2024 Volume 72 Issue 12 Pages 1048-1054
Pharmaceutical packaging is essential for enhancing the storage stability of medicine and can improve medication adherence and usability. Despite their widespread use, blister packs can be challenging to use, especially when pushing out the medication. This study investigates how specific cavity characteristics of blister packs can enhance usability for spherical capsules, which are harder to push out than tablets. The findings of this study show that reducing the thickness of the unformed sheet, or the thickness at the top and corners of the cavities, reduces the effort required to push out the capsules. Similarly, for cavities with different shapes, reducing the thickness at the top and increasing the corner radius also eases the push-out process. These insights emphasize the importance of systematic design in pharmaceutical packaging to improve patient medication adherence.
Medication adherence has attracted substantial attention worldwide because of its effect on achieving optimal therapeutic outcomes and reducing healthcare costs. According to the WHO, the average nonadherence rate among patients with chronic diseases in the United States is reported to be 50%, thus emphasizing the critical need to address nonadherence.1) It has been reported that interventions in pharmaceutical packaging can influence medication adherence.2,3) In addition, there are reports of interventions in pharmaceutical packaging that focus on specific diseases and the problem of aging.4–7) Elderly patients often suffer from multiple chronic conditions and undergo polypharmacy, are more prone to nonadherence, and are at a higher risk of experiencing adverse effects due to poor disease management.8,9) Cognitive, visual, and physical limitations in the elderly can affect their ability for self-management, potentially leading to decreased medication adherence.10,11) Therefore, awareness of improving medication adherence through pharmaceutical packaging has increased, drawing attention to patient-centric pharmaceutical product design.12)
The functionality of pharmaceutical packaging includes various critical aspects, with particular emphasis on usability. Packaging must meet the design requirements for protection, compatibility, safety, and performance.13) Protection is essential to ensure that medications are protected from external potential adverse conditions such as moisture, light, and reactive gases.14) Recently, there has been increasing recognition of performance as an essential component of medication adherence in terms of usability. From the perspective of effectiveness, efficiency, and user satisfaction, ease of opening packaging is of particular importance to the elderly.3) Some countries have introduced child-resistant packaging to prevent accidental ingestion, which can occasionally conflict with usability requirements because of its difficulty in opening.15) Among pharmaceutical packaging options, blister packs excel as individually packaged medications, providing superior protection and portability. Blister packs typically consist of a forming sheet and a lidding foil. The base materials for the forming sheet are primarily thermoplastic resins, such as polyvinyl chloride and polypropylene. Depending on the specific requirements of the medication, other materials like polyvinylidene chloride, polychlorotrifluoroethylene, and polyolefin can be combined to create composite sheets with particular characteristics that enhance barrier properties against moisture, light, and reactive gases. Aluminum is employed when higher barrier properties are required. The thermoplastic resins are shaped into cavities through a thermoforming process, where the material is softened by heating. In contrast, aluminum, which does not soften upon heating, is shaped into cavities via a cold-forming process. For the lidding foil, aluminum is typically used and sealed to the formed sheet to ensure air-tightness. In Europe, 85% of solid drugs are packed in blister packs, whereas in the United States, this percentage is less than 20%; however, the use of blister packs is increasing as both manufacturers and consumers recognize their benefits.16) There is a report indicating that more than half of medication usage-related reports involve difficulties with the opening of packages, with approximately half of them concerning the opening of blister packs.17) Certain usability issues linked to push-through blister packs have been studied in post-marketing surveys and medical settings.18,19) Therefore, addressing the usability issues, particularly those related to the ease of opening blister packs, is crucially important.
The usability problem of blister packs persists, but the specific factors, such as why they are not user-friendly and how they can be made more user-friendly, have not yet been fully elucidated. Opening a blister pack to access the medication therein involves pressing the cavity and breaking the aluminum foil, and difficulties in accessing the medication from blister packs have been reported among elderly individuals and patients with impaired hand function.20–23) Research into the push-out performance of blister packs has progressed, using mechanical evaluations with experimental setups and sensory assessments by human participants.24–31) Mechanical push-out evaluations typically only measure the maximum force required to break the aluminum foil and often overlook the comprehensive assessment of the medication expulsion process post-foil breaking. Moreover, studies on the push-out performance of blister packs have focused on comparing commercial products with different specifications, thus revealing a lack of research aimed at identifying the specific factors that influence push-out performance. To date, there have been no reports on how the thickness distribution and dimensions of the blister cavities numerically affect push-out performance.
