line, endorsed by correlation coefficient values that approach unity, confirms the linearity of the measured responses with concentration. Furthermore, the regression data pertaining to standard deviation of the slope (Sb), standard deviation of the intercept (Sa), and standard deviation of residuals (Sy/x) were used to assess the validity of the suggested method (Table 1).

Table 1.

Analytical performance data for the determination of methocarbamol and guaifenesin applying the proposed method

Parameter Methocarbamol Guaifenesin
Concentration range (µg/mL) 1.0–110.0 1.0–90.0
Limit of detection LOD (µg/mL) 0.021 0.013
Limit of quantitation LOQ (µg/mL) 0.064 0.041
Regression equation y = 0.0094x + 0.0027 y = 0.0123x−0.0068
Correlation coefficient (r) 0.9997 0.9999
S.D. of the residuals (Sy/x) 7.69 × 10−3 5.07 × 10−3
S.D. of the intercept (Sa) 3.13 × 10−3 2.45 × 10−3
S.D. of the slope (Sb) 6 × 10−5 5 × 10−5
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Precision

Repeatability

Through repeated analysis of various drug concentrations in pure form, the repeatability was assessed. Table 2 summarizes the obtained low values of standard deviation, emphasizing on the high repeatability of the suggested method, keeping in mind that the results are based on the average of three separate determinations.

Table 2.

Precision data for the determination of methocarbamol and guaifenesin applying the proposed method

Drug Intra-day precision Inter-day precision
Conc. taken (µg/mL) Mean* %found ± SD Conc. taken (µg/mL) Mean* %found ± SD
Methocarbamol 20.0 98.65 ± 0.05 20.0 98.88 ± 0.29
40.0 97.86 ± 0.15 40.0 98.06 ± 0.41
100.0 98.41 ± 0.08 100.0 98.75 ± 0.36
Guaifenesin 10.0 98.34 ± 0.23 10.0 99.07 ± 0.21
40.0 99.71 ± 0.59 40.0 99.39 ± 0.09
90.0 99.23 ± 0.67 90.0 99.44 ± 0.15
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*Each result is the average of three separate determinations

Intermediate precision

Through replicate analysis of various drug concentrations in pure form over three days in a row, intermediate precision was obtained. Table 2 displays the findings, suggesting an acceptable intermediate precision as reflected from the values of standard deviation.

Accuracy

Accuracy was assessed by applying the proposed method in pure form and in laboratory prepared mixtures (Table 3). By comparing the results obtained from drug analyses using the proposed method in dosage form with those of comparison methods [42, 43]. It was possible to conclude that the proposed method is accurate due to high recovery values and low t and F test values (Table 4) [44].

Table 3.

Assay results for the determination of methocarbamol and guaifenesin in laboratory prepared mixture applying the proposed method

Ratio MET: GUF Parameters 
Methocarbamol Guaifenesin
Conc. taken (µg/mL) Found % found Conc. taken (µg/mL) Found %found
0.5:1 5.0 4.96 99.2 10.0 9.88 98.8
1:0.5 25.0 25.06 100.24 12.5 12.2 97.6
1:1 13.0 12.93 99.46 13.0 12.9 99.23
1:2 15.0 14.58 97.20 30.0 30.4 101.33
2:1 10.0 10.23 102.30 5.0 4.98 99.6
Mean ± SD 99.63 ± 0.54 98.54 ± 0.84
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Table 4.

Application of the proposed method to the analysis of methocarbamol and guaifenesin in their dosage forms

Parameters Methocarbamol Guaifenesin
Conc. taken (µg/mL) %found Comparison method [42] Conc. Taken (µg/mL) %found Comparison method [43]
Dosage forms 20.0 100 100.6 5.0 100.2 99.5
30.0 100 100.1 10.0 100.9 100
40.0 96.9 99.8 20.0 100.5 99.2
50.0 97.6 99.2 30.0 100.3 100
60.0 102.1 100.5 40.0 102.5 100
Mean ± SD 98.97 ± 1.79 100.17 ± 0.4 100.53 ± 0.35 99.56 ± 0.4
t test 0.86 (2.776)* 0.04 (2.776)*
F test 4.41 (6.388)* 1.31 (6.388)*
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∗Tabulated t and F values at p = 0.05[44]

LOQ and LOD

The lowest drug concentration that can be identified under the stated experimental conditions but not necessarily quantified is known as the limit of detection (LOD) [41]. The lowest analyte concentration that can be identified with acceptable accuracy and precision is known as the limit of quantification (LOQ) [41]. The calculated values are listed in (Table 1).

