<p>As amorphous solid dispersions (ASDs) are more widely employed as a formulation strategy for poorly water-soluble drugs, there is a pressing need to increase the drug loading in these formulations. The drug loading is typically kept low to obtain the desired drug release rate, but often results in large or even multiple dosage units, which is undesirable from a patient compliance perspective. We have identified the cause of this conundrum to be the drug loading dependent dissolution mechanism of ASDs. At low drug loadings, the dissolution rate of ASDs is polymer-controlled, while at high drug loadings, the dissolution rate is drug-controlled and considerably slower. This phenomenon is most pronounced for ASDs with hydrophilic polymers, such as poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA) and the change in dissolution mechanism from being polymer-controlled to drug-controlled has been attributed to water-induced amorphous-amorphous phase separation (AAPS) in higher drug loading ASD matrices of hydrophilic polymers. The drug loading limit for this switch has been found to be dependent on drug properties as well as drug-polymer interactions. Interestingly, drug-polymer hydrogen bonding interaction has been found to be detrimental and decrease the drug loading limit for polymer-controlled release while drug log P did not have any impact on this limit. Variable dissolution temperature studies indicated a detrimental impact on the polymer-controlled drug loading limit when the drug-rich phase (of phase separated ASD matrix) exists in a glassy state. ASDs with relatively hydrophobic polymers, such as hypromellose acetate succinate (HPMCAS), have been found to be polymer-controlled up to higher drug loadings. The mechanistic understanding obtained in this body of work can thus be adopted to develop strategies enabling ASD formulations with optimized performance and improved drug loading.</p>

Yes / A study has been carried out to investigate controlled release performance of caplet shaped injection moulded (IM) amorphous solid dispersion (ASD) tablets based on the model drug AZD0837 and polyethylene oxide (PEO). The physical/chemical storage stability and release robustness of the IM tablets were characterized and compared to that of conventional extended release (ER) hydrophilic matrix tablets of the same raw materials and compositions manufactured via direct compression (DC). To gain an improved understanding of the release mechanisms, the dissolution of both the polymer and the drug were studied. Under conditions where the amount of dissolution media was limited, the controlled release ASD IM tablets demonstrated complete and synchronized release of both PEO and AZD0837 whereas the release of AZD0837 was found to be slower and incomplete from conventional direct compressed ER hydrophilic matrix tablets. Results clearly indicated that AZD0837 remained amorphous throughout the dissolution process and was maintained in a supersaturated state and hence kept stable with the aid of the polymeric carrier when released in a synchronized manner. In addition, it was found that the IM tablets were robust to variation in hydrodynamics of the environment and PEO molecular weight. / The research was funded by AstraZeneca, Sweden.