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Abstract

In this work, the inclusion complex of metoprolol with β-cyclodextrin was prepared and investigated using various spectroscopic techniques. The aqueous solution of the inclusion complex was examined using UV-visible, fluorescence spectroscopy, and ¹HNMR, whereas the solid physical mixing was investigated by utilizing Fourier transform infrared. Confirmation of the existence of an inclusion complex is achieved through the observation of alterations in spectroscopic properties. Both 1:1 and 1:2 stoichiometry a host–guest interaction was formed between metoprolol and β-cyclodextrin. The constants that represent the inclusion the interaction was determined to be K1=9.09 × 10⁻⁴ μM⁻¹ and K2=1.96 × 10⁻⁶ μM⁻¹ by using typical double reciprocal graphs. The parameters affecting the inclusion complex formation were investigated and optimized. Based on remarkable increase on the fluorescence intensity, spectrofluorometric method for determination of metoprolol in pharmaceutical formulation was developed. The fluorescence intensity of metoprolol was measured at 297 nm, after excitation at 223. Under the optimum conditions, linear relationship in concentration range of 0.35–1.7 μM, with correlation coefficient of 0.9944, was obtained. The limit of detection has been shown as 0.11 μM, while the limit of quantification was shown as 0.34 μM. The proposed approach was successfully utilized to analyze the drug in its pharmaceutical formulation.

Keywords

β-CD inclusion complex metoprolol spectrofluorimetric method

Introduction

Cyclodextrins (CDs) are cycle-like oligosaccharides created of glucose-based units. They possess the capacity to generate readily soluble in water complexes of inclusion of small molecules. They consist of glucopyranose units connected by $\infty$ -(1–4) glycosidic linkages.¹ The inner part of a truncated cone appears to be hydrophobic in nature, which allows it to efficiently trap a wide variety of compounds, including pharmaceuticals. On the contrary, its exterior border of the truncated cone has a high amount of hydroxyl groups, which are responsible for the structure’s distinctive hydrophilicity (Figure 1).² An inclusion of molecule inside the cavity will alter both the chemical and physical features of the original free molecule that is being hosted or accommodated, such as its solubility, stability, spectroscopic properties. These attributes are being employed in the pharmaceutical business, particularly to boost the solubility and bioavailability of pharmaceuticals. They do this by functioning as transport mechanisms for chemical compounds that are found in biological cells.^3,4 Viewed from an analytical point, inclusion complexes have the capacity to enhance the fluorescence intensity^5–9 and facilitate the separation of chiral substances by capillary electrophoresis.^10–13 Furthermore, the fluorescence behavior of pharmaceuticals that were trapped with CDs was effectively employed to build multiple techniques for identifying various substances in both samples taken from the pharmaceutical industry and the environment.^14–17 When it comes to cardiovascular drugs, β-blockers are often used. These medications are used to treat cardiac diseases such as high blood pressure, heart attack, and irregular heart rhythms.¹⁸ Metoprolol (MET) is a selective beta1-adrenoreceptor blocking agent. Beta1-adrenoreceptors are predominantly found in two specific organs in our body, which are the heart and the kidney. The chemical formula for metoprolol tartrate is 1-[4-(2-methoxyethyl) phenoxy]-3-[(1-methylethyl) amino] -2- propanol hemi-tartrate. The chemical structure is shown in Figure 2.¹⁹ The solubility of β-blockers in aqueous solutions is low. As a result, the low solubility rate and their biological availability have a direct impact on the effectiveness of the treatment. Because of this, to enhance the solubility, inclusion complexes of MET with both β-CD and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), were prepared.^20,21 MET in pharmaceutical formulations and biological products were determined using different approaches, according to a literature review like liquid chromatography,^22,23 capillary electrophoresis,^24,25 gas chromatography,^26,27 and spectrophotometric methods.^28,29

Figure 1.

Chemical structure of β-CD.

Figure 2.

Chemical structure of MET.

