Metoprolol is one of the most widely used $\beta$₁-selective beta-blockers, playing a critical role in the treatment of arterial hypertension and cardiac arrhythmias. In addition, it is approved for use in patients with coronary artery disease, for secondary prevention after myocardial infarction, for the management of certain cardiac arrhythmias, chronic stable heart failure, and for migraine prophylaxis.

After oral administration, metoprolol is rapidly and almost completely absorbed from the gastrointestinal tract. Due to extensive first-pass metabolism, its systemic bioavailability is limited, generally remaining below 50%. It is a lipophilic drug with a plasma half-life of about 3–4 hours; however, its clinical effects on heart rate and blood pressure persist longer than predicted by plasma concentrations. Clinically relevant drug interactions must be considered, particularly in multimorbid patients. Metoprolol may enhance or prolong the effects of insulin and oral antidiabetic drugs and may mask symptoms of hypoglycemia; therefore, regular blood glucose monitoring is recommended. Concomitant use with other antihypertensive agents (e.g., nitrates, diuretics, vasodilators) may result in additive hypotensive effects. Combined administration with calcium channel blockers (especially non-dihydropyridines such as verapamil or diltiazem) or other antiarrhythmic agents can increase the risk of bradycardia, atrioventricular conduction disturbances, and cardiac depression. Caution is also advised when metoprolol is used together with sympathomimetic agents, as blood pressure responses may be altered [1].

Metoprolol was first introduced in the 1980s in the form of its tartrate salt (metoprolol tartrate) and Beloc (Astra) and Lopresor (Ciba) were the first commercial preparations to contain this active ingredient. Since the early 1990s, various generic metoprolol tartrate drug products for oral use have been available on the market in addition to the two originator preparations. These include immediate-release (IR) and extended-release (ER) preparations. The latter represent classical ER matrices with 12-hour first-order release kinetics, which generally require twice-daily administration.

In 1990, a novel ER formulation based on metoprolol succinate (metoprolol hemisuccinate) was introduced under the brand name Beloc-Zok (Astra Zeneca), offering once-daily dosing with a controlled-release profile consistent with zero-order kinetics [2]. It was postulated by the developer that the transition from the IR formulation Beloc to Beloc-Zok would result in a more uniform 24-hour plasma concentration profile with reduced peak–trough fluctuations, thereby potentially supporting therapeutic efficacy while minimizing adverse effects. The Beloc-Zok formulation utilizes a multi-unit pellet system (MUPS) composed of numerous coated pellets, each functioning as an individual diffusion unit. These pellets are designed to release metoprolol succinate at a nearly constant rate for approximately 20 hours, largely independent of physiological variables such as gastrointestinal pH, motility, or food intake. Considering the plasma half-life of metoprolol, this system achieves stable drug concentrations throughout the day, minimizing peak–trough fluctuations and thereby enabling sustained $\beta$₁-blockade across a broad therapeutic dose range (12.5 to 200 mg once daily) [2, 3, 4]. For many years, this was the only available metoprolol formulation with such a release pattern.

From 2001 onward, additional ER formulations of metoprolol tartrate were approved, for which a 24-hour release profile consistent with zero-order kinetics was claimed, despite differences in salt form and formulation technology compared with Beloc-Zok. In these products, metoprolol tartrate is embedded within a hydrophilic polymer matrix that rapidly swells upon oral administration, forming a gel layer at the tablet surface that acts as a diffusion barrier; drug release occurs via diffusion of dissolved metoprolol tartrate through this gel layer and by matrix erosion during gastrointestinal transit, allowing the release kinetics to be approximated by zero-order behavior. With the exception of use in stable, chronic heart failure of mild to moderate severity, these formulations were positioned as generic substitutes [5].

With approvals in 2005 and 2009, generic ER drug products of metoprolol succinate became available that were designed to be therapeutically equivalent to Beloc-Zok. These generics contain the same salt form and employ a significantly different release mechanism compared to the tartrate-based formulations. While both the metoprolol tartrate “twice-daily” and “once-daily” ER formulations use matrix-based technologies, the succinate-based generics are rapidly disintegrating tablets that release multiple coated pellets upon disintegration. These pellets then release the active ingredient in a controlled manner over approximately 24 hours, mimicking the release characteristics of the original Beloc-Zok formulation.

