Introduction

Oral delivery is the most common route of administration for drug products. All oral drug products exert systemic and/or local action in the oral cavity and/or gastrointestinal tract. Oral drug products primarily fall into two categories: solid and liquid dosage forms. Solid dosage forms include, but are not limited to, capsules, tablets, granules, lozenges, and powders. Likewise, liquid oral dosage forms include, but are not limited to, solutions, suspensions, syrups, and emulsions [1]. Tablets are unit dosage forms that offer the greatest capabilities among all oral dosage forms, providing the most precise dose and the least content variability. They are the easiest and cheapest to package in bottles or strips, and are relatively inexpensive. Besides these advantages, tablets have the best chemical and microbial stability compared to other oral dosage forms [2].

Scored tablets are designed with a groove on the tablet surface that facilitates the splitting process into equal portions. Many marketed drugs are available as scored tablets, especially the immediate-release formulations such as analgesics and nasal decongestants [3]. Many factors may affect the accuracy of the splitting, such as the hardness, shape, and size of the tablets, as well as the splitting techniques. There are three common tablet splitting techniques: by hand, with a kitchen knife, and with tablet splitting devices [4–6].

Tablet splitting offers several advantages, including cost savings by allowing patients to purchase higher-dose tablets and split them into smaller doses. It also enables dose flexibility and titration, allowing patients to adjust their dosage according to their individual needs. Additionally, splitting tablets can enhance the ease of swallowing, particularly for individuals who have difficulty swallowing whole tablets [7].

Currently, there are limited and non-harmonized regulatory requirements governing tablet scoring practices. The United States Food and Drug Administration has initiated the development of new guidance for tablet scoring. However, the concept of tablet scoring has not been thoroughly investigated, and the available data are insufficient to draw firm conclusions. There are a few published standard data from drug agencies worldwide that address this practice [5].

Tablet scoring presents both challenges and opportunities in tablet splitting, with the risk of medication errors being a major concern. Addressing these issues requires careful consideration of tablet design, manufacturing processes, and selection of excipients to ensure consistent dosing accuracy and minimize the risk of medication errors during tablet splitting. Further research is needed to better understand the impact of drug content uniformity within split tablets and to develop effective strategies to mitigate these risks [5].

Bisoprolol fumarate (BF) is a synthetic, beta-selective (cardioselective) adrenoceptor blocking agent. It is commonly used to manage cardiovascular conditions such as hypertension and chronic stable angina [8–10]. According to the American College of Cardiology and American Heart Association guidelines, BF is recommended for patients with ischemic heart disease or heart failure with reduced ejection fraction (HFrEF). In HFrEF, it is part of guideline-directed medical therapy to reduce mortality and hospitalizations [11]. BF tablets USP are available as 2.5, 5, and 10 mg scored tablets for oral administration. Physicians regularly prescribe BF as half tablets to achieve doses lower than the smallest available manufactured strength, in addition to the cost-saving potential [12]. Therefore, this issue is particularly important in the case of low-dose medications, such as BF, which are used in low-dose strengths.

The current study aims to investigate dose uniformity among BF scored tablets, ensuring that each split part contains an equal amount of the active pharmaceutical ingredient (API) using the sensitive analytical technique ultra high-performance liquid chromatography (UHPLC). The use of UHPLC provides an efficient analytical approach for assessing dose uniformity and evaluating the quality control of split tablets.

Materials and methods

Results

In vitro dissolution testing

Dissolution testing was performed according to the USP monograph in 900 mL of water. The monograph states that not less than 80% of the drug should be released within 20 minutes. Although both whole and split tablets dissolved more than the stated amount after 20 minutes, a significant difference was observed after the first 5 minutes. A higher BF dissolved from split tablets than from the whole tablets (85.20% vs. 75.10%), the two-tailed p-value based on the t-test was 0.018. The dissolution data for the BF innovator product, both before and after splitting, are presented in Table 10 and Figure 1. The percentage of the drug dissolved from the intact tablets reached 91.72 ± 3.36%, while the percentage of BF dissolved from the split tablets reached 87.22 ± 3.32%, both meeting the USP requirement. The results show no difference between the split and whole tablets. This can be proved by calculating the similarity dissolution parameter f₂. The obtained f₂ value was 62.53 (f₂ ≥ 50), indicating that the two dissolution profiles are similar according to the guidelines [16].