In this research work the inclusion complex of MET with β-CD was prepared in aqueous solution and solid was investigated fluorescence spectroscopy, UV–VIS spectroscopy, ¹HNMR, and Fourier transform infrared spectroscopy (FTIR), respectively. To the best of our knowledge, spectrofluorometric methods based on inclusion complex formation of MET with β-CD have not been reported. Thus, due to enhancement of florescence intensity of MET spectrofluorometric method for determination of MET in pharmaceutical formulation based on inclusion complex was developed for the first time.

Experimental

Chemical and reagents

Dibasic sodium phosphate (99.0%), monobasic sodium phosphate (99.0%), MET standard (98.0%), HP-β-CD (97.0%), and β-CD (97.0%) were acquired from Sigma-Aldrich (St. Louis, MO, USA).

Instrumentations

The spectrophotometric investigations occurred using a Shimadzu UV-1650 pc double-beam ultraviolet-visible a spectrum analyzer (Kyoto, Japan), equipped with a 50 W halogen light and deuterium lamp. The fluorescence spectra and intensity analyses were conducted using the Shimadzu RF 6000 spectrofluorometer (Kyoto, Japan). This device is outfitted with a 150-W xenon lamp. Also, Bruker Ascend 400 spectrometer was utilized to obtain the ¹H NMR spectra (Bruker, Billerica, MA, USA) with the Top Spin 3.5 software). Infrared (IR) measurements were performed using Cary 630 FTIR (Bruker, Billerica, MA, USA).

Preparation of standardized solutions of MET and β-CD

MET standard solution was prepared by dissolving 17 mg of MET in a phosphate buffer with a pH of 7.0. Consequently, a stock solution was formed with a concentration of 1000 μM. The solution was then transferred to a standard flask of 25 mL, then to accomplish dilution more phosphate buffer with an identical pH was inserted. In order to make a stock solution of β-CD with a concentration of 15,000 μM, 1.7 g of β-CD was dissolved in water that is deionized and transferred into a standard flask of 100 mL. Additional more water was added to obtain the desired dilution.

Buffer solution

The solution of buffer having a pH of 7.0 was generated by utilized both 0.1 M of Na₂HPO₄ and 0.1 M of NaH₂PO₄ solutions.

UV spectroscopy measurement

The MET sample of 0.1 mL was transferred into volumetric glass with a volume of 10 mL. Subsequently, at the same container 4 mL of β-CD solution was introduced. Afterward, the flask became filled with a buffered phosphate solution with a pH of 7.0. The resulting solution was subjected to vibration at ambient temperature by placing it in a sonicator at duration of 10 min. Afterward, the intensity of absorption was obtained at a precise wavelength of 223 nm.

Fluorescence measurement

In a volumetric container of 10, 0.1, and 4 mL of MET and β-CD were combined, respectively. For reaching the desired volume, the last combination was diluted by including a phosphate buffer solution with a pH of 7.0. Afterward, the flask ended up in the sonicator at room temperature over a period of 10 min. Finally, the MET-β-CD complex ’s fluorescence intensity was quantified at λ_ex/λ_em 223/297 nm.

Determination of stochiometric ratio

According to the experimental parameters that had been previously computed, the stoichiometry of the inclusion complex was determined by analytical approach called Benesi–Hildebrand plots. The assumption was made that the complexes exhibited a 1:1 ratio. The equation expressed in the form: 1/F–F0 = 1/(F∞-F0) K[β-CD0] + 1/F∞-F0. In the above formula, F∞ denotes the fluorescence intensity when the majority of MET molecules remain locked in β-CD, F indicates the detected fluorescence intensity at each measured concentration of β-CD, and[β-CD0] reflects the initial concentration of β-CD.

Limit of detection and quantification

For calculating limit of detection (LOD) or limit of quantification (LOQ), the value 3.3 is used for LOD and 10 is used for LOQ. The formula is K. SDa/b, where K represents the respective value. The SDa symbol represents the standard deviation of the intercept, while the symbol b indicates the slope.

