Purpose: Direct compression (DC) is the easiest and most cost-effective process for tablet manufacturing because it involves only blending and compression to manufacture tablets. However, active pharmaceutical ingredients (API) exhibiting poor mechanical and micromeritic properties require the use of large amounts of excipients to develop manufacturable DC formulations. Consequently, drug loading in DC tablets is usually low (typically < 30%, w/w). In this study, spherical crystallization by the Quasi-Emulsion Solvent Diffusion method was used to engineer poorly flowing ferulic acid (FA) to attain superior mechanical properties, particle size distribution and morphology. The aim of this work was to develop a DC tablet containing as high API loading as possible by forming free-flowing spherical particles consisting of fine FA crystals.
Ferulic acid (FA) was used as a model compound to prepare spherical agglomerates. The spherical FA agglomerates were prepared using a quasi-emulsion solvent diffusion (QESD) method. 25g ferulic acid was dissolved in 250ml acetone at room temperature, and then the FA solution was poured into a 2L 0.1% (w/v) HPMC aqueous solution stirred at 300 rpm by an overhead digital stirrer. After 1h agitation, the QESD FA particles were collected and dried at 60 °C in an oven. The phase purity of the FA by QESD was verified by PXRD. The particle size and shape were analyzed by microscopy and SEM. Powder flow properties were characterized using a ring shear tester and powder compaction was studied by a Zwick universal material testing machine. Dissolution performance was studied using a single chamber set up.
QESD FA particles consisting of bundles of small needle-like primary crystals show a narrow particle size distribution (between 100-200 μm) and an approximately spherical morphology (Figures 1a and 1b), while the as-received FA crystals exhibit needles with a broad size distribution (50 - 400 μm, Figure 1c) and rough surfaces (Figure 1d). The QESD powder can reach a tablet tensile strength as high as 6 MPa, which is approximately double that of the as-received FA (~3 MPa). The flowability of QESD powder is also significantly better as measured by flowability index (ffc). An amount of 0.75 % crospovidone was verified to sufficiently lower the disintegartion time to about 10 min and 0.25 % magnesium stearate reduced tablet ejection force to below 400 N over the entire range of pressure. The suitability of the 99% QESD FA loading formulation for manufacturing under realistic conditions was further verified in terms of tabletability (tablet tensile strength can reach to as high as 7 MPa, Figure 2a) and flowability (much better than the Avicel PH 102, Figure 2b). Tablet friability (lower than 0.4% at 60MPa compaction pressure, Figure 3a), and dissolution (similar dissolution performance as the 99% FA as-received formulation, Figure 3b) also meet the requirement for successful tablets.
FA spherical agglomerates, prepared by quasi-emulsion solvent diffusion (QESD) method, exhibit both excellent tabletability and flowability. Spherical crystallization enabled the development of a very high API loading DC tablet formulation, at 99%, that meet all critical quality attributes. This work highlights the potential advantages of spherical crystallization in developing high drug loading DC tablet formulations.
Aktham Aburub– Senior Research Advisor, Eli Lilly & Company, Indianapolis, Indiana
Changquan Sun– Professor and Director of Graduate Studies, Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota