A Review on RP-HPLC Method for the Simultaneous Estimation of Carvedilol and Ivabradine In Bulk and Tablet Dosage Form

Abstract

Carvedilol is often hailed by patients as a "miracle" drug for treating serious heart conditions, especially heart failure and left ventricular dysfunction, significantly improving heart function and reducing symptoms. However, many report moderate satisfaction due to common and severe side effects like fatigue, dizziness, and depression, which can lead some to discontinue use. While effective in lowering heart rate and blood pressure, its tolerability varies, necessitating careful dosage management and communication with healthcare providers. Ivabradine, on the other hand, is generally well-regarded for its heart rate-reducing properties and serves as a valuable alternative to beta-blockers. It has an average user rating of 7.1 out of 10, with many praising its effectiveness in lowering heart rates and alleviating symptoms with minimal side effects. Nonetheless, some users experience negative impacts, including visual disturbances and bradycardia, highlighting the need for careful monitoring and potential combination with other heart failure medications. The developed RP-HPLC method for simultaneous determination of carvedilol and ivabradine offers promising future prospects in three main areas: expanded applications, technological advancements, and method optimization. Key objectives include utilizing the validated method for routine quality control and stability testing, adapting it for biological fluid analysis (human plasma and urine) to assist pharmacokinetic studies, and ensuring effective therapeutic drug monitoring. Method refinement will focus on identifying degradation products to meet regulatory standards, with potential transitions to UHPLC or UFLC for improved performance. Integrating mass spectrometry can enhance specificity and sensitivity, while adopting green chemistry principles aligns with sustainability goals. Exploring fluorescence detection may further improve the method's analytical sensitivity. Overall, the RP-HPLC method is set for significant advancements to achieve superior analytical performance.

Keywords

Introduction

Carvedilol (Figure 1) receives mixed reviews from patients, with its effectiveness in treating serious heart conditions often praised, though tempered by common and sometimes severe side effects. Many users, particularly those with heart failure or left ventricular dysfunction, describe the drug as a "miracle" or "lifesaver" that significantly improved heart function and reduced symptoms like swelling, allowing them to lead better lives (1, 2).

Figure 1: Carvedilol

It is widely acknowledged by patients as being effective in lowering heart rate and blood pressure when other medications have failed, especially after the initial adjustment period where side effects can be most pronounced. However, patient satisfaction ratings are only moderate overall, with a significant number of individuals reporting negative experiences (3, 4). The primary complaints revolve around side effects such as extreme fatigue, dizziness, weight gain, shortness of breath, and depression, which some found severe enough to stop the medication altogether. The consensus among users is that while it is a powerful and potentially life-extending medication for appropriate candidates, its tolerability varies widely among individuals, emphasizing the need for careful dosage titration and close communication with a healthcare provider to manage symptoms. Patients are also advised never to stop taking the medication suddenly due to the risk of serious heart problems (5, 6). Ivabradine (Figure 2) is generally well-regarded by patients and clinicians for its specific heart rate-reducing mechanism, offering a valuable alternative or adjunct to beta-blockers for select patients with heart failure or stable angina pectoris. User reviews on platforms like Drugs.com average around 7.1 out of 10, with many highlighting its "game-changer" potential in significantly lowering very high heart rates (e.g., from over 170 bpm down to 75 bpm) and improving symptoms like chest pain and fatigue with minimal side effects (7, 8). Clinically, studies confirm ivabradine can reduce hospital admissions for worsening heart failure and improve quality of life, especially in patients with a heart rate of 70 beats per minute or higher who have reduced left ventricular function (9, 10).

Figure 2: Ivabradine

However, the reviews are not universally positive, and a notable percentage of users report negative experiences, sometimes severe enough to discontinue the medication. The most common side effect is a temporary visual disturbance called phosphenes (seeing bright spots, halos, or blurred vision), which usually occurs within the first two months of treatment and is generally mild to moderate (11, 12). The other significant risk is bradycardia (very slow heartbeat) or irregular heart rhythms like atrial fibrillation, which can lead to dizziness or fainting. Some patients also report increased blood pressure, headaches, or lack of energy. Overall, the consensus is that ivabradine offers significant benefits for the right patient profile, but careful monitoring by a healthcare team is essential to manage potential side effects and ensure it's used correctly, often in combination with other standard heart failure medications. You can find more detailed prescribing information and potential side effects on the Drugs.com ivabradine page or the FDA website (13, 14).

