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

Abstract

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. We present a systematic study of the milling and tableting of an extruded ASD of itraconazole with hypromellose acetate succinate (HPMCAS) as a carrier polymer. 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. 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 established using response surface methodology. 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.

A review of hot melt extrusion paired fused deposition modeling three-dimensional printing for developing patient centric dosage forms

“…The number of elements and offset angle of the mixing zones mainly depend on the melt viscosity of the processing material. The mixing zones can be customized as required depending on the amount of shear that needs to be imparted onto the processing material [39][40][41][42][43][44][45]. Apart from the conveying and mixing elements, the other elements include comb mixing, cutter element, and narrow-toothed mixing elements, which have not been investigated for developing ASDs.…”

A Review of Various Manufacturing Approaches for Developing Amorphous Solid Dispersions

“…As mentioned earlier, the milled extrudates of HME exhibit poor compressibility attributed to their glassy nature. Saurabh M Mishra et al (2022) 50 investigated the effect of milling techniques on the compressibility of milled extrudates and the performance of the compressed tablets. ASDs of itraconazole were prepared using hypromellose acetate succinate (HPMCAS) as a polymeric carrier by HME.…”

Hot melt extrusion: A single-step continuous manufacturing process for developing amorphous solid dispersions of poorly soluble drug substances

“…Saurabh M Mishra et al [20] developed ASD-based tablets using a hot melt extrusion process. Within the investigation, the author has studied the effect of milling extrudates on the performance of tablets.…”

“…Thus, attributing to various issues associated with liquid formulations, the pharmaceutical industries have developed their interest in manufacturing solid oral dosage forms. Among tablets and capsules, tablets are preferred attributed to their low manufacturing cost [18][19][20][21]. In addition, the adulteration of capsules is much easier when compared with tablets.…”

“…The approach of improving solubility for one drug might not be applicable for another, attributing to various concerns related to the physiochemical properties of the drug substance. Among various formulation approaches that have been investigated, amorphous solid dispersions, solid crystal suspension, lipid-based formulations, the salt form of the drug, co-crystal, co-amorphous system, and cyclodextrin complexation have attracted the audience from various avenues of the pharmaceutical industries [18][19][20][21][22][23][24][25][26][27][28]. However, attributed to the use of solvents and lack of proper scale-up strategies, a few applications have been deemed unsuitable for commercial manufacturing [29].…”