The objective of this study is to identify the factors and characteristics that influence the push-out performance of blister packs by optimizing the blister pack design, including the thickness, depth, and shape. Spherical capsules were selected for this investigation because of their shape properties, which present a greater challenge for push-out compared to tablets.31) Through variations in blister specifications, we performed comparative analyses on unformed sheet thickness, cavity depth, cavity thickness distribution, and cavity shape. Factor analysis of the results enabled the identification of blister factors that contribute to push-out performance.
To investigate the effect of variations in the unformed sheet thickness on push-out performance, blister packs prepared from 0.23 and 0.25 mm thick unformed sheets were compared. Blisters formed with the 0.23 mm sheet were designated as A-0, while those formed with the 0.25 mm sheet were designated as A-X. Each blister was produced using a blister pack machine with mold type-A (Fig. 1). The cavity shapes of blisters A-0 and A-X are identical when using the default forming conditions on the blister packaging machine and utilizing mold type-A. The push-out force required for each blister was measured, and the push-out force and displacement were plotted (Fig. 2). The plots showed that the push-out force increased gradually as the top wall of the cavity was compressed. The push-out force suddenly increased as the top wall of the cavity came into contact with the capsule, and upon reaching the peak push-out force, the aluminum foil broke. Subsequently, a decrease in push-out force was observed. The capsule was gradually pushed out of the blister while continuing to compress the cavity’s side walls. As the side walls of the cavity folded, the push-out force increased once more, followed by a decrease upon exceeding the yield point. This phenomenon was observed to be more pronounced in the thicker side walls of blisters A-X compared to those of blisters A-0. Eventually, the capsule fell freely after half of it protruded. In these plots, a consistent trend was noted, with blister A-0 showing lower values compared with blister A-X. Measurements of cavity depth, and the top, corner, and side thickness, as well as the dimensional characteristics of the cavity, are shown in Table 1. Blisters A-0 showed significantly smaller depths (p < 0.01), and corner thickness (p < 0.05) compared with blisters A-X. In addition, there was a tendency for the thickness of the top and sides to be smaller in blister A-0. While the peak of push-out force did not exhibit a significant difference between blisters A-0 and A-X, the work done for push-out was significantly lower in blister A-0 (Fig. 3).
| A-0 | A-X | |
|---|---|---|
| Entrance diameter (mm) | 11.0 | 11.0 |
| Draft angle (degree) | 18.0 | 18.0 |
| Corner radius (degree) | 2.0 | 2.0 |
| Draw ratio | 2.18 | 2.18 |
| Depth (mm) | 7.45 ± 0.01 | 7.53 ± 0.02** |
| Top thickness (µm) | 145.2 ± 2.6 | 149.3 ± 2.7 |
| Corner thickness (µm) | 105.0 ± 2.6 | 113.0 ± 1.9* |
| Side thickness (µm) | 74.2 ± 2.6 | 77.8 ± 2.6 |
Data are presented as the mean ± standard error (S.E.) (n = 6). Asterisks indicate a significant difference in values between blisters A-0 and A-X using the unpaired Student’s t-test, * p < 0.05, ** p < 0.01.
Each column represents the mean ± standard error (S.E.) (n = 6). Asterisks indicate a significant difference in values between A-0 and A-X using the unpaired Student’s t-test, * p < 0.05.
Takeshita et al. investigated the influence of unformed sheet thickness on the required push-out force for tablets in blister packs.29) Their results revealed that thinner, unformed sheets led to a decrease in the peak force required to push out the tablets. Similarly, Akiyama et al. studied the differences in tablet push-out force using blister products for the treatment of Parkinson’s disease.26) They found that thinner, unformed sheets resulted in a reduced peak push-out force required for tablets. Thus, it has been established that thinner, unformed sheets facilitate easier pushing out of tablets from blister packs. Our results similarly showed that blister packs with thinner, unformed sheets exhibited a decrease in both the peak push-out force and the work done for push-out. We measured the peak push-out force values as well as the transition of push-out force plots. The results indicated that thinner, unformed sheets resulted in lower overall plot values. This could be attributed to the reduced overall thickness of the cavity distribution. Therefore, blister packs with thinner, unformed sheets are expected to achieve better push-out performance.
