Effects of Shape on the Disintegration Time and Friability of Sucroferric Oxyhydroxide-Containing Mini-Tablets

Abstract

Sucroferric oxyhydroxide is a phosphate binder for the treatment of hyperphosphatemia in patients with chronic kidney disease undergoing dialysis. This study aimed to determine the effects of tablet size, shape, and tensile strength on disintegration time and friability of sucroferric oxyhydroxide-containing mini-tablets. A linear relationship between the disintegration time and tensile strength was observed across all mini-tablets, except for those with smaller tablets (diameters: <1.8 mm). However, the relationship between friability and tensile strength was not significantly correlated under linear or exponential approximations. Explaining friability solely based on tensile strength was challenging, indicating the role of tablet shape. To visualize the effects of mini-tablet shapes and tensile strength on their disintegration time and friability, response aspects were analyzed. The response surface analysis revealed that the disintegration time was not affected by the tablet shape. The friability of the mini-tablets with a cup depth/diameter of 0.209 was lower (<0.2) than that of tablets with other cup depth/diameter across all tested ranges of tensile strength (1–6). A cup depth/diameter of 0.2 was identified as optimal for minimizing the friability of mini-tablets and can be implemented in commercial production without issues. In conclusion, tablet shape should be carefully considered during the development of mini-tablets to ensure low friability.

Introduction

Sucroferric oxyhydroxide is a phosphate binder for the treatment of hyperphosphatemia in patients with chronic kidney disease undergoing dialysis.^1–3) To date, several products in chewable tablet formulations containing sucroferric oxyhydroxide have been developed.^4–6) Chewable tablets need to be chewed and ingested orally, which is difficult for older adults and patients with reduced masticatory power.⁷⁾ Chewable tablets are often used for high-dose drugs and can be substituted by powdered granules in such cases. However, many older adults complain of the discomfort caused by the spread of the powder through the mouth,⁸⁾ adhering to the throat, and interfering with the dentures. In terms of the hard and colored material of sucroferric oxyhydroxide, many patients express concern about the taste and oral cavity discoloration caused by masticating such drugs. Therefore, there is an urgent need for a novel sucroferric oxyhydroxide-containing formulation that can be used without chewing.

Mini-tablets are defined as tablets with a sub-diameter of 4 mm by the WHO.⁹⁾ They have attracted attention owing to their improved adherence.¹⁰⁾ Uchida et al. reported that in oral preparations containing a large volume of drugs, such as hyperphosphatemia drugs, mini-tablet-type formulations are less likely to impart an unpleasant taste compared with common powder and granular preparations, and present a highly palatable dosage form.¹¹⁾ Formulations containing sucroferric oxyhydroxide are also positioned as oral formulations containing large volumes of the drug. Therefore, the development of a mini-tablet-type formulation that can be ingested with a small amount of water without the need for chewing and has a palatable characteristic that minimizes the taste can improve adherence by reducing the burden when ingesting the drug.

In the production of mini-tablet-type preparations, a manufacturing method based on conventional tablet manufacturing methods is adopted, and a tableting machine equipped with punches suitable for manufacturing tablets of specific size and shape is used.^12–14) During tablet production, defects (chipping, cracking, and friability) may occur owing to various impacts during the transportation process after the tableting process. In the case of mini-tablets, a stick-like packaging form with excellent convenience and ingestibility is sometimes adopted, and a tablet shape that minimizes the occurrence of defects, even during the stick-packaging process, is required. However, the influence of tablet shape on the defects occurring in mini-tablet manufacturing has not yet been determined, and a tablet shape suitable for mini-tablets remains unknown. These defects affect disintegration time and friability. In tablets, disintegration time and friability exhibit a trade-off relationship; in general, when tablet hardness is high and disintegration time is long, friability is low. In such a case, it is possible to achieve the optimum solution by considering the tablet form. This study was conducted as part of the product development of mini-tablets (P-TOL^® Granules 250 and 500 mg) containing sucroferric oxyhydroxide.¹⁵⁾ The aim of the study was to determine the effects of tablet size, shape, and tensile strength on their disintegration time and friability. For the shapes that were considered optimal, the feasibility of manufacturing them in actual production was also examined.