All currently approved generic metoprolol succinate formulations in Europe (EU) have demonstrated bioequivalence to the reference product Beloc‑Zok (EU), based on single-dose pharmacokinetic studies conducted under both fasting and fed conditions, and, in some cases, on multiple-dose studies under fasting conditions, all performed in healthy volunteers. These studies form the basis for regulatory approval but do not directly evaluate clinical interchangeability across diverse patient populations. While regulatory data support the assumption of therapeutic equivalence, real-world evidence indicates that some patients may experience differences in therapeutic response.

Reports from clinical practice worldwide, including patient experiences and anecdotal observations, suggest that some patients, and occasionally healthcare professionals, perceive generic ER metoprolol formulations as not fully equivalent to the branded product. Experience-based reports include variability in blood pressure and heart-rate control, recurrence of arrhythmias, palpitations, dizziness, fatigue, and other general symptoms, with some individuals reporting improvement after returning to the branded formulation or switching between generic manufacturers [6]. While these observations are anecdotal and cannot establish causality, they highlight perceived differences in therapeutic response following substitution. From a biopharmaceutical and clinical perspective, this raises important questions: Can these generics with differing release mechanisms truly serve as interchangeable substitutes in a diverse patient population under real-world conditions? Is the substitution of these formulations, which is frequently driven by cost considerations, rebate contracts, or temporary unavailability due to supply shortages, pharmacologically neutral and clinically safe?

This project aims to address these questions through a series of compendial and physiologically relevant in vitro dissolution studies on selected commercial metoprolol formulations. The objective is to critically evaluate the interchangeability of these products under simulated routine dosing conditions in diverse patient populations, with a particular focus on their predicted in vivo release characteristics and the clinical implications of formulation differences.

The discussion regarding the interchangeability of metoprolol ER formulations has been somewhat of a never-ending story. In particular, since the market introduction of Beloc-Zok, now over 35 years ago, questions and debates on this topic have repeatedly arisen. These issues tend to resurface whenever a new generation of generics enters the market. In the late 1990s and early 2000s, a major problem was that, due to cost constraints, Beloc-Zok was replaced by less expensive generics, which exhibited completely different release kinetics because, unlike Beloc-Zok, they were designed for twice-daily administration [5]. The patient-reported complaints in this context were entirely understandable, as administration of these metoprolol tartrate-based ER formulations according to the Beloc-Zok dosing schedule resulted in a markedly altered plasma concentration profile due to the omission of the second daily dose.

Once this issue was recognized, novel metoprolol tartrate ER formulations with purported zero-order release kinetics were introduced, reigniting the debate on interchangeability. Overall, under simulated gastrointestinal passage conditions in average adults, these formulations demonstrated release profiles similar to the corresponding Beloc-Zok formulation, despite differences in salt form [17]. However, it remained unclear whether this similarity would also be observed under conditions expected in individual patients. At that time, the issue was not further pursued, as German legislation mandated the substitution of brand-name drugs, which could only be avoided in exceptional cases.

With the market introduction of a new generation of generic products formulated according to the same concept as Beloc-Zok, namely tablets composed of compressed ER multiparticulates containing metoprolol succinate and designed as diffusion cells that deliver the drug at a relatively constant rate largely independent of physiological variations in the gastrointestinal tract, this question became relevant again and formed the basis of the present study. Based on the fact that the current “latest” generation of ER metoprolol succinate generics contains the same metoprolol salt, follows the same overarching formulation principle, and that the generic products available on the German market have been shown to be pharmacokinetically equivalent to the originator product Beloc-Zok, such a question initially appears to be entirely irrelevant. However, closer examination of the composition of these generics, two of which were randomly selected as components of the present experimental series, reveals that the coatings of the discrete units of these dosage forms consist of different polymers (Table 1). Under conditions present in the human gastrointestinal tract, these differences may result in at least slightly different drug release rates. For a highly soluble and highly permeable drug like metoprolol, for which in vivo release is the primary determinant of absorption, this can lead to differing plasma concentration profiles. In a mechanistic modeling study by Basu et al. [18], physiologically based pharmacokinetic simulations showed that changes in drug release rates due to formulation variables (such as the release-controlling polymer) can result in significant differences in maximum plasma concentration (C_max) and other pharmacokinetic parameters, even when the active ingredient is the same, indicating that polymer and release characteristics are critical determinants of systemic exposure for ER formulations containing metoprolol succinate. Furthermore, experience from the US market has shown that different generic ER metoprolol succinate formulations were associated with an increased incidence of adverse effects in routine clinical use, leading to the eventual withdrawal of some of these products from the market [6, 19, 20].

