Date of Award

1998

Degree Type

Thesis

Degree Name

Master of Science in Applied Pharmaceutical Sciences

Department

Applied Pharmaceutical Sciences

First Advisor

Serpil Kislalioglu

Abstract

In this study, gelling which occurred during the processing of a peptide drug formulation was investigated. The formulation was prepared by dissolving the drug in a lipid vehicle, composed of mono-, di- and triglycerides of Caprylic (C8) and Capric (C10) Acids (MCM). Gelling was observed during high shear mixing of the formulation. Therefore, to evaluate the gelled material, a solution of the drug in MCM was sheared at 3000 rpm until it turned into an opaque gel. The rheology, thermodynamic properties, chemical structure, polymorphism, particle size, moisture content and stability of the vehicle and pre- and post-sheared formulation were evaluated. The factors such as shear rate, temperature, time, humidity and solution concentration that may affect the development of a gel structure were investigated.

While rheograms of the vehicle and the drug solution showed Newtonian behavior, oscillatory measurements showed that there is a structure build up in the system. This interaction of the drug and the vehicle was postulated to occur via hydrogen bonds, and was shown by a Differential Scanning Calorimeter (DSC) and Fourier Transform Infrared (FT-IR).

It was determined that prolonged shearing changed the rheological behavior of the system from Newtonian to pseudoplastic. Shearing also caused physical modification of the system which was verified with FT-IR studies and X-Ray diffraction. Gelling was found to be a physical phenomenon and was shown to be reversible by heating. Shear rate, shearing time, temperature and humidity were found to be the critical parameters that affect the gelation of the system. Gelling also was found to be highly concentration dependent. As the concentration increases, zero shear viscosity of the solution increases. The slope of the curve of zero shear viscosity vs. concentration changes sharply at a concentration above 17% (w/v) at which gelling starts. At a concentration of 15% (w/v) and below, a gel structure did not form. In addition, appearance of particles above l nm starts at 10% (w/v) concentration and the particle size increases as the concentration increases. DSC studies of the different solution concentrations suggest that the drug at increased concentrations interacts with a vehicle component. The solution reaches saturation at a concentration of 17% (w/v), and addition of the drug beyond this level may increase particle formation which acts as gel nuclei by interaction of the drug with vehicle components. Particle size increases at 40°C and disappears at 80°C. These temperature sensitive particles may cause phase transition upon shearing.

In order to avoid this gelling phenomenon during processing of the formulation of the drug, the vehicle components should be thoroughly characterized. The use of high shear should be avoided. If possible, all processing should be conducted at or above 60°C at low humidity levels.

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