Experimental

Materials

Here, sucroferric oxyhydroxide (CSL Vifor, Glattbrugg, Switzerland) was used as the active ingredient. Light anhydrous silicic acid (Freund Corporation, Tokyo, Japan), talc (Matsumura Sangyo Co., Ltd., Osaka, Japan), and magnesium stearate (Taihei Chemical Industrial Co., Ltd., Osaka, Japan) were used as lubricants. Yogurt microns (Takasago International Corporation, Tokyo, Japan) were used as a flavoring agent.

Formulation of Mini-Tablets

Mini-tablets were formulated with 96% sucroferric oxyhydroxide, a 4% lubricant mixture (light anhydrous silicic acid, talc, and magnesium stearate), and trace amounts of flavoring agent. Rotary tableting machines (HT-AP12SS-U, Hata Tekkosho, Kyoto, Japan; AQUARIUS G-B, Kikusui Seisakusho, Kyoto, Japan; COMPRIMA 300, IMA, Italy; 2090i, Fette Compacting, Germany) were used to compress the mixtures into tablets.

A punch with varying diameters and radii of curvature of the convex portion was installed on the tableting machine. The punches and die were manufactured by Notter (Germany), Two Nine Japan (Japan), IMA, and Fette Compacting, with the surfaces treated using hard chrome coating. The tableting pressure was adjusted to achieve the target thickness, and a forced feeder was employed to produce the mini-tablets listed in Table 1.

Table 1. List of Parameters of Mini-Tablets with Different Shapes

Tablet No.	Diameter (mm)	Thickness	Cup depth	Radius of curvature of the convex portion (mm)	Cup depth/diameter
T1	2.3	2.3	0.480	1.5	0.209
T2	2.3	2.2	0.480	1.5	0.209
T3	2.3	2.2	0.480	1.5	0.209
T4	2.3	2.3	0.480	1.5	0.209
T5	2.3	2.3	0.480	1.5	0.209
T6	2.3	2.3	0.350	1.9	0.152
T7	2.3	2.3	0.090	Trapezoid shape	0.039
T8	1.0	1.0	0.107	1.0	0.107
T9	1.8	1.6	0.213	1.8	0.118
T10	2.0	2.6	0.688	1.0	0.344
T11	2.0	2.8	0.688	1.0	0.344
T12	2.0	2.1	0.688	1.0	0.344
T13	3.0	3.0	0.272	4.0	0.091
T14	4.0	4.0	0.508	4.0	0.127
T15	3.0	3.2	0.272	4.0	0.091
T16	2.3	2.3	0.090	Trapezoid shape	0.039

Although T1, T4, and T5 have identical shapes, T1 was manufactured on a laboratory scale, whereas T4 and T5 were produced on a commercial scale using different manufacturing facilities. Additionally, different lots of the active ingredient were used for T4 and T5.

Shape of Tablets

The parameters defining the shape of the mini-tablet included the diameter, cup depth, radius of curvature of the convex portion, and thickness. Tablet shapes for mini-tablets with various shape parameters are listed in Table 1 and shown in Fig. 1. The mini-tablet was composed of a cap portion in which both surfaces of the cylinder were formed by bulging and molding into a convex shape. Therefore, the degree of sphericity of the tablet can be expressed by calculating the ratio of the depth and diameter of the cap portion; the closer it is to a spherical shape, the higher the value.

