Date of Award

8-2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Research Advisor

James R. Johnson, Ph.D.

Committee

Hassan Almoazen, Ph.D. Gerald M. Rajan, Ph.D. George C. Wood, Ph.D. Arthur D. Straughn, Ph.D

Keywords

Hassan Almoazen, Ph.D. Gerald M. Rajan, Ph.D. George C. Wood, Ph.D. Arthur D. Straughn, Ph.D

Abstract

Solubility behavior is one of the most challenging aspects for drug commercialization and often the main reason of drug that do not reach to its full potential. Now nearly 60% new chemical entities possess solubility problems, whereas practically no drug products with less than 10 µg/ml solubility in 70’s or 80’s. There is an ever increasing need to develop new formulation techniques and exicipients with novel mechanisms of action. Various techniques have been applied to enhance the drug solubility such as co-solvents, particle size reduction, lipid based drug delivery systems, nanosuspension, use of surfactants, salt formation, cyclodextrin complexes and solid dispersion etc.

Chapter 1 is an introduction into biopharmaceutics classification system (BCS) and novel drug solubilization techniques. It provides a brief history of the BCS and its application in drug development. It also looks into the recent poorly water soluble drugs approved by the Food and Drug Administration and the formulation techniques that these drugs used.

Chapter 2 is a brief history of solid dispersion, including its theoretical basis, preparation methods, and characterization and quality control tools. Several drug products using solid dispersion technique are also reviewed. This chapter is intended to combine recent literature on solid dispersion technology for solubility enhancement with various preparation methods, evaluation parameters and commonly used polymer carriers.

Chapter 3 explores the applicabability of a cold water soluble modified starch, octenyl succinic anhydrate starch (OSA starch) as solid dispersion carrier to increase the aqueous solubility and dissolution rate of poorly water soluble drugs. When using OSA starch in solid dispersions via spray drying techniques, the hypothesis is that drug is dissolved in the starch solution, when water evaporate via spray drying, drug will be solidified together with starch and mostly the drug is in amorphous form because the rapid spray drying process (seconds) prevents drug crystallization. In this system, the starch is homogenously distributed in the matrix and thus prevents drug crystalline growth as a characteristic of the polymer. When drug is dispersed in starch solution, the starch will encapsulate drug particles to complete the microencapsulation process and micro-scale drug particles will be retained in the starch matrix. These properties will be helpful in enhancing drug solubility and dissolution rate.

Chapter 4 explores a solid dispersion of furosemide and sulfobutylether-β-cyclodextrin which was another derivative excipient of starch. Solid dispersion preparation method and mechanism are also discussed. The work serves as a positive control for OSA starch solid dispersion. Comparison and contrasting the two solid dispersions assist in the interpretation of OSA starch solid dispersions.

DOI

10.21007/etd.cghs.2012.0385

Comments

Two year embargo expired August 2014

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