Comparison Study on the Cavity Depth and Thickness DistributionTo investigate the effect of differences in the cavity depth and thickness distribution on the push-out performance under the same cavity shape, samples were prepared using an unformed sheet of 0.23 mm thickness and mold type-A. Blister A-0, which demonstrated improved push-out performance, was used as a reference. Blisters A-1–A-4 were prepared by adjusting the formation conditions of the packaging machine. A-1 and A-2 were adjusted to reduce the top and corner thicknesses, while A-3 and A-4 were adjusted to increase these thicknesses. In addition, A-1 and A-3 were adjusted to decrease the cavity depth without affecting the capsules inside. Measurements of cavity depth and the top, corner, and side thickness, as well as the dimensional characteristics of each cavity, are presented in Table 2. Compared with blister A-0, cavity depths were significantly smaller in A-1 and A-3, while A-2 and A-4 exhibited slight increases in depth. Top thickness was significantly reduced in A-1 and A-2 compared with blister A-0, whereas A-3 and A-4 exhibited a significant increase. Similarly, corner thickness was significantly reduced in A-1 and A-2 compared with blister A-0, with a significant increase observed in A-3 and A-4. Side thickness was significantly increased in A-1 and A-2 compared with blister A-0, whereas A-3 and A-4 exhibited a decrease that was not statistically significant. The peak push-out force was significantly lower in blister A-1 compared with blister A-0 (Fig. 4a). The work done for push-out was significantly lower in A-1 and A-2 compared with blister A-0, while that of A-3 and A-4 was significantly increased (Fig. 4b). This demonstrates that reducing the top and corner thickness effectively decreased the work done for push-out. No significant differences were observed between A-1 and A-2 or between A-3 and A-4, indicating that changes in cavity depth do not have a notable effect.
| A-0 | A-1 | A-2 | A-3 | A-4 | |
|---|---|---|---|---|---|
| Entrance diameter (mm) | 11.0 | 10.8 | 11.0 | 10.8 | 11.0 |
| Draft angle (degree) | 18.0 | 18.0 | 18.0 | 18.0 | 18.0 |
| Corner radius (degree) | 2.0 | 2.0 | 2.0 | 2.0 | 2.0 |
| Draw ratio | 2.18 | 2.16 | 2.18 | 2.16 | 2.18 |
| Depth (mm) | 7.45 ± 0.01 | 7.24 ± 0.01** | 7.50 ± 0.01 | 7.22 ± 0.01** | 7.50 ± 0.02 |
| Top thickness (µm) | 145.2 ± 2.6 | 139.5 ± 1.4* | 131.5 ± 2.2** | 171.7 ± 2.0** | 162.7 ± 2.0** |
| Corner thickness (µm) | 105.0 ± 2.6 | 95.7 ± 2.8* | 94.3 ± 1.3** | 123.2 ± 3.1* | 115.0 ± 1.3* |
| Side thickness (µm) | 74.2 ± 2.6 | 106.3 ± 2.3** | 100.8 ± 1.7* | 71.0 ± 2.1 | 71.8 ± 3.2 |
Data are presented as the mean ± S.E. (n = 6). Asterisks indicate a significant difference in values of A-1–A-4 compared with A-0 using Dunnett’s test, * p < 0.05, ** p < 0.01.
Each column represents the mean ± S.E. (n = 6). Asterisks indicate a significant difference in values between blisters A-0–A-4 using Tukey–Kramer’s multiple comparison test, * p < 0.05, ** p < 0.01, *** p < 0.001.
