Date of Award
1-1-2015
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
Seongbong Jo
Relational Format
dissertation/thesis
Abstract
Pharmaceutical research includes investigation and development of a new drug and determination of the delivery route and delivery system, as well as the technology to create the delivery system. It can also consist of a combination of these steps. Researchers studying potential delivery routes have explored oral, nasal, dermal, transdermal, transmucosal, pulmonary, and injection routes for their ability to deliver large and small drug molecules. This research project focuses on the oral route, which is generally accepted as an effective delivery route for many drug products with a large market share, and studies the use of this route for the delivery of poorly soluble actives. Conventional delivery systems used for oral drug delivery are solid dosage forms including capsules filled with milled material, tablets, and pellets. Current research focusing on actives with low aqueous solubility requires new technology to obtain tailored drug release. This research project studies the use of hot melt extrusion (HME), together with hydrophilic polymers, to improve availability of poorly soluble compounds. In recent years HME has become widely accepted as a viable drug delivery system. HME is useful for several different purposes, including solid-state stability enhancement, taste masking, and solubility enhancement, and can be used in the production of a variety of drug dosage forms. The use of HME for solubility enhancement is the subject of this research. Solubility enhancement can be achieved by using HME to disperse a poorly soluble drug in a polymeric carrier matrix, forming a solid dispersion. This method can be used to form both amorphous and crystalline dispersions, but for solubility enhancement amorphous dispersions are used because of the free energy benefits associated with them. To create an amorphous solid dispersion, a drug polymer is melt-extruded then cooled at a rate that prevents recrystallization or processed at a temperature at which the melted drug is immiscible with the carrier. These processes result in kinetic entrapment of the compound in its amorphous state, produce the highest level of specific surface area, and increase saturation solubility, all of which work to improve drug solubility. These processes provide the benefit of increased dissolution rate because of higher thermodynamic activity, but the compounds still have the tendency to return to their crystalline forms. In order to realize the full potential of HME processes in improving drug delivery, it is necessary to have a comprehensive understanding of the physicochemical properties of the amorphous solid dispersions and their In vitro behavior. The most important application of HME technology in the pharmaceutical industry is for developing multi-particulate drug delivery systems. These are primarily oral dosage forms which consist of many, tiny, discrete units, each of which shows the desired characteristics. With multi-particulate systems the drug dosage is divided into multiple sub-units consisting of minute spherical particles with a diameter of 0.05-2.00 millimeters, or mini-tablets with diameters from 2.00-5.00 mm. The research project covered by this dissertation focuses on characterizing several hydrophilic polymeric extrudates produced through HME, and highlighting their various pharmaceutical applications. HME, when used together with an effective pelletizer, has been shown to be a practicable method for the development of novel mini-tablet and pellet dosage forms. Research concerning the use of HME for solubility enhancement focuses on producing amorphous solid dispersions using novel hydrophilic polymers and detailed description of the resulting melt-extrudates. It also studies the effects of different formulation variables and process parameters on the compounds produced. These lines of research aid in the development of modulated-drug-release, stable solid oral dosage form. The key objectives of the chapters in the dissertation are: (1) To Introduce Hot Melt Extrusion as prominent technique in pharmaceutical industry; (2) To prepare novel taste-masked mini-tablets of ketoprofen (KPR) with the taste-masking carrier Eudragit® E PO by HME and to evaluate the effectiveness of the taste masking with multiple in vitro methods. In addition, FTIR imaging was utilized to visually approximate drug homogeneity; (3) To formulate face-cut, melt extruded pellets and to optimize hot melt process parameters on pellets to obtain maximized sphericity and hardness utilizing Soluplus® as a polymeric carrier and carbamazepine (CBZ) as a model drug; (4) To assess the potential of Lutrol® F grades as polymeric surfactants for solubility enhancement of Kollidon®VA64 drug matrices produced by Hot Melt Extrusion.
Recommended Citation
Alshetaili, Abdullah Saud, "Solubility enhancement, mechanical properties and taste masking of poorly water soluble compounds by optimizing hot melt extrusion processing" (2015). Electronic Theses and Dissertations. 1491.
https://egrove.olemiss.edu/etd/1491