Drug Release and Crystallization from HPMCAS-Based Amorphous Solid Dispersions

The success of an amorphous solid dispersion (ASD) lies in its ability to generate a supersaturated solution and maintain it for a physiologically relevant duration. Both these processes could be influenced by the presence of crystalline drug in ASDs. Even a low level of residual drug crystals in a freshly prepared ASD can act as seeds resulting in rapid recrystallization from solution if the drug is a fast crystallizer. Detecting crystallinity in an ASD at such low levels becomes limited by the detection technique. Residual crystallinity in posaconazole-hydroxypropyl methylcellulose acetate succinate (HPMCAS) ASDs was quantified using second harmonic generation based nonlinear optical imaging and its effect on the sustenance of supersaturation was evaluated in real time using orthogonal analytical methods including focused beam reflectance measurement.

Drug release and crystallization are both highly influenced by the polymer present in ASDs. Understanding polymer chemistry is especially important for ionic polymers like HPMCAS which is one of the commonly used polymers and is present in several commercially available ASD-based products. Acetate-to-succinate ratio in HPMCAS and buffer pH determine the polymer hydrophobicity and strength of interaction with a weakly basic drug. The more hydrophilic grade L released the drug at a faster rate but was weaker in its ability to inhibit crystallization as compared to the more hydrophobic grade H which released poorly, whereas M was found to be optimum. Polymer hydrophobicity correlated with the strength of its interactions with the drug as measured by fluorescence spectroscopy.

A major factor determining the rate of drug release from ASDs is its glass transition temperature (T_g). High-T_g drugs release poorly from ASDs making them challenging candidates unless formulated at very low drug loading resulting in pill burden. The effect of glyceryl tributyrate as a plasticizer was evaluated on the release rates of three high-T_g drugs, ivacaftor, cyclosporine, and ARV-825 from their ASDs with HPMCAS. Ternary ASDs containing glyceryl tributyrate had noticeably lower T_gs than their binary counterparts and a significant improvement in the release rates was observed. This enables formulation of high-T_g drugs as ASDs with higher drug loading. This work has helped expand the knowledge of dissolution of ASDs containing HPMCAS and its role in preventing drug crystallization.