(W1130-08-52) Optimizing Compression Pressure for Disintegration Efficiency in ODTs: A Formulation Strategy Using F-MELT^® Platform Technology

Purpose: The development of orally disintegrating tablets (ODTs) via direct compression presents a key formulation challenge of balancing mechanical integrity with rapid disintegration¹. While ODTs are increasingly relevant for pediatric, geriatric, and dysphagic populations, their performance hinges on the interplay between compression dynamics and microstructural properties, especially when using porous excipients. Regulatory agencies emphasize critical quality attributes (CQAs) such as rapid disintegration and robust tensile strength as part of Quality by Design (QbD) paradigms^2,3. This study aims to systematically investigate the influence of compression pressure on these CQAs in ODTs developed using F-MELT^®, a co-processed, surface-engineered porous excipient platform designed for quick disintegration without requiring external superdisintegrants. This is the first known study to integrate Heckel analysis, Scanning Electron Microscopy (SEM) imaging, and disintegration performance data to define an optimal compression design space for ODTs formulated with a porous multifunctional excipient. The study seeks to establish a data-driven compression optimization framework and provide formulators with a practical toolkit for ODT development using multifunctional, porous excipients.

Methods: Tablets were prepared using a rotary tableting machine (HT-AP18SS-II, Hata Iron Works, Japan) in inching mode to mimic commercial-scale compression. F-MELT^® Type C, composed of mannitol, xylitol, microcrystalline cellulose (MCC), crospovidone, and Fujicalin^®, was used at 400 mg/tablet with 10 mm flat punches at 30 rpm. Magnesium stearate was not included in the formulation, but lightly dusted on tooling surfaces to minimize sticking. Compression forces of 250–2000 kgf were applied. The corresponding compression pressure (MPa) was calculated as: Compression Pressure (MPa) = Force/ Area = [(kgf x 9.81)/{(D/2)² X π}] where D is the tablet diameter (10 mm). Tablet dimensions, hardness, and disintegration time (DT) were measured per Japanese Pharmacopoeia (JP) standards. The true density (1.500 g/cm³ ) of F-MELT^® Type C was measured using a gas pycnometer (Microtrac). SEM imaging (SU3800, Hitachi High-Tech) was used to visualize surface microstructure across compression pressures. Further calculations included: Tensile Strength, TS = 2F/πDT where F is tablet hardness (N), D is diameter (mm), and T is thickness (mm). Porosity = 1- (Tablet Density/ True Density) Heckel analysis was conducted by plotting [ln(1/(1–d))] against the applied compression pressure (MPa), where d represents the relative density of the compact, calculated as: d = Tablet density/ True density The slope (K) of the linear region was used to calculate the mean yield pressure (P_y), a parameter indicative of the material’s plastic deformation behaviour, using: P<sub>y = 1/ K

Results: Compression pressure significantly affected both mechanical strength and disintegration performance. As compression pressure increased from 37.3 MPa to 252.0 MPa, tablet porosity decreased markedly from ~29.8% to 7.5%, reflecting progressive densification of the powder bed. This correlated with a steady increase in tensile strength, indicating improved interparticle bonding and tablet integrity. DT exhibited an inverse trend, rising from 11.6 s to 275.3 s across increasing compression pressures. The inverse correlation between porosity and DT highlighted the role of microstructure in fluid penetration and tablet breakup, shown in Figure 1. Optimal performance² (DT ≤30 s, TS >2 MPa) was achieved within a compression range of ~37.3 to ~97 MPa (Figure 2) and porosity between ~30% and ~15% (Figure 3). Notably, a small drop in porosity (from 16% to 13%) led to a sharp DT increase (25.7 s to 88.1 s), highlighting the sensitivity of disintegration to porosity. Heckel analysis showed a linear region from 37.3 to 96.3 MPa, with P<sub>y calculated as ~94 MPa. This low yield pressure confirms plastic deformation as the dominant compaction mechanism for F-MELT^® Type C^3,4,5, consistent with its soft, multi-component matrix. SEM imaging supported these findings, showing a clear reduction in pore structure and increased surface smoothness at higher compression pressures, consistent with the densification and reduced porosity observed through quantitative metrics. The data support the existence of a robust design space for F-MELT^®-based ODTs, enabling QbD-driven formulation by modulating compression pressure to target CQAs while ensuring patient-friendly disintegration performance.

Conclusion: This study introduces a first-of-its-kind compression optimization framework tailored for porous, co-processed excipients like F-MELT^®. Through an integrated approach combining disintegration testing, tensile strength, porosity analysis, Heckel modeling, and SEM visualization, the research establishes a robust, data-driven design space for ODT development. F-MELT^® Type C was confirmed to undergo primarily plastic deformation (P_y ~94 MPa) as per Heckel analysis. An ideal compression window of ~37 to ~97 MPa was identified, maintaining porosity above 15%, tensile strength above 2 MPa, and disintegration times under 30 seconds. These findings not only inform optimal tablet design but also enhance formulation predictability and quality control under QbD frameworks. Importantly, this is the first systematic study to define compression-dependent disintegration performance for a porous platform excipient using visual and analytical insights. The framework outlined here can serve as a formulation blueprint for developers working with modern multifunctional excipients and targeting fast-disintegrating dosage forms.

References: 1. Kokott M, Lura A, Breitkreutz J, Wiedey R. Evaluation of two novel co-processed excipients for direct compression of orodispersible tablets and mini-tablets. European Journal of Pharmaceutics and Biopharmaceutics. 2021 Nov 1;168:122-30.
2. Guidance for Industry: Orally Disintegrating Tablets. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). 2008 Dec.
3. Woyna-Orlewicz K, Brniak W, Tatara W, Strzebońska M, Haznar-Garbacz D, Szafraniec-Szczęsny J, Antosik-Rogóż A, Wojteczko K, Strózik M, Kurek M, Jachowicz R. Investigating the impact of co-processed excipients on the formulation of bromhexine hydrochloride orally disintegrating tablets (ODTs). Pharmaceutical Research. 2023 Dec;40(12):2947-62.
4. Odeku OA. The compaction of pharmaceutical powders. Pharmaceutical Reviews. 2007;5(2).
5. Hooper D, Clarke FC, Mitchell JC, Snowden MJ. A modern approach to the Heckel Equation: The effect of compaction pressure on the yield pressure of ibuprofen and its sodium salt. Journal of Nanomedicine and Nanotechnology. 2016 Jun 21;7(381):2.

Acknowledgements: The authors gratefully acknowledge the support of Fuji Chemical Industries Group, Japan for providing access to equipment and resources necessary for the development and characterization of F-MELT®. The authors declare no conflict of interest, as all contributors are employees of the Fuji Chemical Group.

Disintegration Time vs % Porosity with SEM imaging of F-Melt® type C ODTs

Disintegration Time and Tensile Strength as a function of Compression Pressure: Zone of Optimization

Disintegration Time vs % Porosity: Zone of Optimization