Fig. 1. Parameters Based on the Shape of Mini-Tablets (a) T1, T4, and T5; (b) T2 and T3; (c) T6; (d) T7 and T16; (e) T8; (f) T9; (g) T10; (h) T11; (i) T12; (j) T13; (k) T14; (l) T15

In T1–T5, tablets were compressed to a thickness of 2.2–2.3 mm using a tableting machine with a punch and a die featuring a cup depth of 0.48 mm, and a round depression with a diameter of 2.3 mm and a radius of curvature of 1.5 mm. Although T1, T4, and T5 have identical shapes, T1 was manufactured on a laboratory scale, whereas T4 and T5 were produced on a commercial scale using different manufacturing facilities. Additionally, different lots of the active ingredient were used for T4 and T5.

In T6, the depth of the cups was reduced to 0.35 mm by adjusting only the radii of curvature to 1.9 mm while maintaining a thickness of 2.3 mm. However, in T7 and T16, using a planar pestle without a cup portion, it was tableted to have a thickness of 2.3 mm. In T8, tablets were pressed in a diameter of 1.0 mm and a radius of curvature 1.0 mm to obtain a thickness of 1.0 mm. In T9, tablets were adjusted to a thickness of 1.6 mm, with a diameter and radius of curvature of 1.8 mm. In T10–T12, tablets were compressed so that the thickness ranged from 2.1 to 2.8 mm, with a diameter of 2.0 mm and a radius of curvature of 1.0 mm. For T13 and T15, the tablets were compressed to a thickness of 3.0 or 3.2 mm, with a diameter of 3.0 mm and a radius of curvature of 4.0 mm.

Tableting of Mini-Tablets on a Commercial Scale

Rotary tableting machines (AQUARIUS G-B; Kikusui Seisakusho) were used to compress the mixtures into mini-tablets. Continuous manufacturing was performed for 240 min using a rotary tableting machine with a cup depth/diameter ratio of 0.2 (T4), which was identified as the optimal shape. Hardness and friability were measured at regular intervals during the production process.

Evaluation of the Physical Properties of Mini-Tablets

The hardness of the mini-tablet was measured as the pressure exerted when a force was applied in a constant direction using a hardness meter (PC-30; Okada Seiko Co., Ltd., Tokyo, Japan). This subjected the mini-tablet to a pressure gradient until breakage occurred at a constant rate.

The tensile strength of the mini-tablet was calculated by dividing the hardness by the fracture surface area:

  

$$\mathrm{T}\mathrm{e}\mathrm{n}\mathrm{s}\mathrm{i}\mathrm{l}\mathrm{e}\mathrm{s}\mathrm{t}\mathrm{r}\mathrm{e}\mathrm{n}\mathrm{g}\mathrm{t}\mathrm{h}\left(\mathrm{N}/{\mathrm{m}\mathrm{m}}^2\right)=\frac{2F}{\pi \times \mathit{D}\mathit{i}\mathit{a}\mathit{m}\mathit{e}\mathit{t}\mathit{e}\mathit{r}\times \mathit{T}\mathit{h}\mathit{i}\mathit{c}\mathit{k}\mathit{n}\mathit{e}\mathit{s}\mathit{s}}$$

where F is the hardness of the mini-tablets (N).

Disintegration time was measured using a disintegration tester (NT-2HS; Toyama Sangyo Co., Ltd., Osaka, Japan). The study was performed in accordance with the disintegration test method outlined in the General Test Method of the Japanese Pharmacopoeia, 17th Edition. The mini-tablets were weighed and placed into a glass tube of a disintegration tester. The tester was operated at 37 ± 2°C with water as the test solution. Disintegration of the specimen was observed, and no residue remained in the glass tube. The specimen was judged to have disintegrated, and the corresponding time was recorded.

