Electronic Theses and Dissertations

Date of Award

1-1-2012

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

Department

Biomolecular Sciences

First Advisor

Michael A Repka

Second Advisor

John S. Williamson

Third Advisor

Seongbong Jo

Relational Format

dissertation/thesis

Abstract

Hot melt extrusion (HME) was evaluated as a processing technology for the manufacture of immediate as well as controlled release formulations for oral delivery of two model compounds. For immediate release applications lower molecular weight grades of Hydroxypropyl cellulose polymers, EF and ELF, were utilized as carrier matrices to form solid solutions of a poorly soluble compound, Ketoprofen (KPR). Thermal characterization techniques were used to confirm thermal stability, miscibility and setting up processing conditions for extrusion. Extruded matrices were pelletized to be filled into pellets or further milled and compressed into tablets. Pellets exhibited a carrier dependent release with ELF matrices releasing the drug at a faster rate than EF. Addition of Mannitol further enhanced the release with H4 formulation constituting KPR:MNT:ELF in a 1:1:1, releasing 88.5±1.5% drug in 1hr. Milled H4 matrices compressed into tablets exhibited rapid release with 90% drug release occurring in 15 min, similar to a marketed capsule formulation of the same dose. Stability studies performed utilizing mDSC, XRD and SEM studies confirmed the physical stability of the drug, post storage at 25°C/60%RH and 40°C/75%RH.

Extrusion process also imparts significant physical transformations to the component systems which find utility in tabletting applications. Extruded matrices were compressed into tablets and tabletability profiles generated. Simultaneously tablet hardness evaluation was performed using conventional characterization techniques as well as using a texture analyzer. HME tablets were more compressible and plastic nature in comparison to un-extruded tablets. ELF polymers exhibited better tabletting properties than EF.

The ability of HME to homogenously mix polymers and drug was utilized to manufacture custom controlled release film formulations of a water soluble model drug. Polymer blends comprising Klucel™ EF (HPC), Eudragit ® RSPO and POLYOX® N10 (PEO) were evaluated. Effect of polymer particle size on release was evaluated using in vitro release testing and Near Infrared chemical imaging techniques. Manufactured films exhibited controlled release for ∼24 hrs with HPC exhibiting a more pronounced effect than RSPO. A correlation of 90% was obtained between polymer concentration on fifty percent and eighty percent drug release, T 50% and T80%, respectively, suggesting its applicability to bring about tailored release profiles. Extruded films remained physically and chemically stable for a period of three months at 40°C/75%RH storage conditions.

The ability of Cyclodextrin derivatives to enhance solubility of a poorly soluble drug, Clotrimazole was evaluated. Phase solubility studies were performed to assess the type of association between CT and 2-hydroxypropyl β Cyclodextrin. An AL type curve was obtained suggesting a 1:1 association, which was further confirmed utilizing DSC, FTIR, XRD, NMR and SEM analysis. Gels formulated from complex exhibited a complete release in 92 hrs whereas pure CT gels exhibited only 60% release in the same amount of time. Similar results were obtained with antifungal testing, with complexed gels having a more pronounced fungistatic action.

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.