Purdue University Graduate School
Dissertation_v4_2021-02-08_Formatted.pdf (4.34 MB)

Solid State Crystallization of Amorphous Pharmaceuticals in an Aqueous Environment: Factors Impacting Crystallization and the Role of Additives

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posted on 2021-02-09, 01:36 authored by Andrew S ParkerAndrew S Parker
Amorphous materials play an important role in pharmaceutical formulations due to their ability to generate supersaturation above the crystalline solubility, which is particularly advantageous for improving the bioavailability of poorly soluble drugs. Unfortunately, the high free energy of the amorphous state also means it has a propensity to crystallize, jeopardizing formulation performance. There is considerable interest in understanding the mechanisms of crystallization as well as means of mitigating this undesired phase transformation. Formulation additives such as polymers and surfactants are commonly used as stabilizers, though the ability to inhibit crystallization is specific to the drug and additive pair and the actual mechanisms of inhibition are not fully understood.

This dissertation outlines a project to study one particular trajectory of amorphous pharmaceutical formulations and the influence of additives on the fate of drug molecules. During dosing, it is possible for a sufficiently high supersaturation to occur such that the miscibility limit between water and drug is achieved and the supersaturated solution undergoes a liquid-liquid phase separation event. Liquid-liquid phase separation results in colloidal drug particles which are not intimately mixed with stabilizers and are prone to undergo solid-state crystallization. Thus, it is the intent of this project to study the solid-state phase transformation of amorphous drug surfaces exposed to aqueous media, as well as the impact of dissolved additives on surface evolution.

Experimental crystallization investigations employing the imaging techniques of atomic force microscopy and scanning electron microscopy paired with complementary lattice Monte Carlo models reveal the non-classic nucleation and growth mechanisms driving glass-to-crystal phase transformations. Evidence is also found of the previously uninvestigated role of the amorphous surface energy on the morphology of evolving surface crystals. Additive inhibitory effects are demonstrated to occur through competitive adsorption onto high surface energy sites, reducing surface mobility and blocking lattice integration, while crystallization promotion effects occur by additives partitioning at the drug-water interface and creating a more hydrophobic solution region which enhances molecular mobility. Finally, fundamental transport studies are described for quantitative determination of surface transport properties as well the regulatory effects of additives on surface transport.


Degree Type

  • Doctor of Philosophy


  • Chemical Engineering

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Stephen P. Beaudoin

Advisor/Supervisor/Committee co-chair

Lynne S. Taylor

Additional Committee Member 2

Zoltan K. Nagy

Additional Committee Member 3

Brett M. Savoie