Friability was evaluated using a friability tester (EF-2; ELECTROLAB, Inc., Mumbai, India). This study was conducted in accordance with the guidelines outlined in the Japanese Pharmacopoeia, 17th Edition, regarding the friability test method. The mini-tablets were weighed before testing, weighing at least 6.5 g, and placed into the drums of a friability tester. After 100 revolutions (25 rpm) of the drums, the mini-tablets were removed, broken, and separated powders and small particulates were sieved off, and their masses were measured. Friability was calculated using the following formula:

  

$$\mathrm{F}\mathrm{r}\mathrm{i}\mathrm{a}\mathrm{b}\mathrm{i}\mathrm{l}\mathrm{i}\mathrm{t}\mathrm{y}\left(\mathrm{\%}\right)=\frac{\mathit{T}\mathit{o}\mathit{t}\mathit{a}\mathit{l} mass-\mathit{R}\mathit{e}\mathit{d}\mathit{u}\mathit{c}\mathit{e}\mathit{d} mass}{\mathit{T}\mathit{o}\mathit{t}\mathit{a}\mathit{l} mass}\times 100$$

Observation of Mini-Tablets after the Friability Tests

Mini-tablets after the friability tests were observed using a digital microscope (VHX-1000; Keyence, Osaka, Japan).

Data Analysis

To visualize the effects of tablet shape and tensile strength on their disintegration time and friability, response aspects were analyzed using dataNESIA (Azbil, Tokyo, Japan). DataNESIA uses a response surface method with multidimensional spline interpolation, which is an interpolating method that can predict the nonlinearity of experimental data more accurately and stably. Thus, even complex objects can quickly and easily create a smooth response surface, enabling the visualization of experimental data and efficient optimal designs.^16,17) The “thin-plate double asterisk interpolation” method was used for the analysis of dataNESIA. T7 and T16, which are planar shapes lacking the cup-shaped part, were verified as the experimental models. Considering their impracticality as commercial preparations, they were excluded from the dataNESIA analysis.

Results and Discussion

Physical Properties of Mini-Tablets

Tensile strength, disintegration time, and friability were evaluated (Table 2). Tablet hardness was converted to tensile strength to remove the effect of mini-tablet size. At a cup depth/diameter of 0.209, the disintegration time of T1 was less than 10 min, while the disintegration times of T2 and T3 exceeded 25 min, indicating that the greater the tensile strength, the longer the disintegration time. T10, T11, and T12 were mini-tablets with different thicknesses with a cup depth/diameter of 0.688. As the thickness decreased and the tensile strength increased, the disintegration time increased. In addition, friability ranged from 0.01 to 0.46%, except for T16.

Table 2. Characteristics of Mini-Tablets

Tablet No.	Hardness (N)	Tensile strength (N/mm2)	Disintegration time (min)	Friability (%)
T1	10.80 ± 2.17	1.30 ± 0.26	5.92 ± 0.6	0.02
T2	43.60 ± 3.21	5.49 ± 0.40	25.9 ± 0.4	0.12
T3	40.00 ± 7.18	5.04 ± 0.90	26.4 ± 0.4	0.14
T4	33.20 ± 2.59	4.00 ± 0.31	N.D.	0.05
T5	14.60 ± 4.04	1.76 ± 0.49	N.D.	0.06
T6	16.20 ± 4.21	1.95 ± 0.51	5.10 ± 0.5	N.D.
T7	12.00 ± 1.58	1.44 ± 0.19	3.00 ± 0.6	0.45
T8	8.00 ± 2.92	5.10 ± 1.9	6.68 ± 0.4	N.D.
T9	18.20 ± 5.50	4.03 ± 1.2	7.07 ± 1.3	0.42
T10	20.40 ± 4.22	2.50 ± 0.52	9.17 ± 1.4	0.14
T11	8.40 ± 1.52	0.955 ± 0.17	7.70 ± 0.6	N.D.
T12	12.80 ± 4.21	1.94 ± 0.64	12.7 ± 3.8	0.44
T13	16.60 ± 2.07	1.17 ± 0.15	5.70 ± 0.6	0.46
T14	60.80 ± 10.06	2.42 ± 0.40	14.4 ± 0.7	N.D.
T15	92.20 ± 4.82	6.12 ± 0.32	25.8 ± 5.0	0.01
T16	6.60 ± 0.55	0.795 ± 0.066	1.00 ± 0.0	1.58

Data are represented as the mean ± standard deviation. N.D.: not determined.

