(14d) Pill Burden Reduction through Engineering the Mechanical Properties of Spray-Dried Amorphous Solid Dispersions

Drug candidates with poor oral bioavailability due to low aqueous solubility and dissolution rate are common in the pharmaceutical industry. One of the most mature and well understood techniques to improve oral absorption of drug candidates is to formulate the drug as a spray-dried amorphous solid dispersion (SDD). Given SDDs are diluted with excipients to, primarily, stabilize the amorphous form of the drug, a common challenge in SDD oral delivery of tablets is pill burden. One promising solution to reduce pill burden is engineering the SDD particles to replace the use of tablet fillers, which primarily attenuate undesirable mechanical and powder flow properties of crystalline drugs. Given that the mechanical and powder flow properties of SDDs can be significantly tuned during the spray drying process, the use of fillers can be substantially reduced. However, tuning the particle properties of SDDs is a hierarchical multidimensional optimization problem, and for that reason, a clear relationship between particle properties and physical and chemical state stability of the drug and in vivo performance is generally established prior to optimization of mechanical and powder flow properties. There have been several recent reviews on this subject, but there lacks the direct connection between spray-drying process conditions and their impact on final tablet formulation [1-2].

The aim of the current study is to establish relationships between spray drying process parameters and the resulting physical and mechanical properties of the SDD particles, and secondly, to use these relationships to formulate high SDD loaded (greater than 70%) immediate release tablets. Felodipine spray-dried with PVP VA64 was used as the model SDD system. The powder mechanical properties measured include compression profiles, SEM imaging, modified in-die compression analysis [3], BET surface analysis, and Hiestand indices.

Results showed that, for a given SDD formulation, specific surface area of the powder was controllable by tuning the particle size, particle wall thickness, and to a lesser extent, particle morphology through drying kinetics and atomization during spray drying. This resulted in SDDs that spanned a 10-fold difference in specific surface area. The resulting mechanical properties of these high surface area SDDs included significant increases in tensile strength and bonding index (BI) when compressed, due to larger bonding area between particles [4].

The material properties were strongly dependent on the drug loading, with higher drug loading SDDs having diminished compactibility compared to their placebo counterparts. These results suggest that, counter to selecting the highest drug loading SDD with acceptable physical stability and in vivo performance, a lower drug loading SDD formulation could allow for less filler in the final drug product, resulting in an overall higher loading within the tablet. Consequently, this also improves the physical stability robustness.

In addition, it was observed that, when compressed as the neat material, the compacts had varying degrees of anisotropy, which resulted in greater axial elasticity. High elastic recovery decreases the bonding area between particles, reducing the strength of the tablets and increasing the risk for capping and lamination. Therefore, decreasing the degree of anisotropy could reduce the risk of these tablet defects and should be considered when engineering SDD particles for integration into tablet formulations [5].

Overall, the powder properties resulted in various immediate release tablet formulations with as high as 80% concentration of SDD. It was demonstrated that the SDD could span the tabletability range of typical fillers depending on how it was spray dried, allowing it to “do the job” of different types of fillers. The study ultimately concludes that rationally selecting spray-drying conditions to target specific particle properties, such as high surface area, high compactibility, and isotropic geometries, allows tablet formulations that can successfully decrease pill burden.

[1] Patel, B.B. et al. Revealing facts behind spray dried solid dispersion technology used for solubility enhancement. Saudi Pharm. J. 2015, 23 (4), 352-365.

[2] Singh, A. and Van den Mooter, G. Spray drying formulation of amorphous solid dispersions. Adv. Drug Deliv. Rev. 2015.

[3] Katz, J. M., Roopwani, R., Buckner, I. S. A Material-Sparing Method for Assessment of Powder Deformation Characteristics Using Data Collected During a Single Compression-Decompression Cycle. J. Pharm. Sci. 2013, 102 (10), 3687-3693.

[4] Osei-Yeboah, F., Chang, S., and Sun, C.C. A critical Examination of the Phenomenon of Bonding Area - Bonding Strength Interplay in Powder Tableting. Pharm Res. 2016, 33, 1126-1132.

[5] Sun, C.C. Microstructure of Tablet – Pharmaceutical Significance, Assessment, and Engineering. Pharm. Res. 2017, 34, 918-928.