2. RP-HPLC Method for Simultaneous Determination of Carvedilol and Ivabradine in Bulk and Tablet Dosage Form

Ghazy AA et al., 2025 proposed a method based on oxidation reaction of IVB with a known excess of cerium (IV) ammonium sulphate (Ce (IV)) as an oxidizing agent in acid medium followed by determination of unreacted oxidant by adding a fixed amount of dye e.g. amaranth (AM), methylene blue (MB) and indigo carmine (IC) followed by measuring the absorbance at 520, 664 and 610 nm, respectively. The effect of experimental conditions were studied and optimized. The beer’s law was obeyed in the concentration ranges of 1.0-12, 1.0-18, and 1.0-12 μg mL-1 using AM, MB and IC dyes, respectively with a correlation coefficient ≥ 0.9995. The calculated molar absorptivity values are 2.4971 × 104, 1.8178 × 104 and 2.0833 × 104 L mol-1 cm-1 using AM, MB and IC dyes, respectively. The limits of detection and quantification were 0.29, 0.28 and 0.30 and 0.97, 0.93 and 1.0 µg mL-1 using AM, MB and IC methods, respectively. Intra-day and inter-day accuracy and precision of the methods have been evaluated. No interference was observed from the additives. The proposed methods were successfully applied to the assay of IVB in tablets preparations and the results were statistically compared with those of the reported method by applying Student’s t-test and F-test. The reliability of the methods was further ascertained by performing recovery studies using the standard addition method (15).

Ahmad NR et al., 2025 developed a method that exhibits maximum absorbance at 242 nm in methanol and adheres to Beer’s law within a concentration range of 0.5 - 10 μg/ml. The method demonstrates a relative standard deviation of less than 1.6% and an average recovery of 100 ± 1.3%, indicating high accuracy. Importantly, no interference from common excipients or additives present in Carvedilol formulations was noted, affirming the method's reliability. The technique has been successfully applied to determine Carvedilol content in various pharmaceutical formulations, such as tablets, and industrial wastewater samples. The validation of the method emphasizes its sensitivity and precision, confirming its suitability for routine analysis. This innovative approach is distinguished by its simplicity and rapidity, devoid of complex experimental variables like heating or solvent extraction, and utilizes inexpensive chemicals and techniques. Consequently, it provides an efficient solution for the routine determination and quality control of Carvedilol in pure forms, bulk samples, pharmaceutical preparations, and real industrial wastewater (16).

Yuan L et al., 2025 developed a liquid chromatography method was developed and validated for the accurate determination of carvedilol content while minimizing interference from impurity C and N-formyl carvedilol and allowing precise impurity analysis. The reliability of the method was verified through key parameters such as linearity, precision, accuracy, and stability, ensuring robust performance in the detection and quantification of carvedilol and related impurities. And, the method was tested under varying conditions, including changes in the flow rate, initial column temperature, and mobile phase pH. The results showed that the method demonstrated excellent linearity, with R² values consistently above 0.999 for all analytes. Precision tests yielded RSD% values below 2.0%, confirming the method’s repeatability. Accuracy assessments revealed recovery rates ranging from 96.5% to 101%, while stability studies indicated minimal variation in peak areas and impurity content over extended time periods. These results confirm the method’s reliability for accurate quantification and impurity analysis in pharmaceutical samples (17).

Alossaimi MA et al., 2024 developed a green and highly sensitive synchronous spectrofluorimetric method was developed and validated for the simultaneous estimation of tafamidis (TAF) and carvedilol (CAR) for the first time. The method utilized the inherent fluorescence properties of both drugs, offering high sensitivity and selectivity. The two drugs were measured concurrently at 292 nm and 242 nm for TAF and CAR, respectively at ?λ = 100 nm using water as a green diluting solvent. The method was then validated following the International Council for Harmonization (ICH) recommendations, demonstrating acceptable linearity, precision, accuracy, and selectivity within the specified concentration ranges. The concentrations were linear over the ranges of 10.0–600.0 and 1.0–50.0 ng/mL with limits of detection of 2.67 and 0.08 ng/mL for TAF and CAR, respectively. Due to the high sensitivity, the developed method was applied for analysis of the studied drugs in human plasma samples with high %recoveries (98.27–101.82), indicating good bioanalytical applicability. The greenness and eco-friendliness of the designed methodology were verified using the Green Analytical Procedure Index (GAPI) and the Analytical GREEnness (AGREE) tools. The designed approach is the first analytical approach for TAF and CAR simultaneous analysis without the need for any hazardous chemicals or reagents. The high sensitivity, simplicity, rapidity, greenness, and cost-effectiveness of the proposed method make it suitable for the therapeutic drug monitoring of the investigated drugs (18).

Radwan AS et al., 2024 introduces a pioneering method for the concurrent analysis of the antihypertensive medications Carvedilol (CAR) and Telmisartan (TEL) through a second derivative synchronous spectrofluorimetric technique that is fast, highly sensitive, environmentally friendly, and cost-effective. Specifically, the fluorescence of CAR is detected at 243 nm while TEL is quantified at 274.4 nm, utilizing a wavelength difference (Δλ) of 100.0 nm. The method exhibits exceptional linearity for both medications, with correlation coefficients (r) of 0.9999 within concentration ranges of 1.0–20.0 ng/mL for CAR and 1.0–50.0 ng/mL for TEL. Sensitivity levels are outstanding, with limits of detection at 0.247 ng/mL for CAR and 0.120 ng/mL for TEL, validating the method's appropriateness for bioanalytical applications. The precision of the technique, assessed through both inter-day and intra-day variations, consistently results in relative standard deviations (RSD) below 0.79%. Notably, the method has been effectively applied to measure these pharmaceuticals in tablet formulations and human plasma samples, achieving excellent recovery percentages and low RSD values. The environmental impact of the method was evaluated using GAPI (Green Analytical Procedure Index) and AGREE (A Tool for the Greenness of Analytical Methods) metrics, confirming its greenness and eco-friendliness. Furthermore, the economic viability and practical applicability of the method were analyzed via the BAGI (Benchmark for the Assessment of Green Indicators) tool, all indicating a high level of practicality and sustainability for routine drug analysis. Finally, the method's validation adhered to the ICH Q2 (R1) recommendations, ensuring robustness and reliability of the results (19).

Rashad EA et al., 2023 developed a new, rapid, selective, green, and highly sensitive method has been established to determine ivabradine and carvedilol simultaneously. The first derivative synchronous spectrofluorimetric approach was applied for the determination of the studied drugs. Assessment of the first derivative amplitude of carvedilol and ivabradine has been done at 339 nm and 298 nm respectively which are the zero crossing points of each other. The method validation is estimated and was found to be consistent with International Conference on Harmonization guidelines. Linearity was found to be in the range of 10.0 to 90.0 ng/mL for carvedilol and from 80.0 to140.0 ng/mL for ivabradine. The detection limits were found to be 1.2 ng/ mL and 3.3 ng/mL and the quantitation limits were 3.7 ng / mL and 10.0 ng /mL for carvedilol and ivabradine, respectively. The method was effectively applied for the determination of both drugs in their synthetic mixture in different ratios and in their prepared co-formulated tablets. The results were compared with those of comparison HPLC methods. Ethanol was used as a green solvent (20).

Desai MM et al., 2023 provides a single stability-indicating analytical method for estimation of carvedilol and its organic impurities from bulk and its tablets dosage forms. The method uses Purosphere STAR RP 18-endcapped (250×4 mm, 3 µm) column and a gradient elution with a flow of 1 ml/min. Mobile phase buffer was prepared by adding 1 ml of triethylamine solution to 20 mM potassium dihydrogen phosphate solution, and pH was adjusted to 2.8±0.05 with orthphosphoric acid. Mobile phase A comprises of acetonitrile: buffer (10:1000 v/v), whereas Mobile phase B consist of methanol: acetonitrile: buffer (500:400:150 v/v/v). The eluted compounds were monitored at 226 nm and 240 nm. The column oven temperature was maintained at 50°. In the current chromatographic method total 19 impurities (3 degradation and 16 process related impurities) of carvedilol were separated in a single run. The developed method was validated as per International Council for Harmonisation guidelines for various parameters like system suitability, linearity, precision, accuracy, sensitivity (limits of detection and limits of quantification) and force degradation. All the validation parameters were within the acceptable range. The developed and validated method was quantitatively applied for estimation of all the process and degradation impurities in carvedilol active pharmaceutical ingredient and tablet formulation (21).