Results and discussion

Analysis of absorption spectra

The MET absorption spectra were measured in without and with the addition of 6 × 10³ μM of β-CD which presented in Figure 3. The research results indicated that the wavelength at which MET exhibits which the peak absorption wavelength was 223 nm at pH 7.0. By introducing β-CD to the solutions, the wavelength at which the maximum absorbance occurs stays the same, but there is a minor rise in absorbency. This results in a rise in the molar absorptivity coefficients ε (L mol⁻¹ cm⁻¹) from 19,000 to 29,700.

Figure 3.

Absorbance spectra for MET- β-CD, MET 10 μM, β-CD 6 × 10³ μM at room temperature, time 10 min, pH 7.0.

Infrared spectroscopic analysis

Metoprolol’s infrared spectrum in Figure 4, the detected peaks are displayed as follows: 3500 cm⁻¹ for OH stretching, 3032.6 cm⁻¹ stretching band for = C-H, 2871.19 cm⁻¹ for N-H stretching, 1577 cm⁻¹ for C-O stretching, 1511.47 cm⁻¹ for C=C stretching, 819 cm⁻¹ for scissoring = C-H. These agree with the FT-IR spectrum corresponding to MET reported in the literature.^30,31 Significant alterations in the FTIR spectra were seen following the establishment of the MET-β-CD inclusion complex. The OH stretching band at 3500 cm⁻¹ exhibits significant broadening and a red shift. Also, the peak at 3032.6 cm⁻¹ stretching band for =C-H has a red shift to 3200 cm⁻¹. The band associated with the stretching of NH at 2871 cm⁻¹ was moved to a higher wavenumber of 2873 cm⁻¹, while the band associated with the stretching of C-O was both weaker and shifted to a higher wavenumber of 1583 cm⁻¹. In addition, the band assigned to C=C stretching at 1511 cm⁻¹ looked shorter with blue shift to 1512 cm⁻¹. It is possible that the changes mentioned earlier are due to differences in the microenvironment. The interaction between β-CD and MET in the solid physical mixture had a considerable influence on both hydrogen bonding and van der Waals forces.

Figure 4.

IR of β-CD, MET, and MET-β-CD.

Proton nuclear magnetic resonance spectroscopy (¹H NMR)

¹HNMR spectroscopy is a useful method for examining the complexation of CDs.^32,33 The interactions between host and guest molecules are non-covalent bonds such as van der Waals forces, hydrophobic interactions, and hydrogen bonds through.^34,35 If the guest molecule is incorporated into the b-CD cavity their chemical shifts will be changed. Non-covalent bonds, such as hydrophobic interactions, van der Waals forces, and hydrogen bonds, play a crucial role in connecting host and guest molecules. The ¹H chemical shift values of MET before and after forming the inclusion complex are shown in Table 1. As can be seen from Table 1, the complexation caused several chemical shifts of MET protons. It confirmed that the complex was formed.

Table 1.

NMR of MET and the shift after complex with MET-β-CD.


MET structure
Proton MET	MET free (ppm)ᵟ	MET complexed (ppm)ᵟ	∆ᵟ (MET complexed—MET free) (ppm)
8-H, 8’H	7.119	7.042	−0.077
7-H,7’-H	6.867	6.854	−0.013
5-H	4.694	4.936	0.242
a-H, a’-H	4.160	4.219	0.059
6 -H	4.003	4.195	0.192
6’-H	3.938	3.992	0.054
10-H	3.594	3.545	−0.049
11-H	3.343	3.390	0.047
3-H	3.218	3.215	−0.003
4-H	3.186	3.196	0.01
4’-H	3.084	3.091	0.007
9-H	2.738	2.710	−0.028
1-H	1.237	1.252	0.015
2-H	1.227	1.235	0.008

Characterizing emission spectra

Fluorescence spectroscopy is an extremely effective technique for investigating host–guest molecular systems, offering sensitivity and selectivity. Fluorescence analysis offers notable benefits due to its heightened sensitivity and capacity for accurately measuring substantially smaller quantities compared with spectrophotometric analysis. At first, the spectral characteristics of MET was examined. According to the study results, the MET exhibited a maximum emission wavelength of 297 nm at pH 7.0. After the addition of β-CD to the drug flack, there was an observed rise in fluorescence intensity, although the emission’s maximum wavelength remained unchanged (Figure 5). This phenomenon may be attributed to the engagement by non-covalent interactions like hydrogen bonding and van der Waals forces between MET and of β-CD in the hydrophobic interior of β-CD’s core.