Yamatani et al. performed a study on the measurement of push-out force and the ease of opening blister packs.28) Their findings indicated that reducing the thickness at the top of the cavity resulted in a decrease in the push-out force required. While this study varied in cavity and tablet shape, it utilized the same polyvinyl chloride substrate in the unformed sheet, thus potentially aligning with our findings. In contrast, Takeshita et al. reported that the push-out performance varied with the use of different materials for sheets, such as polyvinyl chloride, polypropylene, and polypropylene-polyolefin composite sheets, even when the unformed sheet thickness was the same.29) In this report, only the peak push-out force was compared, which was found to decrease in the following order: polyvinyl chloride, polypropylene, and polypropylene-polyolefin composite sheets. Our research utilized a polyvinyl chloride-polyvinylidene chloride composite sheet with high moisture and gas barrier properties. As our sheets were based on polyvinyl chloride, similar trends are expected for single-layer polyvinyl chloride sheets and composite sheets made from polyvinylidene chloride or polychlorotrifluoroethylene. Future research is required to determine the applicability of our findings to polypropylene-based container sheets with different base materials. Braun–Münker and Ecker investigated the ease of opening solid oral dosage forms in blister packs, considering elderly individuals.30) According to their findings, reducing the thickness of tablets and increasing their mobility within the cavity resulted in decreased patient satisfaction. These results suggest that smaller cavity clearances in blister packs facilitate easier push-out, which contradicts the findings of this study. This discrepancy may be attributed to the use of aluminum blister packs formed via cold-forming. Excessive drawing of aluminum materials during the cold-forming process can lead to the occurrence of pinholes and cracks in the aluminum layer. Therefore, the cavity is designed to be larger than the medication while maintaining a low draw ratio for the aluminum material. The cold-forming process creates a relatively larger cavity compared to the thermoforming process, potentially amplifying the effect of cavity clearance. Consequently, in blister packs with cavities molded to fit the medication using transparent thermoplastic sheets, as in this study, slight differences in cavity depth are expected to have minimal effect on the push-out performance.
Comparison Study on the Different Cavity Shapes and DimensionsVarious blister packs were produced using different mold types B–G to investigate the effect of cavity shape variations on the push-out performance (Fig. 5). Blister A-1, which required the least work done for push-out, was used as a reference. The formation conditions for blisters B–G were adjusted to achieve the same cavity depth. As cavity depth was considered to have a minimal effect on the push-out performance, comparisons were made at the same cavity depth, and the produced blisters A-1, B–G were analyzed and compared. The design and measurement dimensions for each blister are presented in Table 3. The peak push-out force was significantly lower in blisters B–G compared with A-1 (Fig. 6a). Among them, blister D showed the smallest peak push-out force. Similarly, the work done for push-out was significantly lower in blisters B–G compared with A-1 (Fig. 6b). Blister D showed the lowest value of the work done for push-out and significantly lower values compared with blisters B and F. To investigate which blister shape and dimensions affect the work done for push-out, a forward-backward stepwise multiple linear regression analysis was performed. The entrance diameter, draft angle, corner radius, draw ratio, depth, and the top, corner, and side thickness of blisters A-1, B–G were included in this analysis. The values for each factor are listed in Table 4. The results indicated that the model could explain 75.9% of the work done for push-out (R2 = 0.771, adjusted R2 = 0.759), and the corner radius (β = −0.259, p < 0.01) and top thickness (β = 0.814, p < 0.001) were identified as significant influencing factors.
| A-1 | B | C | D | E | F | G | |
|---|---|---|---|---|---|---|---|
| Entrance diameter (mm) | 10.8 | 10.5 | 9.8 | 9.2 | 10.5 | 9.8 | 9.2 |
| Draft angle (degree) | 18.0 | 16.0 | 12.0 | 8.0 | 16.0 | 12.0 | 8.0 |
| Corner radius (degree) | 2.0 | 2.0 | 2.0 | 2.0 | 4.0 | 4.0 | 4.0 |
| Draw ratio | 2.16 | 2.24 | 2.44 | 2.65 | 2.13 | 2.29 | 2.45 |
| Depth (mm) | 7.24 ± 0.01 | 7.24 ± 0.01 | 7.21 ± 0.01 | 7.24 ± 0.01 | 7.24 ± 0.01 | 7.21 ± 0.01 | 7.17 ± 0.03 |
| Top thickness (µm) | 139.5 ± 1.4 | 119.3 ± 1.3 | 98.8 ± 2.3 | 89.2 ± 1.1 | 117.5 ± 2.0 | 109.7 ± 2.0 | 99.5 ± 2.7 |
| Corner thickness (µm) | 95.7 ± 2.8 | 88.0 ± 2.4 | 79.8 ± 2.7 | 72.0 ± 0.3 | 92.3 ± 3.2 | 88.8 ± 3.5 | 84.2 ± 3.3 |
| Side thickness (µm) | 106.3 ± 2.3 | 112.7 ± 2.9 | 100.7 ± 1.8 | 83.8 ± 1.2 | 116.2 ± 3.7 | 99.2 ± 2.6 | 88.5 ± 2.1 |
Data are presented as the mean ± S.E. (n = 6).
