Isomalt (galenIQ™ 801, Beneo Palatinit GmbH, Germany), dibasic calcium phosphate anhydrite (DCP, Dicafos C 92-05, Chemische Fabrik Budenheim KG, Budenheim, Germany), fumed silica (Aerosil^® 200, Evonik Degussa GmbH, Germany) and magnesium stearate (Bärlocher, Germany) were used. Isomalt and DCP were sieved through a 2000 µm sieve. For the mixture equal parts (w/w) of isomalt and dibasic calcium phosphate were blended for 10 min in a Turbula mixer (T2C, Willy A. Bachofen AG, Basel, Switzerland).

The flowability is characterized in terms of the ff_c value and the Hausner factor. ff_c values below 4 describe cohesive behavior, the range from 4 to 10 points to easy-flowing materials, whereas an ff_c value greater 10 means free-flowability [12]. The results are given in Table 1. Even the lowest specific compaction force of 2 kN/cm improves the flowability of pure isomalt from cohesive (ff_c = 3.24 ± 0.02) to easy flowing (ff_c = 6.80 ± 0.71). Specific compaction forces of 6 kN/cm and higher produce granules which are all free flowing with ff_c values above 10. The Hausner factor behaves accordingly, decreasing from 1.33 for the uncompacted isomalt to 1.11 for granules produced with a specific compaction force of 14 kN/cm.

Similar results are obtained for the isomalt-DCP batches. The ff_c value increases with higher specific compaction forces up to 10 kN/cm, yet displays a slight drop below the free flowing mark of 10 with an ff_c value of 8.41 ± 0.06 at 14 kN/cm. This can be due to brittle behavior of the excipient after being compacted with the highest specific compaction force, thus creating more fines. In this case, the ff_c value is a more discriminating and accurate indicator for the flowability than the Hausner factor, which is 1.15 for both, the 10 kN/cm and 14 kN/cm batch.

The increased flowability can be explained by the strong increase in particle size due to roll compaction (Table 1). Laser diffraction reveals an x₉₀ of 44.64 ± 1.16 µm for pure isomalt and 31.05 ± 1.02 µm for the isomalt-DCP blend. After roll compaction the x₉₀ of pure isomalt as well as isomalt-DCP granules is in all cases above 900 µm. Yet, the isomalt-DCP granules have only small x₁₀ values of around 37 µm which explain the lower ff_c values compared to pure isomalt granules. Only the 2 kN/cm batch of isomalt granules has an equally small x₁₀ value, specific compaction forces ≥6 kN/cm lead to an x₁₀ of ≥140 µm. The x₅₀ value increases from 546 µm to 642 µm in the same step. The largest x₅₀ value is at 6 kN/cm for isomalt granules (642 µm) and at 10 kN/cm for isomalt-DCP granules (590 µm). It decreases again at higher specific compaction forces, indicating a maximum of plastic deformation at these forces. The material begins to behave brittle as soon as the specific compaction force is raised and the particle size decreases.

As a measure of compactibility, the tensile strength was plotted against the tableting force. As depicted in Figure 1a, it is evident that large specific compaction forces (i.e., ≥10 kN/cm) result in weaker tablets of pure isomalt. T-A-2_15 and T-A-6_15 have tensile strengths up to 1.5 MPa, however tablets of granules produced with a specific compaction force of ≥10 kN/cm have lower tensile strengths. Batch T-A-14_15 displays a drop to below 1 MPa. Only one batch of ungranulated isomalt could be produced (T-A-0_15) because lower tableting forces lead to soft and easily breaking tablets. The difference in tensile strength between ungranulated isomalt and isomalt granulated at low specific compaction forces is small, indicating only little work hardening.

The tablets produced with the isomalt-DCP blend behave differently (Figure 1b). The differences in tensile strength are small across all compaction forces. Yet, the overall tensile strength is in all cases lower than the one of pure isomalt tablets. The strongest tablets made from granules are compacted with a specific compaction force of 6 kN/cm and tableted with 15 kN (T-B-6_15). But even in this case, the tensile strength is in average below 0.9 MPa.

These results mirror in the friability test results. None of the isomalt-DCP tablet batches passes the test. It can be assumed that the brittle behavior of DCP is dominant, thus causing weaker tablets. Pure isomalt tablets roll compacted at 14 kN/cm were affected most from work hardening, as these tablets also fail the test (Table 2). The friability test is successful for tableting forces higher than 9 kN and specific compaction forces of 2 kN/cm and 6 kN/cm. Also, batch T-A-6_9 passes the test.

Ritschel defines the approximate target value of breaking force as 10 N times the diameter in millimeter [13]. The tablets compressed in this study have a diameter of 12 mm and a height of about 2.3 mm in average, implying a target breaking force of roughly 120 N. Even the strongest produced tablets show a breaking force of only 40 N.

Furthermore, the disintegration time according to Ph.Eur. was measured. In most cases, the tablets disintegrate as expected. The higher the specific compaction and tableting force, the longer the tablets need to disintegrate (Figure 2a,b). Isomalt-DCP tablets tend to disintegrate slower than isomalt tablets in most cases. This can be due to the very low water solubility of DCP.

During the dry granulation and tableting processes, the intraparticular and interparticular porosities are affected. Whereas the intraparticular porosity is mainly altered during roll compaction, the interparticular porosity decreases with increasing tableting forces. This explains why some batches disintegrate slowly, even though the tableting force was kept low. For example, T-A-14_3 disintegrates within the same time range as T-A-2_9, albeit the tableting force is tripled. The intraparticular porosity is too small to allow quick wicking. The tensile strength of T-A-2 batches is similar to that of T-A-6 batches, yet the tablets disintegrate faster at 6 kN and 9 kN. It can be assumed, that the higher intraparticular porosity due to the lower specific compaction force facilitates the entry of water and therefore accelerates disintegration. The data suggest that the specific compaction force has a higher impact on the disintegration time than the tableting force. Yet, the differences in disintegration time decrease at compression forces ≥9 kN. The impact of the specific compaction force also decreases with increasing compressions forces. Only pure isomalt roll compacted with 14 kN/cm displays higher disintegration times compared to the other batches.