Figure 5.

Emission spectra MET-β-CD, MET 10 μM, β-CD 6×103 μM, at room temperature, time 10 min, pH 7.0.

Optimization of variables affect inclusion complex formation

The study examined multiple variables that influence the creation of inclusion complexes, the kind of CD used (either native β-CD or derivative β-CD), including the pH of the buffer, the duration of complexation, and the concentration of β-CD.

Optimizing of CD type

The present study investigated the impact of CD type on absorbance and fluorescence intensity. Particularly, native β-CD and modified HP-β-CD, were used for this purpose. The outcomes obtained are displayed in (Figure 6 (a) and (b)). As can be observed, the absorbance and the fluorescence intensity were higher when the native β-CD was added to MET solution than HP-β-CD added to the same drug solution. Because of the steric hindrance provided by the HP-β-CD structure, which makes it less favorable for the inclusion complex, which make native β-CD is the optimum CD type for MET-β-CD inclusion complex.^36,37

Figure 6.

(a) Emission spectra of MET, MET-β-CD Inclusion complexes, concentration of MET 10 μM, β-CD 6 × 103 μM, in a 10 min, pH 7.0, at room temperature, and (b) MET-HP-β-CD Inclusion complexes, concentration of MET 10 μM, HP-β-CD 6 × 103 μM, in a 10 min, pH 7.0, at room temperature.

Optimizing the pH of the inclusion complex

The pH of the solution has a greatly influences on the intensity of fluorescence of the complex that builds up between MET and β-CD. The pH was checked throughout the spectrum of 2 to 9, and the outcomes can be seen in Figure 7. MET has a basic pKa value which is 9.6.³⁸ A rise in fluorescence intensity was observed when the pH values increased from 3.0 to 7.0, followed by a decrease in pH 8.0 and 9.0. According to this behavior, the optimum pH for the formation of the complex is the pH with the highest fluorescence intensity, which is pH 7.0. As the drug is a basic drug, any pH which is less than its pKa is considered as an acidic media. As a consequence of this, the inclusion complex of MET-β-CD was suitable in this media, which is where the protonated and ionized form of the drug is favorable for the inclusion complex.

Figure 7.

Emission spectra of MET-β-CD in series of pH from pH 3 to pH 9, concentration of MET 10 µM, β-CD 200µM, at room temperature, time 10 min, the higher fluorescence intensity showed at pH 7.0.

Optimizing of the complexation time

The research examined the optimization of the time required of complexation and its impact on the fluorescence intensity of the MET-β-CD complex. The experiment was carried out at ambient temperature, with a duration ranging from 5 to 25 min (data not shown). The findings suggest that the highest fluorescence intensity value occurred at the 15 min. Consequently, the fluorescence intensity reduced, indicating that it was the optimal period for complexation.

Optimizing of β-CD concentration

In order to optimize the concentration of β-CD, the focus will be on examining the impact of β-CD concentrations on formation of MET complex. The drug concentration was maintained at a constant level of 10 μM, while the β-CD concentration was altered within the range of 50–400 μM (Figure 8). The fluorescence intensity exhibited a continuous and gradual rise until it achieved an unchanging complex at a concentration of 300 μM. Therefore, this specific point has been chosen as the most favorable concentration.

Figure 8.

Emission spectra of MET 10 µM with different concentration of β-CD from 50 to 400 µM, at room temperature, time 10 min, pH 7.0.