Associations between Tensile Strength, Disintegration Time, and Friability

The relationship between disintegration time and tensile strength is shown in Fig. 2a. A linear relationship was observed for all the mini-tablets (y = 3.59x + 0.852, R² = 0.597). The correlation between the disintegration times and tensile strengths was found to be highly significant by calculating a linear approximation of the data, excluding T8 and T9 (y = 4.71x –0.316, R² = 0.903). However, T8 and T9 were plotted away from the straight line, with T8 and T9 having smaller tablet diameters of 1.0 and 1.8 mm. The faster disintegration times obtained for these mini-tablets were attributed to their larger specific surface areas compared to those of the other tablets. The specific surface area was 3.4 m²/g for T8 and 2.1 m²/g for T9, whereas the other tablets ranged from 0.9 to 1.8 m²/g. Conversely, in larger mini-tablets such as T1–T3 having a diameter of 2.3 mm compared with T8 and T9, the higher the tensile strength corresponded to the longer disintegration time. This correlation was previously reported for conventional size tablets.^18,19) Thus, it is hypothesized that a similar trend as observed in the normal-size tablet is recognized when the size is increased to some extent, even in mini-tablets. However, when the size is smaller than 2 mm, there is a high possibility of deviation from this tendency.

Fig. 2. Correlations between the Tensile Strength and Disintegration Time (a) and Friability (b) of Mini-Tablets

Each point represents the value of each tablet. Points in (a) fit a linear equation; the solid line represents the correlations for all mini-tablets (y = 3.591x + 0.8518, R² = 0.597), while the dotted line excludes T8 and T9 (y = 4.708x – 0.3161, R² = 0.903).

The relationship between friability and tensile strength is shown in Fig. 2b. The relationship between friability and tensile strength was not significantly correlated with either the linear or exponential approximations (linear approximation: y = –0.115x + 0.665, R² = 0.337; exponential approximation: y = 0.448e^–0.381x, R² = 0.337). In T7 and T16, the mini-tablets differed in tensile strength despite having similar shape parameters. However, T16, with a lower tensile strength, showed significantly higher friability (1.58%) than T7 (0.05%; Fig. 2b and Table 2). These results suggest that it is challenging to explain friability solely based on tensile strength, indicating that the tablet form factor was related to friability.

Response Surface Analysis of the Effects of Tablet Shape and Tensile Strength on the Disintegration Time and Friability of Mini-Tablets

The effects of tablet shape and tensile strength on the disintegration time and friability of mini-tablets are shown in Figs. 3 and 4, respectively. The tablet shape is expressed as the cup depth/diameter.

Fig. 3. Response Surface Analysis of the Effects of Tablet Shape and Tensile Strength on the Disintegration Time of Mini-Tablets

The colored bar represents the 0–30 min disintegration time range of the mini-tablets. The value decreases as the blue color intensifies and increases as the red color intensifies. Pink points indicate the experimental data.

Fig. 4. Response Surface Analysis of the Effects of Tablet Shape and Tensile Strength on the Friability of Mini-Tablets

The colored bar represents the 0.2–0.6% friability range of the mini-tablets. The value decreases as the blue color intensifies and increases as the red color intensifies. Pink points indicate the experimental data.

As shown in Fig. 3, response surface analysis became planar without displaying a curved surface in response to the analysis, and the disintegration time increased because of the higher tensile strength across all tablet shapes. This result is in line with the findings presented in Fig. 2, suggesting a direct effect of the tensile strength on disintegration time. Additionally, the response surface analysis results indicated that disintegration time was not affected by tablet shape.