LOQ and LOD were calculated according to the following equations [41]:

LOQ = 10 Sa/b

LOD = 3.3 Sa/b

where Sa is the standard deviation of the intercept of regression line and b is the slope of the regression line.

Specificity

By observing the interferences that could be encountered from pharmaceutical dosage form excipients, the suggested method's specificity was evaluated. The findings demonstrated the method's specificity by showing that these excipients had no effect on results of the suggested approach as revealed from the high values of the percent recoveries (Table 4).

Applications

Application of the proposed method to Muslgix® capsules and Gufidrexn® tablets dosage forms

Methocarbamol in its capsules and guaifenesin in its tablets were effectively analyzed using the suggested method, the results exhibited were in good agreement with those obtained via the reference methods [42, 43]. One comparison method [42] applied an HPLC technique using a C18 column and a mobile phase composed of phosphate buffer: methanol (30:70), adjusted to pH 4.5 with orthophosphoric acid, adopting a flow rate 1 mL/min., with UV detection at 281 nm [42]. While the other adopted a spectrophotometric technique using second derivative of the ratio spectra of GUF at 227 nm using methanol as a diluent [43]. The calculated t and F values reflect the agreement between the proposed and reference methods [44]. Table 4 provides an overview of the obtained data.

Our proposed method is superior in terms of greenness compared to the reported chromatographic method [42], as we use UV–Vis spectroscopy, which uses less energy, produces less waste, uses a safer solvent, takes less time, and has a lower LOD and LOQ values than HPLC. By comparing with the previously published spectrophotometric study [43], our tool is greener and more environmentally friendly since we used water as a solvent, which is safer than methanol and has a lower LOD and LOQ values.

Multi-tool greenness, blueness and whiteness evaluation

The development of numerous assessment tools designed to measure the environmental impact of analytical techniques has been spurred by the tendency toward sustainable analytical procedures.

Greenness profile assessment

Four greenness metrics approaches were used to assess the suggested method's level of greenness; (i) Analytical Eco-Scale, (ii) Green Analytical Procedure Index (GAPI), (iii) Analytical GREEnness calculator (AGREE) and (iv) Analytical Green Star Area (AGSA).

  • (i)

    Analytical Eco-Scale [9]: The proposed method has higher eco scores (94) compared to the reported spectrophotometric method (86) [43] and chromatographic method (82) [42]. Table 5 demonstrates the outstanding performance of our developed method.

  • (ii)

    Green Analytical Procedure Index (GAPI): consists of a diagram with five pentagrams that uses traffic light colors (red-yellow-green) to assess the greenness of 15 parameters [10]. Figure 4 demonstrates the greenness profiles of the proposed method which shows superiority compared to the reported ones [42, 43].

  • (iii)

    The Analytical GREEnness (AGREE): is a downloadable calculator that assesses the 12 principles of green analytical chemistry (GAC) using colorations ranging from green-yellow to red [11]. The clock-shaped pictogram is divided into 12 segments. AGREE ranges vary from 0 to 1. If a method's score is closer to 1, it is deemed greener. The approach has an exceptional level of greenness, as shown by its high AGREE score of 0.70 compared to the reported methods which gained scores of 0.44 and 0.59, respectively [42, 43] (Fig. 5).

  • (iv)

    Analytical Green Star Area (AGSA): is an extension of an analogous metric from green chemistry. The larger green area of an analytical method in AGSA, the higher greenness [13]. The suggested method has an exceptional level of greenness, as shown by its high score of 89.39 compared to the reported methods which gained scores of 78.79 and 83.33, respectively [42, 43] (Fig. 6).

Table 5.