Stoichiometry of inclusion complex

It was obtained by examining the previously estimated experimental parameters. The complex was presumed to have a 1:1 ratio. The research used the analytical approach known as Benesi–Hildebrand plots. The equation is expressed in the following manner: The equation may be written as 1/F–F0 = 1/(F∞-F0) K[β-CD0] + 1/ F∞-F0. The equation specifies F∞ as the fluorescence intensity when a large number of MET molecules are immobilized inside β-CD. The symbol [β-CD0] denotes the starting concentration of β-CD, whereas F indicates the fluorescence intensity seen at each detected concentration of β-CD. Figure 9(a) depicts a graph illustrating the relationship between 1/F–F0 and 1/[β-CD0]. The graph shows that there is a 1:1 ratio between MET-β-CD, with an inclusion constant of K1 = 9.09 × 10⁻⁴ µM⁻¹. To precisely ascertain the stoichiometric ratio, the assumption of a 1:2 inclusion complex with β-CD. The assessment was conducted by graphing the reciprocal of the difference between F and F0 as a function of the reciprocal of the square of β-CD (Figure 9(b)). This resulted in a linear correlation, confirming the possibility of forming both 1:1 and 1:2 inclusion complexes of MET with β-CD simultaneously and K2 was found to be 1.96 × 10⁻⁶ µM⁻¹.²³

Figure 9.

(a) Plot of 1/(F–F0) vs 1/[ β-CD] of MET- β-CD complex; MET 10 µM, pH 7.0, and (b) plot of 1/(F–F0) versus 1/[β-CD]² of MET-β-CD complex; MET 10 µM, pH 7.0.

Validation of the procedure

The analytical procedures were validated accordance with International Conference for Harmonization (ICH) guidelines with respect to linearity, LOD, LOQ, accuracy, and robustness.³⁹

Linearity and LODs and LOQ

The suggested techniques showed linear relationships with strong correlation coefficients (n = 8) with varying concentrations from 0.35 to 1.7 μM. The calculated values and data from statistics display in Table 2. The equations used to compute the LOD and LOQ are as follows: LOD or LOQ is equal to K. In the context of calculating LOD, the symbol K is 3.3, but for calculating LOQ, it will be 10. The term “SDa” denotes the standard deviation of the intercept, whereas “b” indicates the slope. The LOD and LOQ were found to be 0.11 and 0.34 μM, respectively.

Table 2.

Parameters for MET-β-CD spectrofluorimetric method.

Parameters	Values
Linear range	0.35–1.7 μM
Slope	125,690
Intercept	5402.3
LOD (μM)	0.11
LOQ (μM)	0.34
Correlation coefficient (r).	0.99
Molar absorptivity of β-CD	1.31 L mol⁻¹ cm⁻¹
Molar absorptivity of MET- β-CD inclusion complex	29,700 L mol⁻¹ cm⁻¹
Optimum pH	pH = 7
Optimum β-CD concentration	300 μM
Optimum complexation time	15 min

Accuracy of spectrofluorometric method

The evaluation was conducted by evaluating three sets of duplicate measurements at three different concentrations levels. Table 3 demonstrates a notable degree of consistency and precision in the acquired data, suggesting that the process is reliable. The exceptional level of accuracy was perfect for ensuring the quality analysis of MET in their pharmaceutical product formulations.

Table 3.

The accuracy and precision of MET-β-CD inclusion complex.

Sample content (μM)	Standard added (μM)	Found (μM)	Recovery% ± RSD^a
0.5	0.1	0.64	106% ± 0.6
0.5	0.6	1.2	109% ± 0.2
0.5	0.9	1.4	102% ± 0.3

Values are the mean of three determinations.

Robustness of spectrofluorometric method

The robustness of the analytical results was evaluated by assessing the impact of small changes in the parameters. In these tests, the recovery was determined for each example by isolating and modifying a single parameter while leaving all other variables constant. Therefore, it was discovered that little modifications in the procedure parameters had negligible consequences for the operations. The values of recovery values can be seen in Table 4.

Table 4.

Robustness of the spectrofluorometric method for MET-β-CD.