Each column represents the mean ± S.E. (n = 6). Asterisks indicate a significant difference in values between blisters A-1 and B–G using Tukey–Kramer’s multiple comparison test, * p < 0.05, ** p < 0.01, *** p < 0.001.
| Variables | B | S.E. | β | t | p | 95% CI | VIF |
|---|---|---|---|---|---|---|---|
| Corner radius | −1.397 | 0.415 | −0.259 | −3.369 | <0.01 | −2.236–−0.558 | 1.009 |
| Top thickness | 0.263 | 0.0249 | 0.814 | 10.576 | <0.001 | 0.213–0.313 | 1.009 |
B, partial regression coefficient; S.E., standard error; β, standardized partial regression coefficient; CI, confidence interval; VIF, variance inflation factor. Multiple R2 = 0.771; Adjusted R2 = 0.759; F = 65.67; p < 0.001.
Kabeya et al. investigated the characteristics of difficult-to-use blister packs by analyzing the data collected from pharmaceutical wholesalers in Japan.18) Their findings identified no significant differences in cavity shape or wall thickness between the easy-to-use and difficult-to-use blisters. Furthermore, no significant differences in the peak push-out force were reported between the easy-to-use and difficult-to-use blisters. These findings are in contrast with our study. We revealed that the cavity shape and the thickness distribution reduce the peak push-out force and the work done for push-out. While our study focused on spherical capsules, their investigation likely included tablets as well. The cavities for spherical capsules are formed more deeply compared to tablets, which leads to greater push-out displacement. As a result, it is suggested that the difference between the peak push-out and the work done for the push-out become more pronounced. Furthermore, we observed greater variability in the work done for push-out compared to the peak push-out force. Traditional studies typically compare peak forces, which represent the moment when the aluminum foil breaks. However, in practical use, the push-out process continues to the point at which the capsule is completely expelled. Measuring the work done for push-out reflects this entire process and could serve as a benchmark for comparing the push-out performance of blisters for capsules and tablets. We observed that increasing the corner radius reduces the work done for push-out, and generally, a larger corner radius enhances strength by mitigating stress concentration. In this study, the cavity was fixed vertically to minimize variation in the compression direction, thus allowing compression only from the top to the bottom of the cavity. As a result, a larger corner radius leads to a smaller contact area at the top of the cavity, which results in less work done for push-out. In actual use, individuals may apply pressure to the cavity at various angles, potentially differing from the controlled conditions in this study. This is particularly relevant for spherical capsule blisters, which have greater depth compared to tablet blisters and are often subjected to angled compression. When subjected to angled compression, cavities with larger corner radii are predicted to increase in strength, thus leading to a larger value of work done for push-out. Therefore, future studies should incorporate evaluation systems that consider the effects of compression at an angle.
We have elucidated the factors that contribute to the push-out properties of spherical capsule blisters. The primary factors influencing the reduction of work done to push capsules out of blisters are as follows: (1) thinner unformed sheet thickness; (2) smaller top and corner thicknesses in cavities of identical shape; and (3) smaller top thickness and a larger corner radius in cavities of different shapes. These findings suggest that optimizing the mold design and distribution of cavity thicknesses in manufacturing may improve the push-out performance of blister packs. In addition to push-out performance, the usability of blisters includes factors such as blister size, cavity arrangement, and sheet material. Therefore, it is important to consider the overall usability of the blister in the package design. In countries where blister packs are widely used, these findings have considerable implications. Our research demonstrates the feasibility of designing blister packs that provide easier access to the medication, and increased usability of blister packs could potentially enhance medication adherence and contribute to the therapeutic efficacy of medications. In addition, this improvement could be applied to innovations in electronic devices, medication services, and disease-specific packaging, thus further increasing usability.32–36)
Packaging plays an essential role in pharmaceuticals and has the potential to improve medication adherence via enhanced usability. While blister packs are a primary form of pharmaceutical packaging, the systematic factors that influence their usability remain only partially understood. Our findings indicate that optimizing the selection of the unformed sheet thickness, as well as adjusting the thickness distribution and shape of the cavity, contributes to enhancing the blister push-out performance. Although our study highlights the potential of blister packs to improve medication adherence through better usability, further research is required to fully understand the systematic factors involved. Specifically, investigating how variations in medication influence the optimal blister design could provide valuable insights. Despite its crucial role in ensuring medication safety and adherence, the persistent challenges in developing more user-friendly pharmaceutical packaging emphasize the necessity for continuous research and innovation in this field.
