Date of Award

Spring 2015

Document Type

Thesis

Degree Name

Master of Science in Pharmaceutical Engineering - (M.S.)

Department

Chemical, Biological and Pharmaceutical Engineering

First Advisor

Piero M. Armenante

Second Advisor

Laurent Simon

Third Advisor

Gerard Bredael

Abstract

Dissolution testing is a critical step in quality control of manufactured final products in the pharmaceutical industry. The United State Pharmacopeia (USP) Dissolution Testing Apparatus 2 (paddle) is the most widely used dissolution test devices in the pharmaceutical industry to formulate solid drug dosage forms and to develop quality control specifications for its manufacturing process.

Mini vessels and mini paddle dissolution testing systems are smaller versions of the USP 2 Apparatus. The concept of the mini paddle apparatus is similar to that of the USP 2 setup but it is scaled down about to 1/5 of the volume and 40% with respect to vessel and impeller sizes. Mini vessel systems, requiring a small volume (200 mL) and a mini paddle impeller, are becoming increasing common in the pharmaceutical industry to overcome the limitations associated with the USP 2 dissolution testing method, especially for dissolution testing involving very small tablets. Mini apparatuses can be useful tools in characterizing drug release profiles since smaller sample sizes and smaller volumes of media are needed, thus offering several advantages in terms of substance, analytical, and material cost savings when evaluating release properties of drug candidates.

Despite their increasing importance in dissolution testing, little information is currently available on mini vessels, and especially on the agitation speed needed to prevent “coning” effects. Typically during dissolution testing, a disintegrating tablet becomes rapidly fragmented, and the resulting solid particles may or may not become suspended depending on the agitation speed of the paddle and other geometric and operating parameters. “Coning” (the accumulation of particle fragments from a disintegrating tablet) often appears in dissolution testing but can be eliminated by increasing the agitation speed N. Therefore, it is important to be able to predict the minimum rotation speed at which coning phenomena disappears in a dissolution testing system and especially in mini vessels systems.

The focus of this work was the determination of the minimum agitation speed, Njs, at which the just suspended state by dispersed particles is achieved in a mini paddle system (thus removing “coning” effects). In the past, Njs, has been experimentally obtained in mixing systems by determining the agitation speed at which no particles are visually observed to be at rest on the vessel bottom for more than one to two seconds. Therefore, the first objective of this work was to develop an observer-independent method to measure experimentally Njs. This was achieved by extending to mini vessel a method that was recently developed in our laboratory and that is based on the determination of the fraction of unsuspended solids in the vessel at different agitation speed (Njs-Ds method). The results of this method agree well the visually observable values of Njs(Njs-visual).

Once new method was validated in mini vessels, Njs was experimentally measured using well characterized solid particles under a number of operating conditions, such as liquid level-to-vessel diameter ratio (H/T), particle size (dp), and paddle clearance-to-vessel diameter ratio Cb/T). The results could be interpreted using the Zwietering Equation originally developed for solids suspension in baffled stirred tanks. The Zwietering “S” parameter was obtained for the mini vessel system thus enabling the use of this equation to predict when “coning” effects can be eliminated in mini vessel systems during tablet dissolution testing.

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