(256d) Enhancing the Oral Bioavailability of Poorly Soluble Drug through Twin-Screw Melt Coating and Granulation

As human understanding of diseases expands, novel drug molecules are being discovered each year. However, formulating these drugs for oral dosages poses a significant challenge due to limited drug bioavailability, which is preliminary attributed to poor solubility. It is estimated that nearly 40% of newly discovered drugs are poorly soluble [1]. To address this problem, several techniques are deployed, such as spray drying and melt granulation [2,3]. Melt granulation is a process that does not require solvents but uses a solid powder binder to transform powder into granules at elevated temperatures (enough to melt the binder). When heated to a specific temperature, the solid binder undergoes a melting process and produces that allows it to coat the active pharmaceutical ingredient (API) while also producing well flowing granules through either distribution or coalescence. Melt granulation is a continuous process and eliminates the need for a drying step, thereby reducing number of process steps, energy consumption, costs, and time required to produce a final product.

This study explores the utilization of melt granulation technique, using a twin-screw granulator (TSG), to improve the solubility and manufacturability of fenofibrate, an API that exhibits poor flow and low solubility. A granule formulation comprising a primarily API (> 80wt.%), disintegrant and low melting point binder (polymer/surfactant), was used to determine the range of operational process parameters for TSG, such as screw configuration, screw rotational speed, granulation temperature, and feeder throughput. Subsequently, a 2k (with k=2) full factorial design of experiments (DOE), with center points, focusing on screw speed and feeder throughput was conducted to find optimal conditions for granulation. The granule size distribution, true and bulk density, and dissolution rate using ultraviolet–visible spectroscopy were evaluated for all conditions. The analysis show that a uniform granule product was produced, that could be further milled down, with a much-improved dissolution profile than the pure API. The granules can be filled into capsules or compact into tablets. The immediate-release granules were used in multiple formulations to produce tablets with immediate-release, sustained-release, and controlled-release profiles. To investigate the effect of shear on tablet hardness and density, as well as the impact of different weight percentages of lubricant in the formulation, the final tablet production blend was subjected to varying levels of shear. In order to demonstrate the manufacturability of the melt coated granules (MCG), the formulation was implemented in the Rutgers C-SOPS continuous direct compaction manufacturing line (continuous DC line) to generate tablets at a high manufacturing rate. The study also investigated the impact of compaction force on tablet hardness and dissolution rate profiles using a mixed-level DOE in continuous DC line. The DOE involved two levels of throughput and feed frame speed, as well as three levels of compaction force. The findings indicated a significant distinction in both, dissolution rate and hardness, relating to changes in compaction force of tablets. The results of this work confirmed that the MCG were easily manufacturable and could result in highly reproducible immediate release final product.

References:

1. Savjani, K. T., Gajjar, A. K., & Savjani, J. K. (2012). Drug Solubility: Importance and Enhancement Techniques. ISRN Pharmaceutics, 2012, 195727. L
2. Lakshman, J. P., Kowalski, J., Vasanthavada, M., Tong, W.-Q., Joshi, Y. M., & Serajuddin, A. T. M. (2011). Application of melt granulation technology to enhance tabletting properties of poorly compactible high-dose drugs. Journal of Pharmaceutical Sciences, 100(4), 1553-1565.
3. Yang, D., Kulkarni, R., Behme, R. J., & Kotiyan, P. N. (2007). Effect of the melt granulation technique on the dissolution characteristics of griseofulvin. International Journal of Pharmaceutics, 329(1), 72-80.