Unichiral drugs, or single-enantiomer drugs, are pharmaceutical compounds composed of only one enantiomer. These have gained significant attention over the last few decades due to their potential to offer a safer, more effective alternative to racemic mixtures. The pharmaceutical industry has increasingly shifted towards developing unichiral drugs, as they often demonstrate improved pharmacokinetics, enhanced therapeutic efficacy, and reduced side effects (Fumagalli et al., 2012) ⁵. The rationale for developing unichiral drugs is rooted in the understanding that biological systems are chiral, and thus, they tend to respond differently to each enantiomer of a drug (Aboul-Enein et al., 2022).

In addition to safety and efficacy, the stereoselectivity of drug transport and metabolism also plays a critical role in drug bioavailability, distribution, and clearance. This is particularly important in pharmacokinetics, where the transport of drugs across cell membranes, often mediated by solute carriers (SLCs), can exhibit enantioselectivity, leading to differences in absorption, distribution, metabolism, and excretion between the enantiomers (Gebauer, 2023). The selective behavior of unichiral drugs has been demonstrated in various therapeutic categories, such as antihypertensives, anti-inflammatories, and neuroprotective agents ⁶.

For instance, (S)-amlodipine besylate, a unichiral form of amlodipine, is widely used as an antihypertensive medication due to its superior safety profile compared to the racemic mixture (Hadžidedić et al., 2014). The unichiral form of the drug exhibits improved efficacy and reduced side effects, such as peripheral edema, which is commonly associated with the racemic formulation. Similarly, unichiral nicotinic acetylcholine receptor agonists have shown potential in neurodegenerative diseases by targeting specific receptor subtypes with high precision, thus minimizing off-target effects (Bolchi et al., 2015) ⁷.

The development and production of unichiral drugs are complex and often require sophisticated techniques to ensure enantiomeric purity. Various methods, such as asymmetric synthesis, chiral resolution, and enzymatic catalysis, have been employed to produce single-enantiomer drugs. Asymmetric synthesis is particularly valuable for achieving high enantiomeric excess (ee), wherein a catalyst selectively favors the formation of one enantiomer over the other (Sui et al., 2009). Chiral resolution, on the other hand, involves the separation of enantiomers from a racemic mixture using specialized techniques such as chromatography. However, these processes can be time-consuming and costly, presenting significant challenges in the large-scale production of unichiral drugs ⁸.

From a regulatory perspective, the FDA and EMA have established guidelines for the development and approval of unichiral drugs. These guidelines emphasize the need for comprehensive studies on the pharmacokinetics, pharmacodynamics, and toxicology of each enantiomer before approval (Singh & Sharma, 2018). The regulatory approval process for unichiral drugs is often more stringent compared to racemic drugs, as manufacturers must provide detailed data demonstrating the safety and efficacy of the chosen enantiomer. For instance, the FDA’s "Policy for the Development of New Stereoisomeric Drugs" requires that both enantiomers in a racemic mixture be evaluated separately to ensure that no adverse effects arise from the presence of the less active or inactive enantiomer (Hadžidedić et al., 2014).

Despite the challenges, the development of unichiral drugs continues to be a promising area of research. Advances in chemical synthesis and biotechnology have led to the development of more efficient methods for producing enantiomerically pure drugs, reducing both the cost and time associated with their production. For example, the use of cyclofructan derivatives as chiral selectors in chromatography has significantly improved the separation of enantiomers, thus enhancing the feasibility of producing unichiral drugs (Aboul-Enein et al., 2022).

Given the increasing focus on unichiral drugs and their potential to improve patient outcomes, it is essential to systematically review the existing literature to provide a comprehensive understanding of their therapeutic applications and pharmaceutical considerations. Systematic reviews play a crucial role in synthesizing existing evidence, identifying knowledge gaps, and offering recommendations for future research ⁹. By integrating data from multiple studies, systematic reviews provide a more robust and reliable assessment of the available evidence compared to individual studies, which may have limited generalizability due to small sample sizes, methodological limitations, or other biases (Moher et al., 2009).

In the context of unichiral drugs, a systematic review is particularly valuable because the literature is often scattered across different fields, including organic chemistry, pharmacology, and clinical medicine. Furthermore, the therapeutic efficacy of unichiral drugs varies significantly depending on the therapeutic area, making it challenging to draw definitive conclusions from individual studies alone. By conducting a systematic review, we aim to provide a comprehensive overview of the therapeutic applications, chemical properties, and pharmaceutical considerations of unichiral drugs, thereby facilitating a better understanding of their potential in improving patient outcomes.

This systematic review will also assess the challenges associated with the production of unichiral drugs, including cost, scalability, and regulatory approval. The review will explore the various chemical methods employed in the synthesis of unichiral drugs, such as asymmetric synthesis and chiral resolution, and evaluate their effectiveness in achieving high enantiomeric purity. The review will discuss the pharmacokinetic and pharmacodynamic benefits of unichiral drugs, particularly in terms of safety, efficacy, and bioavailability.

By synthesizing the available evidence on unichiral drugs, this review will provide valuable insights into their potential as safer and more effective alternatives to racemic drugs. Moreover, the review will highlight the importance of stereochemistry in drug development and underscore the need for further research to overcome the challenges associated with the production and regulatory approval of unichiral drugs.

A comprehensive search was conducted across several major databases, including PubMed, Scopus, Web of Science, and Google Scholar, to identify relevant studies published between 1990 and 2023. The search terms were designed to capture a broad range of studies related to unichiral drugs, with specific emphasis on their therapeutic applications, chemical synthesis methods, pharmacokinetics, and clinical implications.