Islam MS et al., 2023 intended to construct and make affirmation of a facile, economical, very sensitive with high precision and accuracy, reversed-phase high performance liquid chromatographic method for simultaneous estimation of two drugs Ramipril and Carvedilol. The validation parameters were verified based on the standard requirements of International Council for Harmonization (ICH), U.S. Food and Drug Administration (FDA) and United States Pharmacopoeia (USP) by the determination of linearity, accuracy and precision. To develop the method, a C18 column (with a dimension of 250 × 4.6 mm, 5 μ, SUFELCOSILTM LC-18) was used. The mobile phase was comprised of aqueous KH2PO4 buffer solution and acetonitrile at the ratio of 55:45 (V/V) and flow rate was 1 mL per minute. 220 nm wavelengths in the ultra-violet region was used to monitor the effluents and the retention times were found at 5.1±0.1 and 8.1±0.1 minutes for Ramipril and Carvedilol, respectively. Percent recovery for both drugs was above 98%, which demonstrated that the accuracy protocol was maintained. The linearity responses of the method for both Ramipril and Carvedilol were higher than 0.995 and the percentage of Relative Standard Deviation (RSD) (precision) for both of these two drugs were lower than the highest permissible limit or less than 2% (according to FDA). Therefore, it is easily perceptible that the corresponding RP-HPLC method was highly accurate, effective, rapid and precise which can offer huge potential for the application of simultaneous assay of Ramipril and Carvedilol in pure forms (22).

Zakaria RA et al., 2023 developed an indirect simple and sensitive spectrophotometric method for the determination of carvedilol (CAR), olanzapine (OLP) and domperidone maleate (DOM) in pure and pharmaceutical dosages. The method is based on the oxidation of CAR, OLP and DOM with known excess of potassium permanganate in hydrocholric acid medium and subsequent occupation of unreacted oxidant in bleaching of alkali blue 4B dye and measure the absorbance of residual dye at 594 nm. Calibration curves of residual alkali blue 4B dye in the presence of CAR or OLP and DOM were rectilinear over the ranges 1-12, 1-16 and 1-16 µg ml-1 with molar absorptivity of 4.04×104, 2.13×104 and 3.81×104 l.mol-1 .cm-1 for CAR, OLP and DOM respectively. The accuracy (Recovery percentage) was ranged between 99.77 and 100.34 and precision (RSD%) is less than 0.75%. The suggested method was successfully applied for determination of the studied drugs in their dosage forms resulted in a good agreement with certified value, standard British pharmacopeia method and standard addition procedure (23).

Prajapati P et al., 2022 developed a HPTLC method by the implementation of an enhanced analytical quality by design approach based on the principles of analytical failure modes critical effect analysis (AFMCEA) and design of experiments (DoE) as per the upcoming ICH Q14 guideline. The AFMCEA was started by the identification of potential analytical failure modes followed by their critical effect analysis by a DoE-based screening design. The high-risk failure modes were optimized by DoE-based response surface methodology. The method operable design ranges and control strategy was framed for optimized chromatography conditions. The HPTLC method was validated as per ICH Q2 (R1) guideline. The HPTLC method was applied for the assay of FDC of CAR and IVA, and results were found in compliance with the labeled claim. The developed method can be used as an alternative to the published RP-HPLC method for quality control of FDC of CAR and IVA in the pharmaceutical industry (24).