Notably, despite differences in the coatings of the drug-releasing multiparticulates, Beloc-Zok 95 mg (ethylcellulose) and Metoprolol Succinate AL 95 mg (polyacrylate) both exhibited very similar release profiles under all test conditions. In contrast, the extent and rate of drug release from MetoHexal 95 mg was consistently lower under all experimental conditions, although, as for Metoprolol Succinate AL 95 mg, the release in this formulation is also controlled by a polyacrylate coating according to the declared excipients. In the present test series, only these two randomly selected generic formulations were investigated, and the objective was not to perform a statistical comparison with the originator product, as they are approved as bioequivalent. Rather, the study aimed to replicate realistic everyday in vivo conditions with a high degree of variability, in order to better interpret patient-specific complaints and reported adverse effects, such as bradycardia, hypotension, chest pain, increased blood pressure, etc., associated with generic formulations.

Considering the differences observed in some drug release profiles and the large number of generic formulations currently available for Belok-Zok, it can be assumed that slightly different in vivo release patterns in individual patients are likely and difficult to predict. This may lead to minor differences in absorption and the resulting pharmacokinetic parameters, which may be clinically irrelevant for many patients, but in selected individuals could result in significant effects if pharmacokinetic differences impact critical pharmacodynamic parameters. This could explain the issues frequently reported in the lay press and raises the question, particularly for well-controlled patients, of whether it is advisable to follow market-driven cost considerations and switch such patients to generic metoprolol formulations. Beyond potential adverse effects, such switches may also cause considerable uncertainty among patients and negatively affect adherence, which can further compromise therapeutic outcomes.

One approach to improving the therapeutic safety of generic drugs is the use of physiologically relevant in vitro release methods that do not merely aim to simulate the conditions of a standardized clinical study but can also reflect variable physiological conditions in individual patients, as employed in the present study. In combination with physiologically based pharmacokinetic and pharmacodynamic models, these methods are expected to provide better predictions of the spectrum of in vivo performance of such formulations in the future.

Some limitations of this study should be considered when interpreting the results. The primary objective was to investigate and compare the release behavior of selected metoprolol ER formulations under standardized, physiologically relevant in vitro conditions, in order to better understand potential reasons why individual patients may respond differently to the substitution of metoprolol ER products. The aim was not to establish in vitro–in vivo correlations or to demonstrate bio(in)equivalence. Accordingly, no IVIVC validation against clinical pharmacokinetic data was performed, and for the same reason no formal similarity testing of the dissolution profiles was conducted. The set of formulations investigated represents only a limited subset of the metoprolol ER products available on the market. The products were selected as a pragmatic cross-section rather than as a comprehensive survey, also reflecting variability in market availability and substitution practices that may limit the accessibility of specific formulations at a given time. In addition, only a single batch of each formulation was investigated, which may not fully capture potential batch-to-batch variability. An increased number of tested products would likely lead to a broader range of observed release profiles. The data presented already indicate variability and trends in release behavior across the included formulations, but they do not claim to comprehensively represent the full extent of variability across all available products. Finally, while the applied in vitro setup reflects key physiological aspects of the gastrointestinal environment as well as its variability, it cannot fully capture the complexity and interindividual differences of in vivo conditions and, in the present study, did not account for additional influences that may arise from the administration of the dosage forms with food. In light of these limitations, an increase rather than a reduction in variability could theoretically be expected. However, as this study is limited to an in vitro evaluation under controlled conditions designed to simulate selected in vivo scenarios, such effects remain speculative and are therefore not further elaborated here; the interpretation of the results should remain within the scope of the experimental setup.

Physiologically relevant in vitro release studies reveal that small differences in drug release among ER metoprolol formulations are possible despite bioequivalence. While these variations are generally minor, they may affect sensitive patients, highlighting the need for careful consideration when switching from branded to generic medicines. Future studies should incorporate such in vitro testing in combination with physiologically based pharmacokinetic and pharmacodynamic modeling to better predict in vivo performance and support safer therapeutic decisions.

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

FK: Formal analysis, Investigation, Methodology, Visualization. SK: Conceptualization, Project administration, Writing – original draft, review and editing. Both authors contributed to editorial changes in the manuscript. Both authors read and approved the final manuscript. Both authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

Not applicable.

This research received no external funding.

The authors declare no conflicts of interest.