Document Type


Date of Award

Fall 1-31-2013

Degree Name

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


Chemical, Biological and Pharmaceutical Engineering

First Advisor

Rajesh N. Dave

Second Advisor

Ecevit Atalay Bilgili

Third Advisor

Norman W. Loney

Fourth Advisor

Edward L. Dreyzin

Fifth Advisor

Zafar Iqbal


Improving the dissolution rate of Biopharmaceutics Classification System (BCS) class II drugs is an important research area. Micronization which can increase the specific surface area is a promising method to improve the dissolution rate. Micronization alone, however, can lead to downstream processing problems related to poor flow and dispersion properties. The importance of the flowability of pharmaceutical powders is well-documented in the literature. It is, therefore, important to develop a method that can simultaneously overcome these processing issues and allow for micronizing the API. In this work, dry particle coating technique is investigated in the context of micronizing API powders and overcoming problems associated with the micronized fine powders due to their strong cohesive forces. Consequently, the main objective of this dissertation is to investigate if simultaneous micronization and dry coating process (SM-DC) is beneficial for pharmaceutical applications. The work addresses and answers several important issues as discussed next.

First, using ibuprofen as a test-case, it is shown that flow properties and dissolution rate were significantly improved when micronization was performed along with dry coating (SM-DC process). Additionally, co-grinding with water-soluble polymer during micronization was considered and led to further dissolution rate improvement and increased bulk density. The surface modified, micronized powders also showed improved dispersion, significantly higher bulk densities, reduced electrostatic charging, and higher flowability compared to the pure micronized sample. Next, these dry coated fine API powders were formulated into blends with different API loadings. The results showed that the blends containing dry coated API powders had excellent flowability and high bulk density. In contrast, blends containing uncoated APIs had poor flow and lower bulk densities. As the API loading increased, the difference between dry coated and uncoated blends was more pronounced. Tablets prepared from dry coated API blends exhibited superior compactibility and dissolution profiles, particularly for higher drug loadings. This illustrated the advantages of the dry coating during API micronization, without any adverse impact on tabletting operations and tablet properties. Next, an in-depth understanding of the effect of milling and dry coating on the surface properties of milled ibuprofen powders was investigated. Inverse Gas Chromatography technique was used and the dispersive surface energy of pure milled powders was heterogeneous in nature. In contrast, dry coating with nano-particles was found to quench the high energy sites and make the surface energy of the powders comparatively uniform and the average values similar to that of the nano-particle used for the dry coating. Last, a simple shear test based method was developed to estimate the granular Bond number to evaluate the performance of dry coating. This technique eliminates the usual need of detailed, time consuming particle scale characterization via atomic force microscopy. Estimated Bond numbers were compared and verified with those calculated from IGC method. Further, estimated Bond number was correlated with the bulk flow properties. The overall effect of dry coating (changing both the surface energy and nano-scale asperities) can be well demonstrated using the estimated Bond numbers. By addressing these four issues, the main hypothesis of the thesis, dry coating applied to the micronization process is beneficial to the pharmaceutical application, is proven.



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