Patterns of drug release as a function of drug loading from amorphous solid dispersions: A comparison of five...

To reduce the pill burden associated with amorphous solid dispersions (ASDs), which arises from the large quantity of polymer used in the formulation, it is of interest to understand the relationship between drug loading and release properties. The aim of this study was to comprehensively evaluate drug release mechanisms from ASDs with polymers of varying hydrophobicity as a function of drug loading. Surface normalized dissolution rates of drug and polymer were studied for felodipine ASDs with polyvinylpyrrolidone (PVP), polyvinylpyrrolidone/vinyl acetate (PVPVA), Eudragit^Ⓡ S 100 (EUDS), hydroxypropylmethylcellulose (HPMC), and hydroxypropylmethylcellulose acetate succinate (HPMCAS), as a function of drug loading. The water sorption profiles and water contact angle measurements suggested the following rank order for hydrophobicity of the different polymers: HPMCAS  ≃  EUDS > HPMC > PVPVA > PVP. For ASDs with relatively hydrophilic polymers (PVP, PVPVA and HPMC), drug release rates were polymer-controlled at low drug loadings (≤15%), whereas at higher drug loadings, release rates were more similar to that of the amorphous drug. The sudden decline in the release performance of ASDs with hydrophilic polymers when a certain drug loading was reached, was attributed to water-induced phase separation. For ASDs with more hydrophobic polymers (HPMCAS and EUDS), the dissolution rate of both drug and polymer was polymer-controlled for drug loadings as high as 50%, with a more gradual decline in drug release rate at higher drug loadings. Notably, at low drug loadings and across the different polymers, when the polymer dictated the drug release rate, ASDs prepared with the most hydrophilic polymers showed the fastest drug release. This suggested a 'trade-off' in choosing between higher release rates with more hydrophilic polymers at low drug loadings and higher drug loadings achievable with more hydrophobic polymers at the expense of lowered release rates. The findings described herein have significant implications for rational selection of polymers for formulation of ASDs with high drug loading and enhanced dissolution performance.