ParameterStandard condition		Recovery ± SD^a 100.9% ± 0.4
pH	7.2	100% ± 1.3
pH	6.8	109% ± 0.6
β-CD concentration (μM)	320	109% ± 1.0
β-CD concentration (μM)	280	100% ±1.3
Reaction time (min)	10	87% ± 1.2
Reaction time (min)	20	100% ± 0.6

Values are mean of three determinations.

Pharmaceutical formulation analysis

The suggested technique effectively examined MET pharmaceutical formulations with acceptable accuracy in drug detection. The percentage values were 95% calculated from five determinations, as presented in Table 5. Recoveries were accurately calculated as the amount found divided by the amount taken multiplied by 100 values are mean ± RSD.

Table 5.

The method application of MET-β-CD inclusion complex.

Concentration taken (μM)	Concentration found (μM)	Recovery% ± RSD^a
1	0.95	95% ± 0.6

Value is the means of five determinations.

Conclusion

In the present study, we demonstrated that β-CDs can be used as guest complexing agent, which acted as substrate reservoir in a dosage-controlled manner. The results showed that the inclusion process was occurred. The formation of the inclusion complex MET-β-CD was confirmed by FTIR, ¹H NMR, fluorescence, and UV/visible spectroscopy. Based on the enhancement of the fluorescence intensity of MET produced through complex formation a simple, sensitive, and accurate method for determination of MET in the presence of β-CD was developed. The proposed method is fully validated and successfully applied for the analysis MET pharmaceutical formulations.

Footnotes

Acknowledgements

The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the Project No. (Grant No. KFU241279). The authors thank Dr Abuzar Albadri, Qassim University for his help in the NMR analysis.

Author contribution

Conceptualization, A.A.E.; Methodology, H.A.; Validation, H.A.; Investigation, H.A.; Writing—original draft, H.A. and A.A.E.; Writing—review & editing, A.O.A.; Supervision, A.A.E. and A.O.A.; Funding acquisition, H.A. All authors have read and agreed to the published version of the manuscript.

Data availability statement

The data generated and analyzed during the current study are available from the corresponding author on reasonable request.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Medical Research Council (Grant No. KFU241279). The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through the project number (Grant No. KFU241279).

Ethical consideration statement

This article does not contain any studies with human or animal participants.

Consent to participate

The manuscript has been read and approved by all the authors, and that each author believes that the manuscript represents honest work.

Consent for publication

Not applicable

ORCID iD

Abdalla Ahmed Elbashir

References

Ali

Shamim

Structure elucidation of Benzhexol-β-cyclodextrin complex in aqueous medium by 1H NMR spectroscopic and computational methods. SCIRP 2014; 4: 63–70.

Brewster

Loftsson

. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliver Rev 2007; 59: 645–666.

Diez

De la Peña

García

, et al. Fluorometric determination of sulphaguanidine and sulfamethoxazole by host-guest complexation in β-Cyclodextrin and partial least squares calibration. J Fluoresce 2007; 17: 309–318.

Alfaki

Elbashir

. Inclusion complex of metformin and β-Cyclodextrin spectroscopic study and analytical application. Sch Res J 2020; 12: 19–30.

Zhang

Zhu

Huang

, et al. Room temperature phosphorescence from inclusion complex of Beta-Cyclodextrin and 1-Bromonaphthalene in the presence of Phenol and 1-Butanol. Korean Chem Soc 2001; 22: 1397–1399.

Linares

De Bertorello

Longhi

. Solubilization of naphthoquinones by complexation with Hydroxypropyl-β-cyclodextrin. Int J Pharm 1997; 159: 13–18.

Xie

Wang

, et al. Spectrophotometric study of the inclusion complex between β-Cyclodextrin and dibenzoyl peroxide and its analytical application. SAA 2005; 62: 197–202.

Chao

Meng

, et al. Preparation and study on the novel solid inclusion complex of ciprofloxacin with HP-cyclodextrin. Spectrochim Acta A Mol Biomol Spectrosc 2004; 60: 729–734.

Chao

Tong

Liu

, et al. Preparation and characterization of inclusion complexes of pefloxacin mesylate with three kinds of cyclodextrins. Spectrochim Acta A Mol Biomol Spectrosc 2006; 64(1): 166–170.

