Role of Drug Loading and Microenvironmental pH in Generation of Nanospecies during Dissolution of Eudragit-Based Amorphous Solid Dispersions

In the past few years, nanospecies formation during dissolution of amorphous solid dispersion (ASD) has gained significant attention, mainly due to their positive biopharmaceutical attributes. However, limited knowledge is available about the mechanism and factors involved in generation of nanospecies during dissolution of ionic polymer-based ASDs. In the present study, the mechanism of nanospecies formation during dissolution of ASDs containing aprepitant (APR)-Eudragit L100-55 has been investigated as a function of drug loading and microenvironmental pH. APR and Eudragit L100-55 at all drug loadings (5, 20, and 40% w/w) showed congruent release from the dissolving ASD compact surface during surface normalized release (SNR) testing due to drug-polymer interactions and relatively low hydrophilicity of Eudragit L100-55. Nanospecies in a bulk medium were observed only in the case of 5 and 20% w/w drug loaded ASDs. The concentration of the drug released from any ASDs did not exceed amorphous solubility in a bulk solution. Powder X-ray diffraction (pXRD) analysis of the postdissolution compact revealed the absence of crystallinity in ASDs. Confocal laser scanning microscopy (CLSM) and polarized light microscopy (PLM)-assisted analysis showed the absence of amorphous-amorphous phase separation (AAPS) at the surface of hydrated ASD. Experiments were conducted to simulate the unstirred water layer (UWL) and to investigate dissolution behavior. The microenvironmental pH of ASD was influenced by drug loading, and this influenced the amorphous solubility of APR. LLPS in an unstirred water layer (UWL) was one of the potential mechanisms behind nanospecies generation. Further, the solution phase behavior below LLPS concentration indicated nanospecies generation through ion-pair formation between oppositely charged APR and Eudragit L100-55 in UWL. This study accentuates the complexity of dissolution mechanism of ionic polymer-based ASD and should contribute to designing ASDs containing ionic polymers.