Purdue University Graduate School
2023.6.16 Alex Deac_Good version_Final 5.pdf (10.61 MB)

Dissolution Mechanisms of Amorphous Solid Dispersions

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posted on 2023-06-16, 13:28 authored by Alexandru DeacAlexandru Deac

The dissolved concentration of an active pharmaceutical ingredient in biological fluids is of significant importance for establishing a therapeutic effect in patients. However, the current pharmaceutical landscape is abundant in poorly soluble drugs that require solubility enhancing techniques to enable their administration. A promising technique, with increasing commercial success, is to molecularly mix drug and polymer to create an amorphous solid dispersion (ASD). While these mixtures provide enhanced drug solubility and dissolution in aqueous solutions, the mechanistic processes by which they release drug into solution are not well understood. Some unexplained behaviors include rapid drug release even at the maximum supersaturated concentration and spontaneous formation of drug-rich nanoparticles. These are beneficial for rapidly achieving and maintaining a highly supersaturated drug concentration during absorption, if crystallization is inhibited. However, the phenomena occur at typically low drug loading and are abruptly lost above a certain threshold termed the ‘limit of congruency’ (LoC), which has been reported to vary based on the drug-polymer system. In this research, the mechanisms underpinning ASD release at low and high drug loading were studied, and the factors affecting LoC were mechanistically explored by performing dissolution experiments and utilizing imaging, separation, thermal analysis, and spectroscopy methods to characterize the materials in the presence and absence of water. The results show that ASDs developed a gel layer on the surface when exposed to aqueous solution. This water-rich environment was thermodynamically unstable and phase separated into hydrophilic and hydrophobic phases. The morphology of the hydrophobic phase was directly related to the ASD release behavior, where ASDs below the LoC exhibited a dispersed and stable hydrophobic phase morphology, and ASDs above the LoC displayed a continuous or aggregated morphology. In cases where thermodynamic factors were rate limiting, LoC was inferred from features on the ternary phase diagram. Moreover, drug-polymer interactions and polymer molecular weight were demonstrated to affect the morphology of the hydrophobic phase and ultimately the LoC. The conclusions from this work provide the basis of a theoretical framework for rationally designing ASDs and optimizing their release. 


Degree Type

  • Doctor of Philosophy


  • Industrial and Physical Pharmacy

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Lynne S. Taylor

Additional Committee Member 2

Qi Zhou

Additional Committee Member 3

Geoff G.Z. Zhang

Additional Committee Member 4

Ganesan Narsimhan

Additional Committee Member 5

Bryan W. Boudouris

Additional Committee Member 6

Eric J. Munson