(T0930-05-25) Impact of Excipient Types and Drug Loadings on the Tabletability Flip Phenomenon

Purpose: A successful tablet product must possess adequate mechanical strength to survive the journey from manufacturing to administration. Therefore, adequate tabletability, the ability of a powder to form a tablet of specific strength under the effect of compaction pressure, must be attained.1 Typically, more plastic active pharmaceutical ingredients (APIs) can undergo more extensive plastic deformation under compression, leading to larger bonding area (BA) and better tabletability.^2-4 A recently revealed tabletability flip phenomenon (TFP) suggests that less plastic materials, despite showing poorer tabletability by themselves, can exhibit better tabletability when formulated in the same excipient matrix.^5,6 A mechanism for the TFP is the conformation of the soft particle to the hard particle in the soft-hard mixture, leading to a larger BA than in the soft-soft mixture (Figure 1).7 The composition of a formulation, i.e., type and amount of excipients and drug loading, is critical to tablet strength. Thus, the choice of excipients is expected to have an impact on tabletability flip. An investigation of those factors on TFP can offer invaluable insights into the formulation design to ensure adequate tabletability. Hence, the impact of excipient types (with different mechanical properties) and drug loadings was systematically investigated in this work.

Methods: A polymorphic pair, p-aminobenzoic acid (ABA) forms α and β, was selected as model systems. They were mixed with common pharmaceutical excipients, microcrystalline cellulose (MCC), Hypromellose (HPMC), Lactose monohydrate (LM) and dibasic calcium phosphate dihydrate (DCPD), to prepare drug-excipient binary mixtures at various drug loadings. For each powder, a series of cylindrical compacts were compressed over the pressures of 15-350 MPa using a compaction simulator. Tablet tensile strength was calculated from the maximum breaking force and tablet dimensions.8 The tensile strength ratio (TSR) between two polymorphs or their mixtures was used to quantify the extent of TFP. The plasticity of these materials was quantified using the mean yield pressure (P_y,i) values obtained from in-die Heckel analyses.^9,10

Results: The tabletability of α polymorph of ABA (αABA) is significantly better than the β polymorph (βABA).  No intact tablets of βABA could be formed within the entire pressure range.  The better tabletability of αABA is attributed to its higher plasticity, as suggested by its significantly lower P_y,i, (51.5 ± 1.8 MPa) than that of βABA (109.0 ± 6.4 MPa). With different excipients at different loading levels (i.e., 20%, 40%, 60%, and 80% ABA), TFP occurred in some mixtures with MCC (P_y,i = 54.2 ± 1.5 MPa) (20%, 40%, 60% ABA) and HPMC (P_y,i = 30.2 ± 3.8 MPa) (20%, 40%, 60% ABA), but not in mixtures with LM (P_y,i = 141.0 ± 0.4 MPa) and DCPD (P_y,i = 581.4 ± 3.7 MPa) (Figure 2). The occurrence of the TFP when mixing with a soft excipient can be explained by the formation of larger BA in the soft excipient - hard βABA, leading to better tabletability. The extent of the TFP in mixtures with MCC follows a descending order of 40% ABA > 60% ABA > 20% ABA. In mixtures with HPMC, 20% ABA shows more significant TFP than 40% ABA. The ABA-MCC system was further investigated to study the drug loading effect on the TFP (Figure 3). The TFP was only observed at higher pressures. Under 200 MPa and 350 MPa, the TFP highly depends on drug loading. At low drug loadings (2%), the TSRs are close to unity and the TFP is not significant because the two ABA mixtures show similar tabletabilities since BA is dominated by the excipient-excipient contacts.  With increasing drug loading, the TSR reaches a maximum value in the 20% - 60% range, where the extent of the soft-hard contact is greater in the MCC (soft)-βABA (hard) mixture, leading to more prominent TFP. At high drug loadings, the TSRs are lower than unity, because the BA is dominated by the API-API contact and insufficient soft-hard contacts are formed in the βABA-MCC mixture, resulting in a smaller BA and a lower tabletability, i.e., TFP does not occur.

