Solubility-enhancing amorphous solid dispersions are used in the oral delivery of hydrophobic, crystallizable drugs. Effective solid dispersion excipients enable high supersaturation drug concentrations and limit crystallization of the dissolved drug over extended times. We prepared poly(N-isopropylacrylamide)-based excipients of varying molar mass and with various end group identities, and examined their ability to improve the aqueous solubility of the Biopharmaceutical Class System Class II drug, phenytoin. Solid dispersions of these excipients and phenytoin were prepared at 10 wt % drug loading. Performance depended largely on the tendency of the polymer excipient to form micellar aggregates in aqueous buffer. We present several systems that achieved significant improvement of phenytoin solubility, with no indication of drug crystallization over 6 h. This is among the highest enhancement factors seen for phenytoin to date, and the success of these systems is ascribed to the added stability of these “self-micellizing” solid dispersions.

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