(M1330-09-62) A Twin-Screw Melt Coating and Granulation Approach for High Dose Formulations with any Desired Release Profile

Purpose: 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 including melt granulation [2,3]. Simultaneous melt coating and granulation is a process that does not require solvents but uses a solid powder binder to transform powder into highly soluble granules. When heated to a specific temperature close to the melting point of the solid binder, and in the presence of a desired shear rate, the binder melts and coats the active pharmaceutical ingredient (API) to produce well-flowing granules. If the binder is a surfactant, the coating process results in enormous enhancement of wetting and dissolution properties. The process also allows us to produce granules with high drug loading ( > 80 weight percent API). In addition to that, melt granulation facilitates continuous manufacturing process, i.e., enabling the production of solid dosage forms in a continuous flow system, thereby reduction in number of process steps and time, energy consumption, costs to produce a final product. This study explores the utilization of a melt coating and 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. The study also focuses on creating direct compaction (DC) formulation for making tablets with modified release profiles.

Methods: A granule formulation comprising a primarily API ( >80 wt.%), disintegrant (3 to 5 wt.%) and low melting point surfactant (10 to 15 wt.%), was used to determine the range of operational process parameters for TSG, such as screw configuration, screw rotational speed, granulation temperature, and feeder throughput. After identifying the acceptable values of the process parameters, a 2-level 2-factor 2k full factorial design of experiments (DOE), with center points, focusing on screw speed and mass throughput, was conducted to find optimal conditions for granulation. The granules size distribution, true and bulk density, and dissolution rate were evaluated for all DOE conditions. The granules can be filled into capsules or compact into tablets with direct compaction formulation. Granules with immediate release dissolution profile were obtained and developed into several DC formulations to generate tablets with immediate, sustained, and controlled release profiles. Moreover, to demonstrate the manufacturability of the melt coated granules (MCG), the formulation was implemented in the continuous direct compaction (CDC) manufacturing line to generate tablets at a high manufacturing rate.

Results: The analysis of melt-coated granules shows a good flowability, consistently uniform product and exhibits significantly enhanced dissolution profile when compared to the pure API under all experimental conditions specified by the DOE. Comparing 80% drug release times for MCG and pure API; addition of 10% surfactant in granule formulation results in a 60% less time required and the addition of 15% surfactant yields immediate release (IR) granules with a remarkable 80% less time required. Figure 1 provides a visual representation of this data. Figure 2 depicts distinct release profiles of a direct compaction tablet formulation developed using immediate release granules. This tablet formulation primarily comprises melt-coated granules, binder, and lubricant. The results from CDC line confirmed that the MCG were easily manufacturable and could result in highly reproducible final product.

Conclusion: An effective method for converting a poorly flowing and poorly soluble API into granules with excellent flow properties and immediate release characteristics has been successfully demonstrated. Once the immediate release granules are obtained, additional granular material can be incorporated to create a direct compaction tablet formulation. The utilization of immediate release granules to the development of a tablet formulation that can be used in continuous direct compaction, and exhibits a controlled and sustained release profile is also successfully shown.

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.

Figure 1: Dissolution enhancement of melt coated granules

Figure 2: Immediate and modified release tablets from immidiate release melt-coated granules