Conclusion: Tabletability tends to flip when two API solid forms are mixed with a plastic excipient. Therefore, when the model solid form of an API is poorly compressible, plastic excipients, e.g., MCC, HPMC, should be used in the formulation to ensure adequate tabletability. If hard excipients, e.g., LM, DCPD, are used, a formulation containing the more plastic solid form will still exhibit superior tabletability. Additionally, TFP tends to occur in an intermediate range of drug loading.  The drug loading corresponding to the most prominent TFP varies from system to system. The observed influence of the excipient type and drug loading supports the validity mechanism of the TFP (summarized in Figure 1).

References: (1) Sun, C. C; Grant, D. J. W. Influence of Crystal Structure on the Tableting Properties of Sulfamerazine Polymorphs. Pharm. Res. 2001, 18 (3), 274–280. https://doi.org/10.1023/A:1011038526805.
(2) Chang, S.-Y.; Sun, C. C. Superior Plasticity and Tabletability of Theophylline Monohydrate. Mol. Pharm. 2017, 14 (6), 2047–2055. https://doi.org/10.1021/acs.molpharmaceut.7b00124.
(3) Chen, H.; Zhang, J.; Qiao, Q.; Hu, E.; Wei, Y.; Pang, Z.; Gao, Y.; Qian, S.; Zhang, J.; Heng, W. A Novel Soluble Lornoxicam-Sodium Chelate Monohydrate with Improved Plasticity and Tabletability. Int. J. Pharm. 2022, 624, 122060. https://doi.org/10.1016/j.ijpharm.2022.122060.
(4) Hu, S.; Mishra, M. K.; Sun, C. C. Twistable Pharmaceutical Crystal Exhibiting Exceptional Plasticity and Tabletability. Chem. Mater. 2019, 31 (10), 3818–3822. https://doi.org/10.1021/acs.chemmater.9b00441.
(5) Paul, S.; Wang, C.; Sun, C. C. Tabletability Flip – Role of Bonding Area and Bonding Strength Interplay. J. Pharm. Sci. 2020, 109 (12), 3569–3573. https://doi.org/10.1016/j.xphs.2020.09.005.
(6) Wang, Z.; Wang, C.; Bahl, D.; Sun, C. C. The Ubiquity of the Tabletability Flip Phenomenon. Int. J. Pharm. 2023, 643, 123262. https://doi.org/10.1016/j.ijpharm.2023.123262.
(7) Wang, Z.; Wang, C.; Guo, Y.; Bahl, D.; Fok, A.; Sun, C. C. A New Insight into the Mechanism of the Tabletability Flip Phenomenon. Int. J. Pharm. 2024, 654, 123956. https://doi.org/10.1016/j.ijpharm.2024.123956.
(8) Fell, J. T.; Newton, J. M. Determination of Tablet Strength by the Diametral-Compression Test. J. Pharm. Sci. 1970, 59 (5), 688–691. https://doi.org/10.1002/jps.2600590523.
(9) Heckel, R. W. An Analysis of Powder Compaction Phenomena. Trans Met. Soc AIME 1961a, 221, 1001–1008.
(10) Heckel, R. W. Density–Pressure Relationships in Powder Compaction. Trans Met. Soc AIME 1961b, 221, 671–675.

Acknowledgements: CCS thanks the National Science Foundation for support through the Industry University Collaborative Research Center (IUCRC) grant IIP-2137264, Center for Integrated Materials Science and Engineering for Pharmaceutical Products (CIMSEPP).


Figure 1. The BA-dominating mechanism of the tabletability flip phenomenon.


Figure 2. The ratio of tablet tensile strength of βABA and its mixtures to αABA and corresponding mixtures with different excipients at different compositions. Since no intact tablets could be formed for βABA, the ratios are all zero (green lines). The orange dashed horizontal line represents the same tensile strength between the two types of powders. When the ratio is greater than one, tabletability flipping occurs.


Figure 3. The tensile strength ratio (TSR) of ABA polymorphs with MCC at different drug loadings under three compaction pressures. The cartoons signify the compaction characteristic of the soft-hard mixture at low, critical, and high drug loadings.