Electronic Theses and Dissertations

Date of Award

1-1-2013

Document Type

Dissertation

Degree Name

Ph.D. in Pharmaceutical Sciences

Department

Biomolecular Sciences

First Advisor

Michael A Repka

Second Advisor

Samir A. Ross

Third Advisor

S. Narasimha Murthy

Relational Format

dissertation/thesis

Abstract

Research in the pharmaceutical field involves investigation of a new drug, delivery route, a delivery system, a technology to design the delivery system, or a combination thereof. Scientists have explored several delivery routes such as oral, pulmonary, nasal, injection/implant, transdermal/dermal, transmucosal etc. for their potential to transport a variety of small and large drug molecules. In the present research work, oral route, a widely accepted route of administration, for the delivery of products with a major market share, has been considered for the delivery of poorly soluble actives. The use of appropriate carrier matrices (polymers) and excipients help in incorporating these drugs and developing a dosage form/drug delivery system with desired properties. The oral delivery systems are most popular, convenient for administration, and mainly include conventional solid dosage forms such as pellets, tablets, and/ or milled material filled in capsules. Since most of the actives studied under current research have low aqueous solubility, it was necessary to utilize a novel technology such as hot melt extrusion (HME) in combination with hydrophilic polymers to obtain tailored drug release. Over recent years HME technology has found widespread application as a viable drug delivery option in the drug development process. Some of the HME applications include taste masking, solid-state stability enhancement, solubility enhancement etc. Solubility enhancement in the HME process occurs through the dispersion of a poorly soluble drug in a polymeric carrier matrix essentially forming a solid dispersion. While this technology can help in producing amorphous or crystalline solid dispersions depending upon several factors, solubility enhancement applications are centered on generating amorphous dispersions, primarily because of the free energy benefits they offer. Amorphous solid dispersions result when melt extruded drug-polymer is cooled at a rate that does not allow the drug to recrystallize, or processed at temperatures where drug melts but remains immiscible with the carrier. Such processing results in kinetic entrapment of the drug in its amorphous state. These dispersions also provide maximum specific surface area and higher saturation solubility, which ultimately increase drug solubility. Although these types of systems exhibit increased rate of dissolution due to high thermodynamic activity, they have a potential to revert to the more stable crystalline form. Thorough understanding of the physicochemical properties of amorphous solid dispersions and their corresponding in vivo behavior is required for the realization of their true potential in the pharmaceutical industry. In the research projects outlined in this dissertation, the focus has been to characterize the different hydrophilic polymeric extrudates produced utilizing HME technology, and emphasize their pharmaceutical applications. HME, in conjunction with suitable polymers, has been demonstrated as a viable approach to develop a novel pellet dosage form with potential abuse deterrent properties. In addition, its application for solubility enhancement aims at generating amorphous solid dispersions utilizing novel hydrophilic polymers, followed by the in-depth characterization of the produced melt extrudates. Moreover, the effect of various formulation variables and process parameters has also been investigated. This underlying research also facilitates the development of a wide-ranging stable solid oral dosage forms with modulated drug release. The key objectives of the chapters in the dissertation are: (1) To develop an abuse-deterrent (AD) platform technology in the formulation development utilizing HME technique; (2) To investigate the effect of process variables and formulation factors on characteristics of hot melt extrudates containing hydrophilic vinylpyrrolidone/vinyl acetate copolymer (Kollidon® VA 64); (3) To investigate the feasibility of producing stable drug-loaded Soluplus® extrudates utilizing HME technology, and to study the influence of formulation and processing parameters such as drug-load and heating duration, respectively, on the drug-polymer miscibility as well as the release from melt extrudates; (4) To explore the feasibility of producing soluble Soluplus®-Curcumin extrudates utilizing HME technology, including the drug-polymer miscibility studies, and the influence of surfactants on dissolution rate of this poorly water-soluble model drug.

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