The search terms included:

Boolean operators (AND, OR) were used to combine these terms, and the search was limited to studies published in English. The reference lists of all selected studies were also screened for additional relevant articles.

To ensure that the most relevant and high-quality studies were included in the review, the following inclusion and exclusion criteria were established:

The study selection process involved two stages:

Two independent reviewers conducted the screening process to ensure consistency and minimize bias. Any discrepancies were resolved through discussion or by consulting a third reviewer.

The PRISMA flowchart (Figure 1) illustrates the search process, from initial identification of records through final inclusion of studies in the review.

A standardized data extraction form was developed to collect relevant information from each study. The form captured the following details:

The data extraction process was carried out independently by two reviewers, and discrepancies were resolved through discussion. A third reviewer was consulted in cases where agreement could not be reached.

The quality of the included studies was assessed using the Critical Appraisal Skills Programme (CASP) checklist for clinical trials and observational studies ¹¹. The CASP tool evaluates various aspects of study design, including methodological rigor, potential biases, and the generalizability of the findings. Studies were rated as high, moderate, or low quality based on predefined criteria. The results of the quality assessment are presented in Table 1.

Given the heterogeneity of the included studies, a narrative synthesis was conducted to summarize the findings. The data were categorized based on the therapeutic applications, pharmaceutical methods, and clinical implications of the unichiral drugs. Statistical analysis was performed where appropriate, and the results were presented using descriptive statistics (e.g., frequencies, percentages).

The findings were grouped under the following themes:

The development of unichiral drugs has been greatly influenced by advancements in asymmetric synthesis and chiral separation techniques. Out of the 11 studies, 5 focused on the methods of unichiral drug synthesis (Table 1). The predominant techniques identified include asymmetric catalytic hydrogenation, chiral chromatography, and enzymatic resolution. These methods were employed to synthesize drugs with high enantiomeric purity, essential for ensuring the desired pharmacological effects of the active enantiomer.

In studies such as Francotte & Lindner (2007) and Singh & Sharma (2018), the importance of high-throughput chiral separation techniques was emphasized for improving bioavailability and reducing side effects. The synthesis of unichiral analogues in Fumagalli et al. (2012) demonstrated significant improvements in selectivity for specific receptors, contributing to better therapeutic outcomes.

Unichiral drugs have a wide range of therapeutic applications, particularly in the treatment of cardiovascular, neurological, and metabolic disorders. In this review, 6 studies reported clinical outcomes or therapeutic benefits of specific unichiral drugs (Table 2). A significant portion of the research focused on antihypertensive agents, such as S-amlodipine, which demonstrated superior efficacy and a reduced side-effect profile compared to its racemic mixture. Hadžidedić et al. (2013) highlighted the advantages of S-amlodipine besylate, showing enhanced stability and therapeutic effectiveness in the treatment of hypertension. Fumagalli et al. (2012) reported that unichiral 1,4-benzodioxane analogues exhibited potent and selective α1B-adrenoceptor antagonist activity, making them promising candidates for cardiovascular treatments.

The pharmacokinetic profile of unichiral drugs was a major focus in 4 studies. Singh & Sharma (2018) provided insights into the enantioselective pharmacokinetics of D- and L-isomers, demonstrating that unichiral drugs often have improved bioavailability and reduced toxicity compared to racemic mixtures. Gebauer (2023) highlighted the stereoselective nature of drug transport via solute carriers, emphasizing the need for tailored drug development to optimize therapeutic effects. The enhanced pharmacokinetic profiles of unichiral drugs often translate into fewer drug-drug interactions, lower doses, and a reduced likelihood of adverse effects, making them more favorable for clinical use.

Several studies demonstrated that unichiral drugs often exhibit superior clinical outcomes compared to their racemic counterparts. In particular, S-amlodipine was shown to have fewer side effects and better long-term outcomes in hypertension treatment (Hadžidedić et al., 2013). Fumagalli et al. (2012) reported that unichiral 1,4-benzodioxane analogues are promising antihypertensive agents, with high selectivity for α1B-adrenoceptors and minimal off-target effects. Moreover, the selectivity of unichiral drugs for specific biological targets can reduce the risk of adverse drug reactions, especially in populations with co-morbidities or those taking multiple medications. In neurodegenerative disorders, unichiral nicotinic receptor agonists have shown promise for their ability to selectively modulate receptor activity without the broad-spectrum effects seen in racemic mixtures (Bolchi et al., 2015).

Regulatory challenges associated with the approval of unichiral drugs were noted in several studies, particularly those involving drugs with complex stereoisomeric structures. The FDA and EMA have stringent requirements for the enantiomeric purity and safety profiles of these drugs. Regulatory pathways for unichiral drugs were discussed in studies such as Francotte & Lindner (2007), which highlighted the growing importance of chiral drugs in the pharmaceutical industry and the need for robust clinical data to support regulatory approval.

The results of this review indicate that unichiral drugs generally exhibit enhanced performance across several key parameters, including enantiomeric purity, bioavailability, clinical efficacy, and side effect reduction ¹². The Table 5 summarizes the comparative analysis of the studies included in this review, highlighting these key parameters.

The findings from this systematic review indicate a promising future for unichiral drugs in the pharmaceutical industry. As the focus shifts towards personalized medicine and more efficient therapeutic strategies, unichiral formulations could play a critical role. Future research should aim to address the following areas:

The authors declare that there are no conflicts of interest related to this manuscript. No financial or personal relationships with other people or organizations that could inappropriately influence the work have been disclosed.

The authors would like to express their sincere gratitude to Dr. Arul Balasubramaniam, Professor and Head of the Department at Vinayaka Mission College of Pharmacy, for his significant contributions and invaluable support throughout the research process. His expertise and guidance have greatly enhanced the quality of this work.