Tomi? J et al., 2021 aimed at developing a gradient elution reversed-phase high-performance liquid chromatography (RP-HPLC) method for the separation of a complex mixture composed of ivabradine and its eleven impurities, in a reasonable timeframe. In order to obtain a robust and reliable HPLC method for separation of this mixture, Analytical Quality by Design (AQbD) was applied. This approach demonstrated to be useful in development of a long-lasting life cycle methods. Four chromatographic variables were defined as key method parameters (KMPs) and optimized towards the analytical target profile (ATP). Designated KMPs were initial and final amount of acetonitrile in the mobile phase, pH value of the aqueous phase and gradient time, while resolutions of critical peak pairs were denoted as critical method attributes (CMAs). Relationships between KMPs and CMAs were obtained with the aid of Design of Experiments (DoEs) methodology among which Box-Behnken design (BBD) was employed to gain valid mathematical models. Obtained mathematical equations were used to construct the Design Space (DS) and select reliable optimal separation conditions. They included 11% (v/v) and 34% (v/v) of initial and final amount of acetonitrile, respectively, as well as 45 min of gradient elution time and 20 mM ammonium acetate as aqueous mobile phase with pH set to 7.35. The possibility to separate the diastereoisomers of impurity X was also evaluated. It was demonstrated that this separation could not be achieved in gradient elution mode within the defined variable domains and in a reasonable time span. The developed method was validated according to ICH Q2 (R1) guideline and met all the required criteria (25).

FUTURE SCOPE OF THE STUDY

The developed RP-HPLC method for the simultaneous determination of carvedilol and ivabradine presents significant future opportunities primarily in three areas: expanded applications, technological advancements, and method optimization. One major focus is applying the validated method for routine quality control and stability testing of carvedilol and ivabradine in various pharmaceutical formulations. This ensures that these drugs maintain efficacy and safety over their shelf life. Moreover, adapting the method for analysis in biological fluids such as human plasma and urine can facilitate pharmacokinetic studies to analyze how these drugs are absorbed, distributed, metabolized, and excreted. Implementing therapeutic drug monitoring (TDM) would also ensure that patients receive optimal drug levels. Further, refining the method to identify and quantify potential degradation products and impurities in compliance with regulatory guidelines (like ICH Q14) is essential. The method's stability-indicating results from forced degradation studies can promote including comprehensive impurity profiling in the future. Transitioning from conventional HPLC to Ultra-High-Performance Liquid Chromatography (UHPLC) or Ultra-Fast Liquid Chromatography (UFLC) could enhance the method's performance through reduced analysis times (under 3 minutes), lower solvent usage, and improved resolution. Furthermore, integrating the RP-HPLC method with Mass Spectrometry (MS) or tandem MS (LC-MS/MS) could significantly increase its specificity and sensitivity, especially beneficial for analyzing complex biological samples or impurities. A focus on green chemistry principles, such as using environmentally friendly mobile phases, will ensure that the method aligns with sustainable practices. Adopting a Quality by Design (QbD) approach in method development in line with the forthcoming ICH Q14 guideline could enhance robustness and reliability, establishing a clear Method Operable Design Region (MODR). Additionally, exploring alternative detection methods, such as fluorescence detection for carvedilol, could further improve sensitivity and selectivity. In summary, while the current RP-HPLC method is well-suited for routine quality control, its future scope involves adapting it for broader applications, utilizing advanced technologies, and optimizing the methodological framework to ensure superior analytical performance.

CONCLUSION

In conclusion, although the existing RP-HPLC method is well-equipped for routine quality control, its prospective developments promise broader applications, the integration of advanced technologies, and an optimized methodological framework to deliver superior analytical performance. The RP-HPLC method developed for the simultaneous determination of carvedilol and ivabradine is poised for substantial advancements in three key areas: expanded applications, technological enhancements, and method optimization. A primary aim is to apply this validated method for routine quality control and stability testing of these drugs across various pharmaceutical formulations, ensuring their efficacy and safety throughout their shelf life. Additionally, the adaptation of this method for the analysis of biological fluids, notably human plasma and urine, can significantly advance pharmacokinetic studies that investigate the absorption, distribution, metabolism, and excretion of the drugs. This method will facilitate therapeutic drug monitoring (TDM), helping ensure optimal drug levels for patients.

5. Conflict of Interest

None.

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