(M1130-07-47) Downstream Processing of Spray Dried Amorphous Solid Dispersions via Roller Compaction

Purpose: Amorphous solid dispersions (ASDs) are commonly employed to improve the bioavailability of poorly water soluble drugs. ASDs comprise an amorphous drug dispersed within a (polymer)matrix  to provide enhanced stability. Spray drying is commonly used for ASD manufacturing, where ASDs are created by solvent evaporation of a drug-polymer solution¹. However, spray dried powders typically exhibit a low bulk density and poor flowability, compromising subsequent direct compression into tablets. Consequently, the impact of an intermediate dry granulation step via roller compaction (RC) simulation was evaluated to overcome the inherent poor powder quality obtained after spray drying and therefore, enabling subsequent tableting. In current study, it was evaluated how the specific compaction force (SCF) during RC affected ASD stability, tabletability and dissolution performance.

Methods: a. Spray drying: An indomethacin/PVP VA64 (1:2, w/w) ASD was produced by spray drying a 12%w/w organic solution at 15g/min, using a 4M8-TriX spray dryer (PROCEPT). The spray dryer was equipped with a 1.0mm bi-fluid nozzle (5.5L/min atomization gas) to atomize the feed into a heated chamber (inlet airflow: 0.3m³/min, inlet temperature: 85°C), and a large-sized cyclone to capture the dried particles. b. The spray dried ASD was blended with 25% binder (MCC PH102) and 0.5% lubricant (Mg-stearate) before RC. Before tableting an additional 35% of filler/binder (lactose/MCC, 1/1, w/w), 5% disintegrant (sodium croscarmellose) and 0.5% Mg-stearate was added. The Styl’One Evolution (Medelpharm) was used to mimic the RC and tableting process. During RC simulation (flat-faced EU-D punches: 20x10mm, simulated roll speed of 3RPM) a SCF of 5 and 10kN/cm was evaluated, while keeping the gap size fixed at 2mm. For tableting (EU-B punches: 11.28mm), a force study was performed at 100, 200 and 300MPa compaction pressure (tablet weight of 250mg). A Quadro® comill (round screen, 1397µm) was used to mill the ribblets into granules. The tensile strength of ribblets and tablets was measured using a three-point bend test (Texture analyser, Stable Micro Systems) and a hardness tester (ST50, Sotax), respectively. The solid fraction was calculated based on the envelope density of the ribblet/tablet (Geopyc 1365) and the true density of the uncompacted powder blend (Accupyc II 1345), both from Micromeritics. c. Powder and granule characterization: Particle size distribution (PSD) of powder and granules were evaluated via dry powder laser diffraction (LD) or dynamic image analysis (DIA) (RODOS-HELOS and GRADIS-QICPIC, both Sympatec). Morphology was evaluated via scanning electron microscopy (SEM, Phenom Pro Suite, Phenom). The flowability through an orifice was evaluated using a FlowPro^TM (iPAT). d. ASD evaluation: Solid state was evaluated after processing via spray drying and RC, and upon storage (at 25°C/60%RH in open vials) via X-ray Powder diffraction (Aeris diffractometer, Malvern PANalytical) and modulated differential scanning calorimetry (DSC2500, TA instruments). Dissolution performance was evaluated on tablets (targeted tensile strength: 2MPa and solid fraction: 0.85) in a phosphate buffer (pH 6.8, 37°C) using a USP II method (AT X-tend, Sotax).

Results: Spray drying of the API-polymer solution resulted in a high recovery of 80%. The spray dried powder (D50: 20µm) was compacted with a low and high SCF, resulting in ribblets with a solid fraction of 0.64±0.05 (tensile strength: 0.6±0.0MPa) and 0.85±0.00 (tensile strength: 2.3±0.2MPa), respectively. After ribblet milling, a mixture of granulated and non-granulated particles was observed for both SCFs, typically reported for dry granulated materials² (Fig.1). An improved bulk density and flowability was obtained after RC, which was more pronounced at high SCF. This is due to a higher degree of granulation and less fines at high SCF, as evidenced by a large increase in D50/D90 (PSD) and a higher amount of granulated particles (SEM). Dry granulation of the spray dried ASD did not affect the stability, as the granules remained amorphous for (at least) two months. A loss of tabletability, that was more pronounced at a high SCF, was observed after an intermediate dry granulation step (Fig.2). This is consistent with literature attributing reduced granule reworkability to size enlargement and decreased porosity³. Nevertheless, high tablet tensile strengths ( >1.7MPa) could still easily be achieved. Moreover, it has been reported that dry granulation of spray dried ASDs can negatively impact the disintegration and dissolution performance⁴. Consequently, tablets were created with a targeted tensile strength of 2MPa (1.8-2.1MPa) and a solid fraction of 0.85 (0.81–0.87). However, no profound differences were observed in dissolution rate, indicating that an intermediate dry granulation step had no adverse effect on tablet dissolution.

Conclusion: Current study demonstrated that the properties of a spray dried ASD can successfully be enhanced through the implementation of a dry granulation step, without compromising the stability of the ASD. Although a loss of tabletability was observed after intermediate dry granulation (more pronounced for a high SCF), high tensile strengths were nonetheless attainable. Moreover, an intermediate dry granulation step did not adversely affect the tablet dissolution.

References: 1. Moseson, D. E., Tran, T. B., Karunakaran, B., Ambardekar, R., & Hiew, T. N. (2024). Trends in amorphous solid dispersion drug products approved by the U.S. Food and Drug Administration between 2012 and 2023. International Journal of Pharmaceutics X, 7, 100259.
2. Mangal, H., Kirsolak, M., & Kleinebudde, P. (2016). Roll compaction/dry granulation: Suitability of different binders. International Journal of Pharmaceutics, 503(1–2), 213–219.
3. Sun, C., & Himmelspach, M. W. (2005). Reduced tabletability of roller compacted granules as a result of granule size enlargement. Journal of Pharmaceutical Sciences, 95(1), 200–206. https://doi.org/10.1002/jps.20531
4. Démuth, B., Nagy, Z. K., Balogh, A., Vígh, T., Marosi, G., Verreck, G., Van Assche, I., & Brewster, M. E. (2015). Downstream processing of polymer-based amorphous solid dispersions to generate tablet formulations. International Journal of Pharmaceutics, 486(1–2), 268–286.


Fig. 1: Illustration of the impact of a dry granulation step on spray dried ASD properties


Fig. 2: Impact of an intermediate dry granulation step on the tabletability


Fig. 3: Impact of an intermediate dry granulation step on the tablet dissolution