(M1230-05-26) Manufacturability, Stability, and In Vitro Release of 60% Drug Loaded Amorphous Nanoparticle Tablets of a BCS IV Compound: ABT-530

Purpose: Amorphous solid dispersion (ASD) formulations are widely used to enhance the solubility of poorly water-soluble compounds. However, current ASD formulations have limitations in terms of drug loading (DL; typically ≤ 25% (w/w)). This results in a high pill burden for patients, as large tablets are required to deliver the desired dose. In our previous studies, we developed amorphous nanoparticle powders/formulation intermediates with DL (≥ 60% (w/w)), among the highest reported in literature.^1–5 These formulation intermediates demonstrated excellent re-dispersibility into nanoparticles upon contact with water, an important attribute required for achieving in vivo performance. However, the intermediates still required further processing to convert them into final dosage forms such as tablets or capsules while maintaining high DL and not compromising re-dispersibility. The objective of this research was to develop an amorphous nanoparticle formulation based final dosage form, specifically tablets that are high in DL (≥ 50% (w/w)) and can re-disperse into drug-rich nanoparticles upon contact with an aqueous environment.

Methods: We utilized a BCS IV compound, ABT-530 (Pibrentasvir; an HCV inhibitor and component of MAVIRET™ (EU); MAVYRET™ (USA)),⁶ as a model compound. A controlled solvent-antisolvent precipitation method using a multi-inlet vortex mixer (MIVM) was employed to generate a dilute suspension containing drug-rich amorphous nanoparticles (ANPs; 90% w/w; particle size ~160 nm), as described previously.⁷ Subsequently, the organic solvent was removed and the nanosuspension was concentrated using tangential flow filtration (TFF). Prior to freeze-drying (FD), PVPVA and mannitol were added to the ANP suspension to protect the ANPs against both freezing and drying stresses, facilitating direct FD in preformed tablet blisters. This addition also aimed to enhance the re-dispersibility and mechanical strength of the resulting tablets. Pre-FD ANP suspensions with solid loadings (SL) ranging from 24% (w/v) to 32% (w/v), mannitol to PVPVA ratios from 0% (w/w) to 50% (w/w), and ANP to polymer ratio of 2:1 (w/w) were studied. The impact of process variables on the final dosage form was investigated using various characterization techniques including dynamic light scattering (DLS), scanning electron microscopy (SEM), high-performance liquid chromatography (HPLC), micro computed tomography (μ-CT) scanning, and Brunauer-Emmett-Teller (BET) surface area measurement.

Results: The average particle size distribution of the ANP suspension was measured to be 146.7 ± 0.2 nm after MIVM and 145.5 ± 0.4 nm after TFF, indicating that no significant change in particle size distribution occurred during the filtration and up-concentration processes. The FD tablets maintained their structural integrity throughout the FD process and displayed an elegant appearance (Figure 1, insets). This was evidenced by an intact cake that occupied the same volume as the original frozen form, with no signs of collapse or shrinkage (Figure 1). SEM analysis further confirmed the presence of nanoparticles embedded within the porous matrix of the tablets. The incorporation of mannitol resulted in tablets with enhanced ease of handling, specifically those prepared with a 50:50 ratio of PVPVA to mannitol. ABT-530 ANP tablets, prepared from suspensions with SL up to 30% (w/v), could re-disperse into primary nanoparticles (average particle size < 200 nm) upon contact with water in about 60 seconds (Figure 2A), ensuring efficient drug release. Above this concentration, at 32% (w/v), we observed a decrease in re-dispersibility of the tablets (light green trace in Figure 2A, showing secondary peak around 5000 nm). HPLC analysis confirmed that the re-dispersibility of the tablets decreases by 11% as the SL in the pre-FD suspension increases from 28% (w/v) to 30% (w/v) (Figure 2B). SEM imaging of the suspensions revealed that this reduction in re-dispersibility is due to particle coalescence at higher SL, e.g. 32% (w/v) (Figure 2C). Further characterization by μ-CT scanning demonstrated that tablets derived from a 24% (w/v) SL suspension had slightly larger pore sizes and higher porosity than those from a 32% (w/v) SL suspension (Figure 1C and D). Hence, we concluded that optimal re-dispersibility correlates with higher porosity; while higher solid loading resulted in smaller, mechanically stronger tablets, it adversely affected re-dispersibility. Therefore, the 28% (w/v) SL ANP suspension, with a PVPVA:mannitol ratio of 80:20, was found to be optimal for preparation of 60% DL freeze-dried tablets, balancing size, strength, and re-dispersibility effectively. Re-dispersibility assessments over time showed that the tablets remained stable for two months when stored under proper conditions (Figure 3), such as at 2-8 °C/ambient RH or at 25 °C/60% RH).

Conclusion: Considering that the current commercial ASD formulation of ABT-530 has a DL of 10% (w/w), our approach, yielding 60% (w/w) DL, represents a significant improvement in the development of high drug load final dosage forms. The ability to deliver a tablet of reasonably small size offers significant advantages in terms of patient compliance and convenience. The ANP formulation approach developed here provides a pathway for formulating final dosage forms for poorly water-soluble compounds in the BCS Class IV category with a large dose requirement.

References: (1) Pandi, P.; Bulusu, R.; Kommineni, N.; Khan, W.; Singh, M. Amorphous Solid Dispersions: An Update for Preparation, Characterization, Mechanism on Bioavailability, Stability, Regulatory Considerations and Marketed Products. Int. J. Pharm. 2020, 586, 119560. https://doi.org/10.1016/j.ijpharm.2020.119560.
(2) Oberoi, H. S.; Arce, F.; Purohit, H. S.; Yu, M.; Fowler, C. A.; Zhou, D.; Law, D. Design of a Re-Dispersible High Drug Load Amorphous Formulation. J. Pharm. Sci. 2023, 112 (1), 250–263. https://doi.org/10.1016/j.xphs.2022.10.002.
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Acknowledgements: AbbVie sponsored the study; contributed to the design; participated in collection, analysis, and interpretation of data; and in writing, reviewing, and approval of the final version.


Figure 1. SEM images of ABT-530 Tablets prepared from the pre-FD suspensions at (A) 24% (w/v) SL and (B) 32% (w/v) SL (insets: representative photographs of freeze-dried ABT-530 Tablets prepared from the suspensions at 24% (w/v) SL (top) and (B) 32% (w/v) SL (bottom). High-resolution 3D topography images of ABT-530 Tablets prepared from the pre-FD suspensions at (C) 24% (w/v) SL and (D) 32% (w/v) SL. The Dragonfly software was used to acquire the 3D visualization, segmentation, porosity, and overall pore size distribution.


Figure 2. (A) Size distribution of ANPs after re-dispersion from Tablets prepared from suspensions at 24% (w/v) SL to 32% (w/v) SL. (B) Filtrate potency values for re-dispersed ABT-530 Tablets prepared from the pre-FD suspensions at 24% (w/v) SL to 32% (w/v) SL. Values are normalized to corresponding unfiltered suspension control. (C) SEM images of the re-dispersed ABT-530 Tablets prepared from suspension at 28% (w/v) SL (left) and 32% (w/v) SL (right).


Figure 3. Assessment of ABT-530 ANP Tablets stability over time. Filtrate Potency Assay for tablets stored at (A) 2-8 °C/ambient RH; (B) 25 °C /60% RH; (C) 30 °C/75% RH.