Table 10. Dissolution data of the BF innovator product, whole and divided tablets.

Time (min)	% Dissolved whole tablets	% Dissolved 1st half	% Dissolved 2nd half	% Dissolved split tablets (1st + 2nd half)
0	0	0	0	0
5	75.10 ± 4.05	97.38 ± 4.15	73.01 ± 8.44	85.20 ± 6.30
10	80.73 ± 5.31	83.78 ± 4.48	78.06 ± 6.70	80.92 ± 5.57
20	91.72 ± 3.36	88.93 ± 4.15	85.52 ± 2.49	87.22 ± 3.32

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BF: bisoprolol fumarate.

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Figure 1. In vitro dissolution profiles of BF from intact and split innovator tablet product. ^* P < 0.05.

Table 11 shows the dissolution data of BF from Generic-1, before and after tablet splitting. After the first 5 minutes, the results showed a significant difference between the whole and the split tablets (93.07% vs. 75.94%, respectively), the t-test was higher than the critical two-sample paired test (25.29 vs. 2.57, respectively) with a p-value of 0.0000018. At the end of the experiment, the percentage of BF dissolved from the intact tablets was 94.75 ± 3.36%, and almost reached 100% from the split tablets. The amount of the drug dissolved before and after the splitting met the USP requirement (≥ 80% dissolved in 20 minutes). Figure 2 shows the dissolution profile of BF from intact and split tablets. Although both profiles reached similar values at the end of the run, a pronounced variation was observed after 5 minutes. The percentage of the drug dissolved from the split tablet was nearly 20% lower than that from the intact tablets. The f₂ similarity factor showed that the dissolution profiles of BF from Generic-1 before and after splitting are dissimilar, with a value of 48.90.

Table 11. Dissolution data of the BF Generic-1 product for whole and divided tablets.

Time (min)	% Dissolved whole tablets	% Dissolved 1st half	% Dissolved 2nd half	% Dissolved split Tablets (1st + 2nd half)
0	0	0	0	0
5	93.07 ± 4.95	74.81 ± 4.15	77.07 ± 8.45	75.94 ± 6.30
10	92.43 ± 5.31	80.95 ± 4.48	81.68 ± 6.70	81.31 ± 5.59
20	94.75 ± 3.36	86.34 ± 4.15	112.27 ± 2.49	99.31 ± 3.32

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BF: bisoprolol fumarate.

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Figure 2. In vitro dissolution profiles of BF from the intact and split Generic-1 tablet product. ^* P < 0.05.

Regarding the dissolution of BF from Generic-2, Table 12 shows the data on the % dissolved before and after splitting. Although after 20 minutes, the percentage of BF dissolved from the split tablets was similar to that from the whole tablets, a significant difference in the percentage dissolved after 5 minutes [two-tailed p-value = 0.0000326, |t| is far larger than t critical (two-tailed) = 2.57]. The amount of the drug dissolved before and after the splitting met the USP requirement. Figure 3 shows the dissolution profile of BF from intact and split tablets. Although both profiles reached similar values at the end of the run, a significant variation was observed after 5 minutes. The percentage of the drug dissolved from the split tablet was 39.9% higher than that from the intact tablets. The f₂ similarity factor showed that the dissolution profiles of BF from Generic-2 before and after splitting are dissimilar, with a value of 34.43.

Table 12. Dissolution data of the BF Generic-2 product for whole and divided tablets.

