Date of Completion


Embargo Period



Amorphous, Crystal, Solubility Enhancement Ratio, Crystallization Kinetics, Desupersaturation Kinetics, pH, Structurally Related Compounds, Impurity

Major Advisor

Dr. Robin H. Bogner

Associate Advisor

Dr. Xiuling Lu

Associate Advisor

Dr. Sheri Shamblin

Field of Study

Pharmaceutical Science


Doctor of Philosophy

Open Access

Open Access


Supersaturating drug delivery systems, especially amorphous formulations, are used to achieve higher oral bioavailability for poorly soluble drugs. However, amorphous formulations, being thermodynamically unstable, recrystallizes upon contact with water, making experimental measurement of amorphous solubility enhancement challenging. In this work, factors affecting the re-crystallization of poorly soluble drugs and amorphous solubility enhancement were studied.

The various approaches in the literature employed in the calculation of amorphous solubility enhancement ratio (Rs) were compared and moreover, the nuances associated with the estimation of Rs, were also explored. Based on the sensitivity and error analysis on the calculated value of Rs, it was shown that maximum variance in the calculated value of Rs, is due to the uncertainty in the measurement of the heat of fusion. Moreover, it was also shown that the variation between the estimates of Rs as estimated by various equations were within the error estimate of the calculated value. Furthermore, additional methods for the calculation of free energy difference between amorphous and crystalline forms for special molecules undergoing additional phase transitions (other than glass transition and melting) were developed, employing itraconazole as a model drug.

The desupersaturation kinetics of a weakly acidic system, indomethacin, was investigated as a function of pH. The desupersaturation kinetics of indomethacin decreased with an increase in pH. Two previously unexplored mechanisms limiting crystallization were explored to explain the effect of solution pH on desupersaturation kinetics. Reactive diffusion (resulting in a higher surface pH as compared to bulk pH) and inhibition of crystallization by structurally similar ionized indomethacin at higher pH are explored in detail. Experimental and mathematical modeling support the mechanism of ionized indomethacin as a crystallization inhibitor.

The effect of structurally related compounds and impurities as a factor influencing the crystallization kinetics of pharmaceuticals was investigated. The two structurally related compounds for indomethacin cis-sulindac and trans-sulindac investigated here, acted as crystallization inhibitors, while the impurity of indomethacin, indomethacin related compound-A, was not a crystallization inhibitor of indomethacin. The difference in the effectiveness of the compounds investigated in indomethacin growth inhibition led to a basis for providing a mechanistic understanding of the inhibition.

Prediction of Supersaturation from Amorphous Drugs and Mechanisms of Crystallization Inhibition from Supersaturated Solutions

May 12th, 2019

Arushi Manchanda, B.Pharm., University of Delhi

M.Pharm, University of Delhi

PhD., University of Connecticut

Directed by: Professor Robin H. Bogner

Available for download on Tuesday, October 31, 2023