Date of Award

Summer 2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemical Engineering - (Ph.D.)

Department

Chemical, Biological and Pharmaceutical Engineering

First Advisor

Norman W. Loney

Second Advisor

Boris Khusid

Third Advisor

R. P. T. Tomkins.

Fourth Advisor

Laurent Simon

Fifth Advisor

Lisa Axe

Abstract

The significance of controlled release drug delivery systems (CRDDS) lies in their ability to deliver the drug at a steady rate thus reducing the dosage interval and providing a prolonged pharmacodynamic effect. But despite the steadily increasing practical importance of these devices, little is known regarding their underlying drug release mechanisms. Mathematical modeling of these drug delivery systems could help us understand the underlying mass transport mechanisms involved in the control of drug release. Mathematical modeling also plays an important role in providing us with valuable information such as the amount of drug released during a certain period of time and when the next dosage needs to be administered. Thus, potentially reducing the number of in-vitro and in-vivo experiments which in some cases are infeasible. There is a large spectrum of published mathematical models for predicting drug release from CRDDS in vitro following conventional approaches. These models describe drug release from various types of controlled delivery devices for perfect sink conditions. However in a real system (human body) a sink condition may not be applicable. For a CRDDS along with the physiochemical properties (solubility, diffusion, particle size, crystal form etc.) the physiological factors such as gastrointestinal tract (GI) pH, stomach emptying, (GI) motility, presence of food, elimination kinetics etc., also affect the rate of drug release. As the drug delivery system is expected to stay in the human body for a longer period of time when compared to a immediate release dosage form the process of drug release occurs in conjunction with the absorption (for oral delivery systems) and elimination kinetics. Earlier work by Ouruemchi et.al.[71] include prediction of the plasma drug concentration for an oral diffusion controlled drug delivery system. Amidon et.al.[68] developed several models for predicting the amount of drug absorbed within through the intestine walls for immediate release dosage forms. However none of these models study the effect of absorption rate on the rate of drug release for an oral controlled drug delivery system.

In this work mathematical models are developed for prediction of drug release from both diffusion controlled and dissolution controlled drug delivery systems taking into account the affect of absorption rate. Spherical geometry of the particles is considered. The model is developed by assuming that the drug is release into a finite volume and is thereby absorbed through the intestine wall following first order kinetics. A closed form solution is obtained for the prediction of fraction of drug released for a diffusion controlled drug delivery system. The results are compared with both experimental data (taken from literature) as well as existing models in the literature. Whereas for a dissolution-diffusion controlled drug delivery system non linear dissolution kinetics are taken into consideration and the problem is solved by both numerical and analytical techniques. In addition two simple models are also presented for dissolution controlled drug delivery devices.

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