Assessment of the greenness of the developed and reported methods according to the analytical Eco-scale tool

Reagent/instrument Penalty points
Analytical eco-scale
a) The proposed method
Distilled water 0
Spectrophotometer 0
Occupational hazard 0
Waste
 Amount 3
 No treatment 3
Total penalty points ∑6
Total score 94
Reagent/instrument Penalty points
b) The reference method [42]
Methanol Hazard = 5 Amount = 1 (7 mL) 5
Phosphate buffer Hazard = 0 Amount = 1 (3 mL) 0
o-phosphoric acid Hazard = 3 Amount = 1 (< 1mL) 3
Energy  < 1.5 1
Occupational hazard Emission of vapors and gases (Acid + Methanol) 3
Waste Amount = 3 (10 mL) Treatment none = 3 6
Total penalty points ∑18
Analytical eco-scale total score 100–18 82
Reagent/instrument Penalty points
c) The reference method [43]
Methanol Hazard = 5 Amount = 1 (7 mL) 5
Energy  < 0.1 0
Occupational hazard Emission of vapors and gases (Methanol) 3
Waste Amount = 3 (10 mL) Treatment none = 3 6
Total penalty points ∑14
Analytical eco-scale total score 100–14 86
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Fig. 4.

Fig. 4

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GAPI assessment of the developed method (a), the reported HPLC method (b) and the reported spectrophotometric method (c)

Fig. 5.

Fig. 5

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AGREE assessment of the developed method (a), the reported HPLC method (b) and the reported spectrophotometric method (c)

Fig. 6.

Fig. 6

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AGSA assessment of the developed method (a), the reported HPLC method (b) and the reported spectrophotometric method (c)

Blueness profile assessment

The Blueness Assessment Graphical Index (BAGI) [45] was developed in recognition of the crucial significance of approach practicality in real-world applications. It provides more details to aid in comprehending the practical and economic aspects. The geometric mean of the results for ten parameters during the analytic process is used to generate the composite BAGI score. More applicability, usefulness, and suitability for its intended application are indicated by a higher BAGI score. our developed technique achieves a BAGI score of 80.0. According to the results of the BAGI evaluation, as shown in Fig. 7, our system offers significant benefits in terms of overall performance, danger reduction, time and cost savings.

Fig. 7.

Fig. 7

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Blueness assessment of the developed method

Whiteness profile assessment

As an extension of Green Analytical Chemistry (GAC), the concept of White Analytical Chemistry (WAC) is developed. The scope of sustainability concerns may be the subject of a more in-depth investigation by researchers. This calls for a thorough analysis of what needs to be improved or scaled back, as well as a realistic evaluation of the approach. To recognize whiteness of the proposed method, we use the Multi-Color Assessment (MA) Tool [12], the first automated digital platform that unifies four validated color-coded sustainability dimensions, GEMAM (green), BAGI (blue), RAPI (red), and VIGI (violet), into a single interactive system. Through a four-segment typographic letter "M," the platform offers real-time scoring and interpretive visualization. The results are averaged to create a composite "Whiteness Score," which is shown as a stylized white letter "A," signifying overall technique quality and sustainability. The proposed method was white, suited for the intended use, and scored 74.0, as seen in Fig. 8.

Fig. 8.

Fig. 8

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Multi Assessment Tool of the developed method

Conclusion

For the first time, a novel second derivative spectrophotometric method was performed for determination of methocarbamol and guaifenesin in their pure forms, laboratory synthetic mixtures and dosage forms, demonstrating high accuracy and selectivity. The ICHQ2 (R1) guidelines were followed in the validation of the developed approach. The new spectrophotometric method was proven to be environmentally friendly than the published methods based on the greenness (AGREE, GAPI, AGSA and analytical eco-scale), blueness (BAGI), and whiteness (MA) assessment metrics.

Author contributions

Maram Attia: Writing original draft, Methodology, Software, Investigation, Validation; Ghada M. Hadad: Conceptualization, Writing—review & editing, Supervision; Randa A. Abdel Salam: Validation, Writing—review & editing; Mary E.K. Wahba: Conceptualization, Methodology, Resources, Writing-review and editing, Supervision. All authors have approval the final version of the manuscript.

Funding

Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). No fund to be reported.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The manuscript does not contain any work that involve human subjects or laboratory animal.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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