Abstract
Novel polymeric carriers for amorphous solid dispersions (ASDs) are highly demanded in pharmaceutical industry to improve the bioavailability of poorly-soluble drug candidates. Besides established polymer candidates, hydroxypropyl celluloses (HPC) comes more and more into the focus of ASD production since they have the availability to stabilize drug molecules in aqueous media against crystallization. The thermodynamic long-term stability of HPC ASDs with itraconazole and fenofibrate was predicted in this work with PC-SAFT and compared to three-months enduring long-term stability studies. The glass-transition temperature is a crucial attribute of a polymer, but in case of HPC hardly detectable by differential scanning calorimetry. By investigating the glass transition of HPC blends with a miscible polymer, we were for the first time able to estimate the HPC glass transition. Although both, fenofibrate and itraconazole reveal a very low crystalline solubility in HPC regardless of the HPC molecular weight, we observed that low-molecular weight HPC grades such as HPC-UL prevent fenofibrate crystallization for a longer period than the higher molecular weight HPC grades. As predicted, the ASDs with higher drug load underwent amorphous phase separation according to the differential scanning calorimetry thermograms. This work thus showed that it is possible to predict critical drug loads above which amorphous phase separation and/or crystallization occurs in HPC ASDs.
Highlights
Amorphous solid dispersions (ASDs) play a major role as enabling formulations for poorly water-soluble new chemical entities (Vascon celos et al, 2007; Chiou and Riegelman, 1971; Dhirendra et al, 2009)
It is of high interest to identify an optimal polymeric excipient for ASD formulations, e.g. by using completely new synthetic polymers (e.g. Soluplus®, a polyvinyl caprolactam-co-polyvinyl acetateco-polyethylene glycol graft copolymer or the polymethacrylates and poly methacrylic acid based Eudragit® grades (Shamma and Basha, 2013)), or by utilizing polymer mixtures combining the advantages of different polymers (Monschke and Wagner, 2020; Lehmkemper et al, 2018a; Janssens et al, 2008)
The glass-transition temperatures of spray-dried hydroxypropyl celluloses (HPC)/PVPVA64 blends with 10 wt%, 25 wt%, 50 wt%, 75 wt% and 90 wt% HPC were investigated in this work
Summary
Amorphous solid dispersions (ASDs) play a major role as enabling formulations for poorly water-soluble new chemical entities (Vascon celos et al, 2007; Chiou and Riegelman, 1971; Dhirendra et al, 2009). Popular polymeric excipients like polyvinyl pyrrolidone (PVP) or the copolymer poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) show high API solubilities and are theoretically able to stabilize the amorphous API during storage very well (Prudic et al, 2014a; Prudic et al, 2014b; Lehmkemper et al, 2017a; Tao et al, 2009; Sun et al, 2010) They are disadvantageous with respect to hydrophi licity (high amount of water absorbed at humid storage conditions leading to a destabilization and API crystallization (Qi et al, 2013; Saboo and Taylor, 2017; Chen et al, 2018a; Luebbert and Sadowski, 2017)) and their low potential to stabilize high API concentrations in aqueous media during dissolution (weak parachute effect) (Schittny et al, 2020). The predicted phase diagrams were validated via twelve-weeks-enduring long-term studies of spray-dried ASDs, dur ing which the crystallization was monitored weekly
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