(T1430-06-33) Downstream Processing of Itraconazole:HPMCAS Amorphous Solid Dispersion: From Hot-Melt Extrudate to Tablet Using a Quality by Design Approach

Purpose: The downstream processing of hot-melt extruded amorphous solid dispersions (ASDs) into tablets is challenging due to the low tabletability of milled ASDs. Typically, the extrudate strand is sized before milling, as the strand cannot be fed directly into the milling system. At the lab scale, the strand can be sized by hand-cutting before milling. For scaling up, pelletizers or chill roll and flaker systems can be used to break strands. Due to the different techniques used, differences in milling and tablet compaction are to be expected. Thus, in present work, systemic study of the milling and tableting of an extruded ASD of itraconazole with hypromellose acetate succinate (HPMCAS) as a carrier polymer.

Methods: Poorly soluble model drug Itraconazole (ITZ) was mixed with HPMCAS-ASMMP in ratio of 20:80 and hot melt extruded using corotating twin screw extruder at 165^° C using 3 kneading zone. The strand was sized using different techniques at the end of the extruder barrel (hand-cutting, pelletizer, or chill roll and flaker) before being milled at varying milling speeds with varying screen sizes (Figure 1). The effects of these variables (sizing technology, milling speed, and screen size) on the critical quality attributes (CQAs) of the milled ASD, such as yield, mean particle size (D50), tablet compaction characteristics, and tablet dissolution, were studied using response surface methodology. The feed rate of materials, screw speed, and the die size of the extruder were varied according to the sizing process (Table 1).

Results: Change in downstream equipment at the end of extruder barrel results in differently shaped and sized feedstock materials for milling with premilled feedstock (HCF) as the finest material. Whereas by using pelletizer, regular-shaped cylindrical pellets (PEs) of approximately 2 mm diameter and length were obtained. The chill roll flakes (CRFs) were irregular-shaped shards with different diameters and approximately 1 mm thickness. From DSC and XRD study all three feedstocks (HCF, PE and CRF) shows ITZ in amorphous state with single glass transition temperature and absence of any crystalline peak. From response surface methodology, it was found that, among the feedstocks, the highest percentage yield with a lower PSD was observed for chill roll flakes compared to hand cut filaments and pellets. The tensile strength and ITZ release from ASD tablets were also found to be the highest after the milling of chill roll flake feedstock. A detailed analysis of results using the Pearson correlation coefficient test indicated that the lower PSD achieved in the case of CRF feedstocks resulted in the higher tabletability and dissolution of ITZ, indicating PSD as the most important CQA of milled ASD extrudates. Furthermore, although the feedstock for milling showed morphological differences, it was found that by careful selection of milling speed, a similar PSD was observed after the milling of HCF in comparison with the milling of pellets or chill roll flakes, demonstrating an easy transfer from early-formulation hand-cut processing at the lab scale to industrial applicable processes.

Conclusion: A systematic study of the milling and tableting of an extruded ASD of itraconazole with hypromellose acetate succinate (HPMCAS) as a carrier polymer using QbD approach was carried out. It was found that the CQAs varied according to sizing technology, with chill roll flakes showing the highest percentage yield, the lowest D50, and the highest tabletability and dissolution rate for itraconazole. Pearson correlation coefficient tests indicated D50 as the most important CQA related to tabletability and dissolution. For certain milling conditions, the milling of hand-cut filaments results in similar particle size distributions (PSDs) to the milling of pellets or chill roll flakes thus can be successfully transferred from lab scale studies to production scale.

Figure 1: Downstream processing of extruded strands by hand-cutting (a), pelletizing (b), and chill roll technology (c) and subsequent milling (d).



Table 1: Experimental design for studying the effect of independent variables on CQAs of ITZ:HPMCAS ASD extrudates.