Date of Award
1-1-2023
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
First Advisor
Michael A. Repka
Second Advisor
Majumdar Soumyajit
Third Advisor
Ashour Eman
Relational Format
dissertation/thesis
Abstract
Most current active pharmaceutical ingredients (APIs) exhibit poor water solubility, necessitating higher doses or repeated administration. Numerous methods were explored to augment solubility, including but not limited to amorphous solid dispersions, cocrystals, salts, and nanoformulations. The hot-melt extrusion (HME) technique has gained immense popularity due to its solvent-free and continuous manufacturing capabilities, contributing to its increasing use to enhance solubility and bioavailability. In the first chapter, hydrochlorothiazide (BCS-IV class) cocrystals were produced using coformers such as nicotinamide (NIC), resorcinol (RSL), and catechol (CAT) through HME technology. The cocrystals were compared against liquid-assisted grinding (LAG) cocrystals and then analyzed by DSC, FTIR, PXRD, and SEM. The processing temperature was critical for producing high-quality cocrystals in HME. Cocrystals had better solubility than the native drug, with HCT-NIC showing a two-fold increase. HCT-RSL and HCTCAT also had improved solubility and diffusion due to drug-coformer interactions. Coformer solubility was the critical factor in enhancing cocrystal performance. The second chapter focused on continuous pellet manufacturing for colon targeting using a combination of HME and a die-surface cutting pelletizer. Ketoprofen (KTP) was selected as the model drug due to its thermal stability and upper gastrointestinal toxicity. To achieve enzyme-triggered release, different grades of pectin were utilized as a release matrix, while hydroxypropyl methylcellulose was used to retard premature release. The optimized formulation achieved a low premature drug release (~13%) and extended-release profile of KTP for over 24 hours. Developed formulations followed non-Fickian drug release controlled by erosion and diffusion mechanisms, making the HME and palletization process a promising approach for colon-targeted drug delivery. Finally, the third chapter explored a new application of hot-melt extrusion to develop a thermodynamically stable solid crystal suspension (SCS) of carbamazepine to enhance the drug solubility and dissolution rate. The drug is homogenously distributed in the molten sugar alcohol (mannitol/xylitol) when passed through the hot melt extrusion. The molten material immediately solidifies due to the polyol’s rapid recrystallization property. The SCS formulation demonstrated significant improvement in the carbamazepine dissolution rate. The API was present in a thermodynamically stable crystalline form in this system, which is a significant advantage.
Recommended Citation
Narala, Sagar, "Novel Formulation Strategies with Hot-Melt Extrusion Technology to Address Physicochemical and Physiological Constraints for Improved Oral Drug Delivery" (2023). Electronic Theses and Dissertations. 2763.
https://egrove.olemiss.edu/etd/2763