Response surface analysis revealed areas of high friability (>0.40) at a cup depth/diameter of 0.091–0.101 and tensile strength of 1.17–4.30, and at a cup depth/diameter of 0.339–0.344 and tensile strength of 1.17–1.98 (Fig. 4). Mini-tablets with the largest radius of curvature resulted in the smallest cup depth/diameter (0.091–0.118) and were shaped like a cylinder (T9, T13, and T15; Figs. 1f, 1j, 1l). Shallow convex- and cylindrical-shaped tablets with a single radius have been reported to exhibit chipping due to low-density areas at the edges, which are insufficiently strong to resist breakage.^20,21) In tablets with a cylindrical shape, the friability increased because of the friable nature of the tablet edge portion. In fact, several tablets with damaged edges were observed after the friability tests (Figs. 5a, 5b). In contrast, greater friability was observed in spherical mini-tablets with a smaller radius of curvature, which had the largest cup depth/diameter (0.344). Many broken tablets were observed at the top of the radius of curvature (Fig. 5c). Mini-tablets are typically manufactured by compressing powder filled in a die with upper and lower punches.^22,23) In cylindrical tablets, compression pressure is evenly distributed, whereas in convex tablets, pressure distribution is skewed, especially with increased curvature. Smaller cup depth/diameter ratios make it harder for pressure to transmit to the convex regions.^24,25) If the punch cup had a convex shape with a smaller radius of curvature, the compression pressure could not be effectively transmitted, likely resulting in breakage at the top of the radius of curvature in the mini-tablets.

Fig. 5. Images of the Damaged Edge Portion of the Mini-Tablets (a, b) and Tablets Broken at the Top of Radius of Curvature (c)

Interestingly, the friability of the mini-tablets with a cup depth/diameter of 0.209 was lower (<0.2) than that of tablets with other cup depth/diameter ratios across all tested ranges of tensile strength (1–6). Even if the tensile strength was low, the friability did not exhibit a high value. Although the response surface analysis demonstrated that low friability was observed in the area with high cup depth/diameter (0.3–0.35) and tensile strength (3–6), compressing these tablets is not feasible as they are difficult to manufacture owing to the pressure resistance of the punch used in manufacturing. Therefore, a cup depth/diameter of 0.2 was considered optimal for the mini-tablet shape to reduce friability. Response surface analysis indicated that friability was affected by the tablet shape. Therefore, the shape of the tablet should be considered when developing mini-tablets with low friability.

Verification Results at Commercial Scale for Mini-Tablets

Mini-tablets of T4 with a cup depth/diameter ratio of 0.2 were continuously produced using a rotary tableting machine. After 240 min of continuous manufacturing, the tensile strength and friability of the mini-tablets were within the ranges of 4.0–4.7 N/mm² and 0.05–0.08%, respectively, without any significant issues. These results demonstrate that a cup depth/diameter ratio of 0.2 is suitable for the commercial production of mini-tablets.

Conclusion

This study is a report on mini-tablets containing sucroferric oxyhydroxide. When attempting to develop mini-tablets, we aimed to determine the effects of tablet size, shape, and tensile strength on disintegration time and friability. The relationship between friability and tensile strength was not significantly correlated with either the linear or exponential approximations. It was difficult to explain friability using tensile strength alone, suggesting that the tablet form factor may be crucial in determining friability.

To visualize the effects of tablet shape and tensile strength on their disintegration time and friability, response aspects were analyzed using dataNESIA. The response surface analysis results indicated that the disintegration time was not affected by the tablet shape. Response surface analysis revealed an area with high friability (>0.40). However, a cup depth/diameter of 0.2 was found to be optimal for reducing friability, allowing mini-tablets to be manufactured at a commercial scale without complications. Tablet shape should be carefully considered during the development of mini-tablets to ensure low friability.

Conflict of Interest

Mr. Omori, Dr. Kurashima, and Dr. Isshiki are employees of Kissei Pharmaceutical Company, Ltd. The other authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study.

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