Time (min)	% Dissolved whole tablets	% Dissolved 1st half	% Dissolved 2nd half	% Dissolved split Tablets (1st + 2nd half)
0	0	0	0	0
5	39.40 ± 8.45	88.23 ± 8.86	70.37 ± 12.81	79.30 ± 10.84
10	69.58 ± 12.31	83.24 ± 5.82	72.83 ± 11.65	78.04 ± 8.74
20	88.80 ± 2.00	90.12 ± 3.05	81.04 ± 2.49	85.58 ± 3.45

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BF: bisoprolol fumarate.

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Figure 3. In vitro dissolution profiles of BF from intact and split Generic-2 tablet product. ^* P < 0.05.

Discussion

In this study, a published HPLC assay for BF was applied using a sensitive UPLC. The validation analysis showed the linearity of the system used, with a high correlation and lower LOD and LOQ compared with other published assays [13, 17]. Percentage recoveries and precision results showed excellent repeatability, with RSD values below 2%, meeting the required acceptance criteria.

The % loss test measures the fragment lost during the division. From a clinical point of view, this directly impacts the administered dose taken by the patients. The ideal loss should be less than 3%; all examined products showed an ideal % loss.

The difference in the disintegration time between the products could be related to the tablet’s composition. BF Generic-1 contains polyethylene glycol, which may act as a binder, increasing the intermolecular force between the powder mixture and thus prolonging the disintegration time, but still within the acceptable range. On the other hand, BF Generic-2 contains crospovidone, which acts as a superdisintegrant, which may account for the shortest disintegration time. Moreover, the method of preparation, direct compression or wet granulation, and the uniformity of the tablet mixture blending could explain the difference between the two halves.

For content uniformity, the average values for BF innovator products and both generic products, before and after splitting, were all within the USP specified range of 85–115%. Some variation between the two halves of Generic-1 and Generic-2 tablets was observed, which could be related to the splitting process, leading to differences in individual halves [18, 19]. This is in agreement with Hill et al. [19], who found that the variation of the drug content for warfarin sodium, metoprolol succinate, and lisinopril could be due to weight variation and fragmentation that occurs during splitting.

Generally, the percentage of BF dissolved within 20 minutes is higher than the stated amount in the monograph (80%).

For more details, a statistical difference was observed in the first 5 minutes in all products. The in vitro dissolution study for Generic-1 showed a lowered dissolution rate for split halves compared to the intact one.

In contrast, a higher dissolution rate from split halves was observed compared to the intact tablets for brand and Generic-2.

This could be explained by the fact that the part of the tablet is uncoated, which facilitates the action of superdisintegrants upon contact with the surrounding media and thus enhances the disintegration and the dissolution of the drug. The calculated f₂ similarity factors indicated that the dissolution profiles of the BF Innovator tablets before and after splitting were similar, but those of both generic products were dissimilar.

The quality control assessment of the BF split tablet is crucial to ensure that drug dosing and tablet properties remain unchanged, which might affect therapeutic efficacy [20]. Tablet splitting might result in unequal portions or loss of tablet mass, which might lead to dose inaccuracies [21]. This issue is particularly critical for drugs whose therapeutic effects are highly dose-dependent, including low-content APIs, such as BF.

Helmy [22] investigated the effect of tablet splitting on tablet weight and drug content uniformity for 16 cardiovascular medications (including BF) in the outpatient setting and provided recommendations for safe tablet-splitting prescribing practices. The study revealed that tablet splitting could be safer and easier when drug- and patient-specific criteria are met. In addition, it was concluded that a drug with a wide therapeutic index and long half-life may be a more appropriate candidate for tablet division.

Finally, the findings emphasize the importance of carefully evaluating the quality of scored tablets following splitting, as variations in parameters such as drug content and dissolution rate can affect therapeutic efficacy and patient safety. Healthcare professionals should be aware of these differences and consider them when prescribing or recommending split tablets to patients.

Further research into the effects of tablet splitting on other medication formulations is warranted to establish guidelines and best practices for this common practice in clinical settings. Additionally, manufacturers should strive to improve the uniformity and consistency of scored tablets to ensure reliable dosing and patient outcomes.