Eldecalcitol capsules 0.75 µg (diameter: 6.5 mm, weight: approximately 164 mg) were used as the contents within the cavities of the blister packaging (Sawai Pharmaceutical Co., Ltd., Osaka, Japan). The blister packaging consisted of a polyvinyl chloride-polyvinylidene chloride composite sheet VSL-4606 (total thickness: 0.23 mm) or VSL-4603 (total thickness: 0.25 mm) (Sumitomo Bakelite Co., Ltd., Tokyo, Japan), along with the aluminum foil (aluminum layer thickness: 20 µm, Toyo Aluminium K.K., Osaka, Japan).
Formation of Blister Cavities Using a Blister Packaging MachineWe used the blister packaging machine FBP-800E (CKD Corporation, Aichi, Japan) with the formation molds to produce the blister cavities. Various cavity specifications were produced by altering the formation conditions and the shape of the formation molds. The draw ratio for each cavity was calculated by dividing the cavity surface area after formation by the sheet area before formation. The blister sheets were cut to a size of 92 × 35 mm. Blister A-0 was made using a sheet with a thickness of 0.23 mm, while blister A-X was made using a sheet with a thickness of 0.25 mm; both employed mold type-A (Fig. 1). Blister cavities with varying depths and thickness distributions (A-1–A-4) were formed using mold type-A by adjusting the formation conditions of the blister packaging machine, which were within the operational limits of the blister packaging machine. We also prepared blister cavities with various shapes and dimensions using different formation molds, as shown in Fig. 5 (types B–G).
Numerical Measurement of Cavity Depth and Thickness DistributionA caliper with a constant force device series 536 (Mitutoyo Corporation, Kanagawa, Japan) was utilized to measure the depth of the blister cavities. A Thickness Gauge Digimatic Type (Mitutoyo Corporation, Kanagawa, Japan) was employed to measure the thickness of the blister cavities.
Measurement of Push-Out Force and Calculation of Work Done for Push-OutThe required push-out force of the blister packs was measured using the EZ Test EZ-LX (Shimadzu Corporation, Kyoto, Japan). Each blister pack was divided and cut at each cavity; these were then compressed with a cylindrical jig (diameter: 5 mm) at a rate of 50 mm/min from top to bottom to measure the continuous force transition until the capsule was pushed out. The 5 mm-diameter jig was selected to simulate the actual usage conditions and was designed to deform starting from the cavity corners. This study utilized a rate of 50 mm/min, which is reported to be close to the blister opening rate observed in healthy individuals.28) We calculated the area under the curve of the push-out force versus the displacement to quantify the work done to push out the capsule until half of it is exposed. This calculation was based on the observation that once the aluminum foil broke and half of the capsule protruded from the cavity, the capsule was fully expelled from the blister pack because of free fall.
Statistical AnalysisThe dimensional measurement results of the blister cavities were analyzed using an unpaired Student’s t-test and Dunnett’s test. The peak push-out force and the work done for push-out were analyzed using an unpaired Student’s t-test and Tukey–Kramer’s multiple comparison test. The forward-backward stepwise multiple linear regression analysis was performed to identify the factors that influence the blister cavities for the work done for push-out. We assessed the presence of multicollinearity by checking the values of the variance inflation factor (VIF). We determined that multicollinearity was not severe when the VIF value was <5. All statistical analyses, including the forward-backward stepwise multiple linear regression analysis, were performed using EZR, a modified version of R Commander specifically tailored to include commonly used statistical functions in biostatistics.37) Statistical significance was determined based on a p-value <0.05. The number of samples examined is specified in each figure, and the error bars in the figures represent the standard errors of the means.
Financial support for this study was partially provided by Sawai Pharmaceutical Co., Ltd. Kazuya Sugimoto and Ken Yuki are employees of Sawai Pharmaceutical Co., Ltd.