10.

Hancu

Papp

Tóth

, et al. The use of dual cyclodextrin chiral selector systems in the enantioseparation of pharmaceuticals by capillary electrophoresis: an overview. Molecules 2021; 1426(8): 2261.

11.

Elbashir

Suliman

Saad

, et al. Capillary electrophoretic separation and computational modeling of inclusion complexes of Beta-Cyclodextrin and 18-Crown-6 Ether with primaquine and quinocide. BMC 2010; 24: 393–398.

12.

Peluso

Chankvetadze

. Native and substituted cyclodextrins as chiral selectors for capillary electrophoresis enantioseparation: Structures, features, application, and molecular modeling. Electrophoresis 2021; 42(17–18): 1676–1708.

13.

Quirino

. Chiral selectors in capillary electrophoresis: trends during 2017–2018. Molecules 2019; 24(6): 1135.

14.

Elbashir

Dsugi

Mohmed

, et al. Spectrofluorometric analytical applications of cyclodextrins. J Lumin 2014; 29: 1–7.

15.

Elbashir

Abdalla

FAA

Aboul-Enein

. Host-guest inclusion complex of mesalazine and β-cyclodextrin and spectrofluorometric determination of mesalazine. Luminescence 2015; 30(4): 444–450.

16.

Elbashir

Dsugi

Aboul-Enein

. Supramolecular study on the interaction between ofloxacin and Methyl β-Cyclodextrin by fluorescence spectroscopy and its analytical application. J Fluoresce 2014; 24(2): 355–361.

17.

Rajbanshi

Saha

Das

, et al. Study to probe subsistence of host-guest inclusion complexes of α and β-Cyclodextrins with biologically potent drugs for safety regulatory dischargement. Sci Rep 2018; 8: 13031.

18.

Al- Ghannam

. A simple spectrophotometric method for the determination of beta-blockers in dosage forms. Int J Pharm Res Biomed Anal 2006; 40(1): 151–156.

19.

Alhemiary

Shediwa

. Spectrophotometric determination of metoprolol in pharmaceutical formulation by charge transfer complexation. Int J Chem Stud 2015; 3: 24–29.

20.

Radulovic

Karljikovic-Rajic

Lucic

, et al. A preliminary study of β-Cyclodextrin/Metoprolol tartrate inclusion complex for potential enantiomeric separation. Int J Pharm Res Biomed 2001; 24(5–6): 871–876.

21.

Ikeda

Motoune

Ono

, et al. Potential use of 2-Hydroxypropyl-β-Cyclodextrin as a release modifier of a water-soluble drug, metoprolol tartrate, from ethylcellulose tablets. J Drug Deliv 2004; 14(1): 69–76.

22.

Rodina

Melnikov

Dmitriev

, et al. Simultaneous determination of metoprolol and bisoprolol in human serum by HPLC-MS/MS for clinical drug monitoring. Pharm Chem 2018; 51: 1111–1118.

23.

Raoufi

Ebrahimi

Bozorgmehr

. Application of response surface modeling and chemometrics methods for the determination of Atenolol, Metoprolol and Propranolol in blood sample using dispersive liquid–liquid microextraction combined with HPLC-DAD. J Chromatogr B Biomed 2019; 1132: 121823.

24.

Chen

Yang

. Pharmacokinetic study of metoprolol in rabbit plasma by capillary electrophoresis with laser-induced fluorescence detection. J Anal 2012; 67: 572–576.

25.

Duan

Cao

Wang

, et al. Determination of metoprolol tartrate and bisoprolol fumarate by capillary electrophoresis coupled with tris (2,2′- bipyridyl)-ruthenium (II) electrochemiluminescence detection and study on the interaction between the drugs and human serum albumin. Anal Chem 2015; 9: 3946–3951.

26.

Ervik

. Quantitative determination of metoprolol in plasma and urine by gas chromatography. Acta Pharmacol Toxicol 1975; 36: 136–144.

27.

Yilmaz

Arslan

Akba

. Gas chromatography–mass spectrometry method for determination of metoprolol in the patients with hypertension. Talanta 2009; 80: 346–351.

28.

Braza

Modamio

Lastra

, et al. Development, validation and analytical error function of two chromatographic methods with fluorimetric detection for the determination of bisoprolol and metoprolol in human plasma. Biomed Chromatogr 2003; 16: 517–522.

29.

Donchenko

Vasyuk

. Spectrophotometric determination of metoprolol tartrate in pure and dosage forms. J Fac Pharm Ankara 2018; 42: 33–42.

30.

Ciciliati

Cavalheiro

ÉTG

. Studies of thermal behavior of metoprolol tartrate. J Therm Anal Calorim 2019; 138: 3653–3663.

31.

Liu

Song

Chen

, et al. Heat treatment induced specified aggregation morphology of metoprolol tartrate in Poly(ε-caprolactone) matrix and the drug release variation. Polymers 2021; 1313(18): 3076.

32.

Xing

Guo

, et al. Identification of metoprolol tartrate-derived reactive metabolites possibly correlated with its cytotoxicity. Chem Res Toxicol 2022; 35(6): 1059–1069.

33.

Rossi

Paoli

Chelazzi

, et al. The solid-state structure of the β-blocker metoprolol: a combined experimental and in silico investigation. Acta Crystallogr C Struct Chem 2019; 75(Pt. 2): 87–96.

34.

Haouas

Falaise

Leclerc

, et al. NMR spectroscopy to study cyclodextrin-based host-guest assemblies with polynuclear clusters. Dalton Trans 2023; 352(38): 13467–13481.

35.

Ray

Gawenis

Harmata

, et al. NMR internal standard signal shifts due to cyclodextrin inclusion complexes. Magn Reson Chem 2022; 60(1): 80–85.

36.

Upadhyay

Ali

. Solution structure of loperamide and β- cyclodextrin inclusion complexes using NMR spectroscopy. Chem Sci J 2009; 121: 521–527.

37.

Roy

Mahato

Roy

, et al. Exploring inclusion complexes of cyclodextrins with quinolinone based gastro protective drug for enhancing bioavailability and sustained dischargement. Zeitschrift für Physikalische Chemie 2021; 235: 723–744.

38.

Zhang

Lai

, et al. Piroxicam/2- hydroxypropyl-β-cyclodextrin inclusion complex prepared by a new fluid-bed coating technique. J Pharm Sci 2009; 98: 665–675.

39.

Borman

Elder

. Q2(R1) Validation of analytical procedures: text and methodology. In: Teasdale

Elder

Nims

, et al. (eds) ICH Quality Guidelines. Hoboken, NJ: Wiley, 2017, pp. 127–166.

Supramolecular interaction of metoprolol with β-cyclodextrin: Spectroscopic characterization and analytical application

Abstract

Keywords

Introduction

Experimental

Chemical and reagents

Instrumentations

Preparation of standardized solutions of MET and β-CD

Buffer solution

UV spectroscopy measurement

Fluorescence measurement

Determination of stochiometric ratio

Limit of detection and quantification

Results and discussion

Analysis of absorption spectra

Infrared spectroscopic analysis

Proton nuclear magnetic resonance spectroscopy ( 1 H NMR)

Characterizing emission spectra

Optimization of variables affect inclusion complex formation

Optimizing of CD type

Optimizing the pH of the inclusion complex

Optimizing of the complexation time

Optimizing of β-CD concentration

Stoichiometry of inclusion complex

Validation of the procedure

Linearity and LODs and LOQ

Accuracy of spectrofluorometric method

Robustness of spectrofluorometric method

Pharmaceutical formulation analysis

Conclusion

Footnotes

Acknowledgements

Author contribution

Data availability statement

Declaration of conflicting interests

Funding

Ethical consideration statement

Consent to participate

Consent for publication

ORCID iD

References

Proton nuclear magnetic resonance spectroscopy (¹H NMR)